Genetics Board Stat Pearls Flashcards

Question

Crouzon Syndrome

Answer 1

Crouzon syndrome is inherited in an autosomal dominant pattern and is caused by a mutation in the fibroblast growth factor receptor (FGFR)-2 and -3 on chromosome 10. Triad of skull deformities, facial anomalies, and proptosis. Crouzon syndrome is a fairly rare entity and is estimated to occur in 1 in 60,000 newborns; however, it is the second most common craniosynostosis syndrome behind only the more recently described Muenke syndrome.

Answer 2

“Rugger Jersey spine” Due to failure of osteoclasts Anemia due to bone marrow sclerosis AD- less severe/asymptomatic until pathologic fracture occurs AR- severe, multiple pathologic fractures, earlier onset

Answer 3

About two-thirds of patients with aniridia follow an autosomal dominant pattern. For de novo variant: Sporadic cases account for one-third of patients. A rare autosomal recessive variant (Gillespie syndrome) is associated with aniridia, cerebellar ataxia, and intellectual disability. The implicated gene abnormality is 11p13. Sporadic aniridia may be associated with WAGR syndrome (Wilm tumor, aniridia, genitourinary anomalies, and mental retardation). In sporadic congenital aniridia, the Wilm tumor must be ruled out by ultrasonography of the abdomen.

Answer 4

“Heart hand” examination reveals the presence of hand and upper limb abnormalities (triphalangeal thumb and radial dysplasia). An echocardiogram, if done, would confirm the presence of atrial secundum typical of the syndrome. Holt-Oram syndrome is an autosomal dominant disorder with complete penetrance. The underlying defect is found in the long arm of chromosome 12 (12q2), which contains the genes TBX5 and TBX3. Mutation of these genes gives an embryologic prevalence for ASD, VSD, and left-sided malformation. Radial aplasia can also be seen in syndromes like Fanconi anemia, thrombocytopenia absent radius (TAR) syndrome, and VACTERL. Fanconi anemia and TAR syndrome show autosomal recessive inheritance. VACTERL has a sporadic inheritance.

Answer 5

Progressive cerebellar ataxia, oculomotor apraxia, oculocutaneous telangiectasia, etc. Degeneration of purkinje and granular cells in the cerebellum 25-30% develop neoplasia, most commonly leukemia and lymphoma early in life Later in life - breast, ovarian, melanoma, gastric, liver tumors. Associated with severe radio sensitivity so avoiding XR and gamma rays. UV is ok.

Answer 6

LPL deficiency is the commonest cause of familial chylomicronemia in children. It is an autosomal recessive disorder and due to homozygous or compound heterozygous mutations of LPL. It can result in severe chylomicronemia which increases the risk for pancreatitis. It invariably presents in infancy or childhood.

Answer 7

Children with Cornelia de Lange syndrome often develop intrauterine growth restriction, resulting in low birth weight (less than 2.2 kg). Children that are small for gestational age will have prolonged difficulty gaining weight. Gastrointestinal problems are a key manifestation of patients with Cornelia de Lange syndrome. Gastrointestinal problems may include poor appetite, feeding problems, gastrointestinal reflux disease (GERD), vomiting, diarrhea, and constipation. Special diets that incorporate supplemental formulas can provide the nutrition necessary to overcome feeding and weight gain issues

Answer 8

Striatum atrophy (caudate and putamen) Jerking movements, irritability, and dementia

Answer 9

PTH resistance is a common feature of pseudohypoparathyroidism and acrodysostosis with hormonal resistance (acrodysostosis type 1). Acrodysostosis type 1 occurs due to an inactivating mutation in PRKR1A. Hypocalcemia, hyperphosphatemia, and elevated PTH suggest PTH resistance. PTH resistance should be suspected even when serum calcium is normal. If evidence of PTH resistance is present, evaluation for other hormonal resistance (serum thyroid-stimulating hormone and serum-free thyroxine) should be conducted. Hormonal resistance is not a feature of acrodysostosis type 2 (PDE4D mutation).

Answer 10

Decarboxylation of branched-chain alpha-keto acids Maple syrup urine disease occurs due to a pathogenic defect in any subunit of the branched-chain ketoacid dehydrogenase enzyme complex. Other diagnostic tests include a dinitrophenylhydrazine (DNPH) test. DNPH test can be used as a screening modality in newborns greater than 48-72 hours of age. DNPH reagent and urine are mixed in equal volumes. The mixed sample is observed for 10 minutes for precipitation and color change. Clear urine with no precipitate indicates a score of zero. Whereas, a yellow-white precipitate with opaque urine indicates a score of 4. In our patient, a positive test result is noted. Branched-chain amino acid transaminase converts leucine, isoleucine, and valine into their respective alpha-ketoacids. Branched-chain ketoacid dehydrogenase (BCKAD) is the second enzyme in the pathway of branched-chain amino acid metabolism. It is responsible for the oxidative decarboxylation of their respective alpha-ketoacids. A defect in BCKAD can result in elevations of alpha-ketoacids, which are responsible for the clinicopathological manifestations of maple syrup urine disease. There are five subtypes of MSUD. These include the classic, intermediate, intermittent, thiamine responsive, and E3 deficient subtypes. They are clinically distinguished based on their clinical presentation, age of onset, and residual BCKAD enzyme activity. The mainstay of treatment is a dietary restriction of branched-chain amino acids and regular monitoring of blood chemistry.

Answer 11

Lynch syndrome is associated with an increased risk of upper tract urothelial cancer. They tend to have a higher involvement of the ureters, are more likely to be found in females, and there is a possible predisposition to bilaterality. TCC of the upper tracts can be found in up to 28% of patients with Lynch syndrome. In women, Lynch syndrome is associated with endometrial and ovarian cancers. Any patient, especially a non-smoker who presents with TCC of the upper tracts before age 60, should be suspected of having Lynch syndrome. Diagnosis is established by clinical criteria, tumor tissue testing, and genetic evaluation. Other cancers: colorectal cancer, brain, skin, stomach

Answer 12

Fabry disease is a very rare, x-linked lysosomal storage disorder. There is a deficiency of enzyme alpha-galactosidase, which leads to the accumulation of ceramide in blood vessels, nerves, and the heart. The disorder eventually affects the heart and kidneys. Angiokeratomas are common painless lesions around the umbilicus and lower abdomen. Fatigue and neuropathy are the most common presenting symptoms. Other features of the disorder include the inability to gain weight, vertigo, and tinnitus. Diagnosis is made by chromosomal analysis. Treatment is via enzyme replacement. Expense remains a barrier for most people afflicted with this disorder. Antiplatelet agents are generally used, but sometimes warfarin is needed to prevent strokes.

Answer 13

This patient has likely presented with a vaso-occlusive crisis due to sickle cell disease. In sickle cell disease (SCD), a point mutation causes a single amino acid replacement in beta- chain (substitution of glutamic acid with valine), resulting in the formation of HbS in place of HbA, which causes extravascular and intravascular hemolysis. The type of point mutation in SCD is called a missense mutation in which a single nucleotide substitution results in changed amino acid. In SCD specifically, an A to T mutation (GTG>GAG) at the sixth codon of the beta-globin gene occurs, leading to the production of a defective form of Hb. The defective form of Hb in the presence of low O2, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerized), resulting in anemia due to hemolysis and vaso-occlusive disease. A missense mutation is called conservative if a new amino acid is similar in chemical structure.

Answer 14

Birt-Hogg-Dube syndrome is an autosomal dominant syndrome of fibrofolliculomas, multiple renal tumors, and pulmonary cysts. It is associated with 17p12q11 abnormality involving the folliculin protein. Associated renal tumors are usually chromophobe carcinomas or oncocytomas. Oncocytomas will have an eosinophilic granular cytoplasm on fine-needle aspiration and will show minimal pleomorphism. Patients usually have multiple tumors with a mean of 5.3. If a patient has multiple renal tumors, Birt-Hogg-Dube syndrome should be considered. Tuberous sclerosis is associated with angiolipomas of the kidney. Von Hippel-Lindau disease is associated with renal cell carcinoma. Beckwith-Wiedemann syndrome is associated with somatic overgrowth and frequently has associated renal anomalies including nephromegaly and collecting system abnormalities.

Answer 15

Piezogenic pedal papules are small papular herniations of subcutaneous tissue on the heel that occur only upon standing or with the application of pressure. They do not appear to have a hereditary transmission in most patients. No direct link has been made to a specific connective tissue defect or condition. However, the literature has noted an association in groups of patients with Ehlers–Danlos syndrome and Prader-Willi syndrome presumably due to weakness in collagen, although no specific mechanism has been proven.

Answer 16

In severe forms of monilethrix, other hairy areas such as the eyelashes, the eyebrows, or the secondary sexual hairs may be involved. Perifollicular abnormalities are usually associated with the hair shaft fragility. Most commonly found on the occiput, these perifollicular abnormalities range from perifollicular erythema to large hyperkeratotic follicular papules. Monilethrix may as well be associated with rare ectodermal symptoms such as syndactyly, cataracts, dental abnormalities, and nail abnormalities (koilonychia).

Answer 17

BRAF mutational testing is recommended for high-risk stage III cutaneous melanoma for patients in whom BRAF targeted therapy might be an option for adjuvant treatment. Patients with BRAF mutation can be considered for targeted BRAF inhibitor drugs in the adjuvant setting. BRAF mutations are identified in over half the patients with cutaneous malignant melanoma. Serum LDH levels are indicated in patients with disseminated or metastatic disease.

Answer 18

The features of the patient suggest a diagnosis of pseudoxanthoma elasticum (PXE). Angioid streaks, which are crack-like breaks in the Bruch membrane, are commonly seen in pseudoxanthoma elasticum (PXE). Choroidal neovascularization is an essential complication of angioid streaks, which can cause metamorphopsia. Other ocular features of PXE include peau d'orange appearance of the retina usually at the temporal macula, optic disc drusen, macular pattern dystrophy, and crystalline bodies, some of which may have a tail like a comet.

Answer 19

Familial melanoma is associated with a point mutation in the CDKN2A locus at 9p21. Most melanomas have multiple chromosomal alterations. This feature differentiates melanomas from nevi. A malignant melanoma developing in healthy skin is said to arise de novo without evidence of a precursor lesion.

Answer 20

his patient most likely has seborrheic keratosis. Seborrheic keratosis is a common type of epidermal tumor that is prevalent throughout middle-aged and elderly individuals. Seborrheic keratosis results from benign clonal expansion of epidermal keratinocytes. There is believed to be a genetic component for the development of a high number of seborrheic keratosis lesions. Activating mutations in the tyrosine kinase receptor known as fibroblast growth factor receptor-3 (FGFR3) are common in cases of sporadic seborrheic keratosis and are believed to be what drives the growth of this benign tumor. Under the microscope, seborrheic keratosis typically shows a proliferation of keratinocytes with keratin-filled cysts.

Answer 21

The presence of bilateral iliac horns is pathognomonic for nail-patella syndrome (NPS). Nail changes are the most common clinical manifestation of NPS, which may include absent, hypoplastic, or dystrophic finger and toenails. The classical clinical tetrad of NPS includes elbow deformities, presence of iliac horns, and absent or hypoplastic patellae. Both surgical and non-surgical treatment options exist for patients with NPS and knee symptoms.

Answer 22

Chediak-Higashi syndrome results from a microtubule polymerization defect causing dysfunction of leukocyte lysosomes and impaired immunity. It is characterized by oculocutaneous albinism, easy bruising, abnormal functions of the natural killer cells, and recurrent pyogenic infections and is a result of a mutation in the lysosomal trafficking regulator (LYST) gene. Patients often die before the age of 10 years. The best treatment is allogenic bone marrow transplantation.

Answer 23

Hartnup disease is characterized by a defect in gastrointestinal uptake of neutral amino acids. Neurological complications like seizures, psychosis, and delirium can occur in the patient. The patients can also have skin hyperpigmentation and dryness at the site of eruptive lesions. Short stature and below-average school performance have been reported in patients.

Answer 24

Fuchs endothelial dystrophy (FED) Progressive worsening vision, corneal edema, outpouchings of Descemet membrane in areas of endothelial cell loss, and thickening of Descemet membrane. FED can be caused by a dysfunction of the endothelial pump mechanism. Dysfunction of the endothelial pump impairs corneal deturgescence and causes fluid retention in the cornea. Channelopathies frequently involved, such as those caused by AD mutations in the SLC4A11 gene.

Answer 25

The infant described has tetralogy of Fallot with a right aortic arch as defined by a right innominate artery. The most common genetic syndrome associated with tetralogy of Fallot and a right aortic arch is DiGeorge syndrome. DiGeorge syndrome can be diagnosed the majority of times by FISH for the 22q11 deletion. Noonan syndrome is most commonly associated with supravalvular pulmonic stenosis. Turner syndrome is associated with left-sided lesions (coarctation of the aorta, bicuspid aortic valve). Williams syndrome is associated with supravalvular pulmonary and aortic stenosis.

Answer 26

This patient has a follicular adenoma. Follicular adenomas are one subset of benign neoplasms that can occur in the thyroid gland or ectopic thyroid tissue. They typically present as a solitary thyroid nodule or in association with nodular hyperplasia or thyroiditis. Follicular adenomas exhibit rearrangement of the PAX8-PPAR gamma 1. PAX8 helps follicular cell differentiation by encoding a nuclear protein product necessary for the transcription of thyroid-specific factors. Genetic rearrangement of the PAX8-PPAR gamma 1 gene causes loss of follicular growth inhibition, thus facilitating the development of follicular neoplasms. PAX8-PPAR gamma 1 has a high predictive value for differentiated thyroid cancer.

Answer 27

Cockayne syndrome belongs, like xeroderma pigmentosum and trichothiodystrophy, to the group of diseases that affect DNA repair by nucleotide excision (NER). The most common form of Cockayne syndrome (type I) occurs during the first year of life. Children have very thin skin and sensitive to ultraviolet rays. The slightest exposure causes severe sunburns that can sometimes leave scars or hyperpigmented spots. Dysmorphic features include a long face, a small protruding chin, and big ears. Enopthtalmia is common because of the disappearance of the fat that is normally behind the eyeball. The muscles are often insufficiently tonic (hypotonia), and the reflexes are abnormal. Children with the most common form of Cockayne syndrome (type 1) have very good communication skills for a very long time despite the illness. Their socialization and schooling should be encouraged as much as possible. On the other hand, children with the severe form (type 2) have little possibility of interaction with their surroundings because of the severity of sensory and intellectual impairment. The lives of patients with a lighter form (type 3) are close to normal early on, and children attend formal schooling.

Answer 28

(TTD) is a rare inherited, genetic disease characterized a broad spectrum of abnormalities. Patients with different manifestations are linked together by the common feature of short, dry, brittle, sulfur-deficient hair which has a characteristic tiger tail pattern under polarizing microscopy. Typically, patients are born pre-term and with low birth weight. Maternal pregnancy complications are common. Infants may be born with a shiny parchment-like covering on the skin that peels off over several days to weeks (collodion membrane). Through childhood they may have developmental delay or intellectual disability, short stature with poor weight gain, dry, scaly skin (ichthyosis), eye abnormalities (the most common being congenital cataracts), recurrent infections and bone abnormalities. Nearly half (42%) of patients with TTD have extreme sensitivity to ultraviolet radiation (UV) and develop blistering burns on minimal exposure to UV.

Answer 29

Alagille syndrome (ALGS) is an autosomal dominant disorder with a wide spectrum of penetrance. Offspring of an individual with the condition have a 50% chance of inheriting a gene mutation, whereas, among those affected with ALGS, 50% to 70% of individuals have a mutation de novo. Variants of JAG 1 Notch ligand (chromosome 20p12.2), which encodes protein ligands for the NOTCH2 receptor (chromosome 1p11-p12) account for 94% to 96% of ALGS cases, while variants in NOTCH2 cause around 1% to 2%. No correlation has been found between a specific mutation and expressed phenotype.

Answer 30

This patient is presenting with delayed puberty, as shown by the lack of development of secondary sexual characteristics, low testicular volume, and low blood levels of GnRH, FSH, LH, and testosterone. Delayed puberty in males is defined by a testicular volume of less than 4 mL by the age of 14 years old. There are many potential causes of delayed puberty in males. Defective migration of GnRH cells during fetal development is a possible cause of delayed puberty and is known as Kallman syndrome. Kallman syndrome is an X-linked form of hypogonadotropic hypogonadism. It is defined by defective migration of GnRH cells and defective formation of the olfactory bulb during fetal development. Patients present with delayed onset of puberty with low levels of GnRH, FSH, LH, and testosterone. These patients will also exhibit anosmia (loss of the ability to smell), due to defective olfactory bulb formation. Anosmia is the primary differentiating sign between Kallman syndrome and other causes of delayed puberty.

Answer 31

The patient has neurofibromatosis type 1, also called von Recklinghausen disease. It is characterized by cafe-au-lait spots, subcutaneous tumors, gliomas, bone cysts, Lisch nodules, macrocephaly, epilepsy, meningiomas, precocious puberty, and pheochromocytomas. It is an autosomal dominant condition caused by a mutation of the NF1 gene. Optic nerve gliomas are the most common brain tumor in NF1 patients. Optic nerve sheath meningioma can be differentiated by MRI demonstrating diffuse, tubular thickening of the optic nerve sheath encasing the optic nerve, producing a characteristic "tram track" sign on the axial section or a "doughnut" sign on the coronal section. Choroidal meningiomas are uncommon in NF-1 patients. Arachnoid hyperplasia is a meningeal response associated with gliomas of the anterior optic pathway when these gliomas invade the leptomeninges. Medulloblastomas are the most common brain tumor in children in general.

Answer 32

The child has nonclassical phenylketonuria (PKU). Classical PKU is due to a defect in phenylalanine hydroxylase, leading to the accumulation of phenylalanine derivatives. In nonclassical PKU, the required cofactor for the phenylalanine hydroxylase reaction, tetrahydrobiopterin, is deficient. Seratonin requires the cofactor tetrahydrobiopterin for the synthesis. Giving 5-hydroxytryptophan bypasses the block in serotonin biosynthesis, and would have to be a supplement for these children. These interfere with amino acid transport into the brain and can lead to cognitive disorders if not treated, usually, by a low-phenylalanine diet. Signs include delayed developmental milestones, microcephaly, hypopigmentation, hyperactivity/behavior problems, seizures, and a musty odor to skin and urine. Phenylketonuria is caused by a deficiency of the enzyme phenylalanine hydroxylase and has an autosomal recessive inheritance. If the heel stick is positive for PKU, further blood and urine samples are obtained to confirm the diagnosis.

Answer 33

Duodenal cancer occurs in 4-12% of FAP patients

Answer 34

Lipomas typically present as soft, solitary, painless, subcutaneous nodules that are mobile and not associated with epidermal change. A characteristic "slippage sign" may be elicited by gently sliding the fingers off the edge of the tumor. They are typically slow-growing and grow to a final stable size of 2 to 3 centimeters. However, they are occasionally greater than 10 centimeters and referred to as "giant lipomas." Lipomas may appear anywhere on the body but tend to favor the fatty areas of the trunk, neck, forearms, and proximal extremities. Multiple lipomas may be the presenting feature of a variety of syndromes. This patient most likely has Gardner syndrome. Gardner syndrome is due to autosomal dominant mutations in the adenomatous polyposis coli (APC) gene. Almost all patients develop adenocarcinomas of the gastrointestinal tract. Cutaneous changes include multiple lipomas or fibromas. Other associated findings include congenital hypertrophy of pigment epithelium of retina, osteomas of the skull, maxilla and mandible, supernumerary teeth, and various malignancies, including papillary thyroid carcinomas, adrenal adenomas, and hepatoblastomas. Gardner syndrome is caused by a mutation in the adenomatous polyposis coli (APC gene), located in chromosome 5q21 (band q21 on chromosome 5). This gene is also mutated in familial adenomatous polyposis (FAP), a more common disease that also predisposes to colon cancer. Bannayan-Riley-Ruvalcaba syndrome (BRRS) is due to PTEN gene mutations and may represent a pediatric form of Cowden syndrome. Clinical findings include multiple lipomas, intestinal hamartomas, genital lentigines, macrocephaly, and mental retardation. The neurofibromas found in neurofibromatosis 2 would not demonstrate the slippage sign seen in lipomas.

Answer 35

D The infant has jaundice due to cholestasis. The physical examination reveals a heart murmur that is consistent with peripheral pulmonic stenosis. This is the most frequent cardiac condition found in patients with Alagille syndrome (ALGS). The finding of a butterfly vertebra on chest x-ray is the third major clinical feature guiding towards the diagnosis of ALGS. Patients with hepatic vein occlusion and congenital cytomegalovirus can present with signs and symptoms of cholestasis; however, associated cardiac conditions or skeletal abnormalities are not commonly seen with this condition. The diagnosis of ALGS can be challenging due to the variability of clinical manifestations ranging from no symptoms to life-threatening, even among individuals from the same family that share the same mutation. Most patients present with jaundice or cardiac-related symptoms. Stenosis and congenital paucity of intrahepatic bile ducts represent the underlying etiology for jaundice in this patient.

Answer 36

Neonatal Bartter syndrome presents as polyhydramnios secondary to intrauterine polyuria leading to preterm delivery. Laboratory findings show hypokalemic, hypochloremic metabolic alkalosis with increased urinary potassium and chloride and increased plasma renin and aldosterone. The blood pressure stays normal. The pathophysiological basis of the disease can be explained by the mutation involving the Na+/K+/Cl cotransporter (NKCC2). This results in salt and water loss resulting in activation of the renin-angiotensin-aldosterone system secondary to volume depletion. Patient with Gitelman syndrome will have low 24-hour urinary calcium levels as opposed to Bartter syndrome.

Answer 37

The patient's hypercalcemia, likely due to elevated parathyroid hormone, and hyperprolactinemia, probably due to prolactinoma, suggest multiple endocrine neoplasia (MEN) Type I. It includes a varying combination of endocrine and non-endocrine tumors. Multiple endocrine neoplasia (MEN) type I syndrome involves a menin gene mutation. The clinical diagnostic criteria for multiple endocrine neoplasia (MEN)1 syndrome include the presence of two endocrine tumors that are parathyroid, pituitary, or gastrointestinal tract tumors. Multiple endocrine neoplasia (MEN) type I gene mutations present with an autosomal dominant inheritance pattern. Treatment is multidimensional and focused on the primary manifestations. Subtotal or total parathyroidectomy is indicated for parathyroid adenoma. Surveillance is needed to monitor progress. Genetic counseling is indicated for patients. Multiple endocrine neoplasia (MEN) type II gene mutations involve the RET gene and are predominantly inherited in an autosomal dominant pattern.

Answer 38

Lissencephaly is a spectrum of severe brain malformations, including agyria (absent gyri), pachygyria (broad gyri), and subcortical band heterotopia. In lissencephaly, literally means smooth brain, the surface of the brain appears smooth. It is caused by a defect in neuronal migration during embryonic development between 12 and 24 weeks of gestation and results in the absence of normal development of brain gyri and sulci. LIS1 is responsible for classic lissencephaly (type 1). Examination of the brain in type I lissencephaly shows a cerebral cortex with four layers instead of six layers in normal patients. A six-layered cortex is associated with DCX gene mutation, compared to lissencephaly caused by LIS1 mutations. Lissencephaly has different levels of severity and symptoms. Symptoms may include seizures, feeding difficulty, muscle spasm, mental retardation, severe psychomotor impairment, failure to thrive, developmental delays, and sometimes hands, fingers, or toes anomalies. However, some children may develop normally with a mild learning disability.

Answer 39

The NCCN guidelines recommend germline testing for all patients with metastatic disease or where there is a father or brother with prostate cancer before age 60, a first degree relative with breast cancer before age 50 and for patients with Ashkenazi Jewish descent. Germline testing is used for treatment optimization but is most helpful in family counseling to modify screeinings for family members who may be at higher risk. Specific germline mutations recommended by the NCCN for prostate cancer include ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, MLH1, MSH2, and MSH6. We also suggest adding the following if possible: EpCAM, HOXB13 (especially in African Americans), FANCA, P53, and NBN

Answer 40

The presence of family history, mucocutaneous pigmentation, and equal or more than two hamartomatous polyps is a classical triad of Peutz–Jeghers syndrome. Colonoscopy can help in the diagnosis of hamartomatous polyps. Peutz-Jeghers syndrome (PJS) can present with mucocutaneous pigmented macules. These flat dark blue to brown lesions are distributed on the lips, perioral areas, buccal mucosa, eyes, nostrils, fingertips, palms, soles, and perianal areas. Patients with PJS are at a greater risk for gastrointestinal intussusception with bowel obstruction due to the development of benign hamartomatous polyps in the GI tract. Hamartomatous polyps in the gastrointestinal tract of patients with PJS may cause intussusception, obstruction, repeated bouts of abdominal pain, bleeding, and rectal prolapse. All individuals who meet more than two out of three diagnostic criteria should be evaluated for the germline mutation in the STK11 gene for confirmatory purposes.

Answer 41

Patients with Klinefelter syndrome are at an increased risk for germ cell tumors and breast cancer. The risk of breast cancer is 20 times that of healthy males. Other cancers also common in Klinefelter include leukemias, lymphomas, and gonadal tumors. Non-cancerous conditions include osteoporosis and deep vein thrombosis. Patients often present with an initial complaint of male infertility.

Answer 42

The patient has bilateral vestibular schwannomas. Bilateral vestibular schwannomas are usually associated with neurofibromatosis type 2. The neurofibromin 2 gene produces merlin (schwannomin), a tumor suppressor. The neurofibromin 2 gene is located on chromosome 22.

Answer 43

Alexander disease is a progressive, lethal leukodystrophy with three forms. They have in common, a defect at chromosome 17q21. Pathology shows aggregated glial fibrillary acidic proteins and small stress proteins in astrocytes. They form intracellular inclusions called Rosenthal fibers. Infants have megalencephaly, seizures, intellectual disability, and premature death. The juvenile and adult forms are characterized by ataxia, bulbar signs, and spasticity.

Answer 44

Congenital myotonic dystrophy (CMD) is an autosomal dominant neuromuscular disorder with multisystem involvement. It is a subtype of myotonic dystrophy type 1. Features include severe hypotonia and generalized muscle weakness; myotonia is classically absent in infancy. CMD is caused by the expansion of trinucleotide (CTG) repeat sequence of the myotonic dystrophy protein kinase (DMPK) gene. The severity of the disease is correlated with allele size (number of repeats). However, mild cases were reported with long expansions. More than 50 full-penetrance alleles are associated with disease manifestations. In CMD, repeats are usually >1000, compared to <37 in normal individuals, and 38-49 in premutation allele patients (asymptomatic). Offspring of premutation patients can inherit longer repeats, increasing the risk of disease and decrease the age of onset in the next generations. This phenomenon is known as anticipation. Contrary to the classic (adult), the maternal transmission is up to ~90% of cases, and only 9-12% are paternal. The mechanism is not yet well understood; however, maternal and intrauterine environment are considered contributing factors.

Answer 45

Androgen insensitivity syndrome (AIS), also known as testicular feminization, is an X-linked recessive condition caused by a mutation in the AR gene. This condition causes failure of masculinization in the external genitalia of male genotypes. Affected persons have normal testes with the average testosterone production and its conversion to dihydrotestosterone (DHT). The testes produce normal amounts of müllerian-inhibiting substance (MIS) or anti-müllerian hormone/factor; affected individuals do not have ovaries, fallopian tubes, a uterus, or a proximal vagina. Overall, female external genitalia with testes and distal vagina; breast development may be present

Answer 46

B If a patient is from Southeastern Iran, factor XIII deficiency must be considered in your differential for patients presenting with coagulopathies due to its unique prevalence in that region. Factor XIII is a key clotting factor in the coagulation cascade known for stabilizing the formation of a blood clot. Common symptoms of factor XIII deficiency include bruising, hematomas, muscle bleeds, and delayed post-surgical bleeds. You must consider this rare factor in your differential among other more common coagulopathies. Common clinical signs for coagulation factor deficiencies clinically include mucosal bleeding, bleeding pre, and post-medical procedures, and hemorrhagic diathesis. During an ammonia release assay, factor XIIIa transglutaminase activity using a synthetic amine peptide substrate reaction generates ammonia. The creation of ammonia is monitored to evaluate the levels of factor XIII. First-line detection of factor XIII includes a nitrogen release assay and/or a quantitative functional factor XIII assay.

Answer 47

Capillary malformation-arteriovenous malformation (CM-AVM) is a rare, combined vascular malformation, characterized by the presence of multiple capillary malformations/port-wine stain and arteriovenous malformation or fistulas. In the majority, it is attributed to dominantly inherited RASA1 gene mutation with high penetrance and intrafamilial clinical variability or sporadic occurrence. Recently EPHB4 gene mutation has also been proposed as a cause of CM-AVM syndrome. Port-wine stains are slow-flow vascular malformations and have an atypical appearance in CM-AVM syndrome. Multiple port-wine stains are usually seen over the face, trunk, and extremities of the affected individual, at birth, or later in life. They are multifocal, randomly distributed, pink-to-reddish brown colored, of variable size, with geographical margins and can have a pale/white halo around the lesion. It can be mistaken for a café-au-lait macule due to its brownish hue. Arteriovenous malformation is a fast flow vascular malformation found in one-third of the patients with CM-AVM syndrome. Depending on the site involved, they can present with various symptoms or life-threatening complications. In CM-AVM, AVM can be present in the skin, muscle, bone, spine, and brain. Pain, bleeding, congestive heart failure, and neurological symptoms are some of the important complications. Although symptoms can develop at any age, they commonly present during infancy or early childhood. Early detection and treatment can prevent associated morbidity or mortality. Parkes Weber syndrome is characterized by multiple arteriovenous fistulas with bone and soft tissue hypertrophy, usually affecting the extremities. RASA1 gene mutation is seen in the patients having port-wine stains on the skin of the affected limb; hence, it is considered as a clinical variant of CM-AVM.

Answer 48

Inherited peripheral neuropathies are a group of disorders that include hereditary motor and sensory neuropathies (HMSN), hereditary motor neuropathies (HMN), and hereditary sensory neuropathies (HSN) or hereditary sensory, and autonomic neuropathies (HSAN). The commonest entity, HMSN is also known as Charcot-Marie-Tooth disease (CMT). The clinical picture reveals clawing of fingers (intrinsic minus hands). There is a loss of innervation to intrinsic muscles of both hands, depicting median and ulnar nerve palsy. CMT may present with cavovarus feet, clawing of toes, hip dysplasia, progressive scoliosis, and hand intrinsic muscle wasting. The CMTs are genetically determined disorders with implications of nearly 100 genes. Over 80% to 90% of the genetic abnormalities are due to copy number variation in PMP22 and mutations in GJB1, MPZ, and MFN2 genes. The frequency of abnormalities in other genes individually is rare. Copy number variation in PMP22 is the commonest cause of CMT. PMP22 is a large gene that is located in the middle of the 1.4 Mb regions in chromosome17p.12. This region is susceptible to frequent genomic rearrangements. Duplication or deletion in PMP22 leads to disease via a gene dosage effect. Nerve conduction studies help in confirming the diagnosis of neuropathy and categorizing patients broadly into demyelinating and axonal subtypes. Patients with CMT have a progressive clinical course and need periodic monitoring. Composite scoring systems are available to assess longitudinal changes in function/ disability, including natural history and outcome. Ankle foot arthrosis (AFO) and insoles are used as conservative management. Mubarak et al and faldini et al devised operative surgical procedures for the correction of cavovarus feet deformity.

Answer 49

The most likely diagnosis is Fanconi anemia. Fanconi anemia is an inherited bone marrow failure syndrome that presents with cytopenia and has an increased risk of malignancy (leukemia). Physical abnormalities associated with Fanconi anemia include short stature, microcephaly, and café-au-lait skin lesions. Other physical malformations may also be present, although these are the most common. Fanconi anemia is a rare hereditary disorder of DNA repair that, in most cases, is autosomal recessive or X-linked. Mutation of FA genes results in impaired double-stranded DNA repair. To date, more than 23 FA complementation genes (FANC) have been recognized, and all of them are involved in the DNA repair pathway. Among cytopenias, thrombocytopenia is the first to develop and often the only finding on initial evaluation. Neutropenia and eventually anemia develops, indicating bone marrow failure. Children with Fanconi anemia also have hypogonadism, strabismus, anomalies of the thumbs and radii, and renal abnormalities such as horseshoe kidneys. Intellectual disability and microphthalmia may also be present.

Answer 50

Pompe disease is a deficiency in the lysosomal enzyme alpha-1,4-glucosidase. It is responsible for digesting glycogen-like material accumulating in lysosomes. The tissues most severely affected are those that have glycogen stores, including cardiac muscle and peripheral skeletal muscle. Infants present with cardiomegaly, hypotonia, or lethargy.

Answer 51

This patient has Sertoli-cell-only (SCO) syndrome. It is also called germ cell aplasia and Del Castillo syndrome. Patients with SCO syndrome present with normal sexual characteristics and infertility. They are usually between 20 and 40 years of age. Their physical examinations are usually normal. A semen analysis will usually show azoospermia. Microdeletions in the Yq11 region, also known as the azoospermia factor (AZF) region of the Y chromosome, have been found in some patients with SCO syndrome. Some patients with SCO syndrome with some level of sperm count can still be considered for testicular sperm extraction (TESE). TESE allows the removal of the sperm from the patient's testes, and the sperm can be used to fertilize an egg via intracytoplasmic sperm injection (ICSI).

Answer 52

Specific characteristics of men with non-obstructive azoospermia (NOA) are small volume testes, a higher level of FSH, along normal semen volume. NOA will typically relate to the impaired sperm production. On the contrary, a normal testicular length of above 4.6 cm, FSH level of lower than 7.6, and/or semen volume of lower than 0.5 or 1.0mL are most likely present in the obstructive azoospermia (OA). The mentioned laboratory tests are highly predicted in the OA, especially when the physical examination is significant for enlarged proximal epididymis or the absence of vasa deferentia. Ruling out cystic fibrosis (CF) is the most crucial step in diagnosing Young's syndrome. Cystic fibrosis shares many similar signs and symptoms of Young syndrome. Men with evidence of congenital obstructive azoospermia, including those with congenital bilateral absence of the vas deferens (CBAVD) should be further evaluated for CF. Mutations in the CFTR gene are present in up to four-fifth of men with CBAVD, and a significantly lower percentage of 20% of men with congenital unilateral absence of the vas deferens (CUAVD). Moreover, up to 21% of men with idiopathic epididymal obstruction have positive genetic testing for CFTR. Abdominal imaging should be requested in men with vasal agenesis irrespective of the CFTR status. Cystic fibrosis also manifests with recurrent sino-pulmonary infections and infertility. In the rare cases where the man has laboratory and physical examinations suggestive of OA, without epididymal engorgement, a testicular biopsy might be obtained for diagnostic purposes. Scrotal ultrasound should not be included as a primary routine step in the evaluation of infertile men. Request a testicular color Doppler ultrasound might be recommended in uncommon occasions of sub-optimal physical examination in an obese patient or contraction of the dartos muscle even in a warm room while performing the physical exam.

Answer 53

The patient has a classic presentation for Vogt-Koyanagi-Harada (VKH) disease, which is a systemic autoimmune condition. There is an increased prevalence of VKH among certain ethnic groups, with a higher rate in Japanese people. People with HLA-DR1 and HLA-DR4 are at higher risks of getting the disease. The OCT shows that the patient has an exudative, or serous retinal detachment. Exudative detachments are typically managed medically and not surgically. Exudative/serous retinal detachments typically occur in the acute uveitic phase. The uveitis often begins posteriorly. In this stage, the first sign often includes thickening of the posterior choroid with signs of optic disc edema, circumscribed retinal edema, and multiple exudative retinal detachments following. The inflammation causes the retinal blood vessels to leak, and subretinal fluid develops underneath the retina cause a detachment. This can often be best seen with OCT. The inflammation eventually spreads to the anterior chamber, causing panuveitis. The treatment for VKH is immunosuppression. Intravenous high dose steroids are usually advised for three days following a steroid taper. Treatment may consist of other immunosuppressants. Referral to rheumatology is typically recommended. In VKH, the prodromal stage presents much like a viral illness and often lasts three to five days. The patient may have fever, headaches, nausea, dizziness, light sensitivity, tinnitus, and orbital pain. The uveitic phase typically presents with blurry vision along with the previously mentioned uveitic sequelae. The chronic/convalescent stage often occurs weeks after the uveitic stage and may last for months. Patients develop poliosis, vitiligo, and choroid depigmentation. The recurrent stage consists of panuveitis with exacerbations of anterior uveitis. Exudative retinal detachments are uncommon in this stage.

Answer 54

CHARGE is the abbreviation of the characteristic features of this disease, such as coloboma, heart defects, atresia choanae (choanal atresia), growth retardation, genital abnormalities, and ear abnormalities.

Answer 55

Bilateral involvement of the extremities with both upper and lower motor neuron signs and symptoms is characteristic of many forms of amyotrophic lateral sclerosis (ALS). Some phenotypes of familial ALS have prominent frontotemporal symptoms, which may have been misdiagnosed as Alzheimer’s in his mother, especially given her relatively rapid deterioration. A hexanucleotide repeat on C9ORF72 is a gene variant that has been found in approximately 40% of familial ALS, making it the most common. ATXN2 is a gene that, when mutated, causes spinocerebellar ataxia type 2 and may be a susceptibility factor for the development of sporadic ALS.

Answer 56

This girl has signs of secondary sexual development before the age of 8 years along with accelerated height velocity. This clinical picture is suggestive of precocious puberty. The presence of excess adult-type pubic hair, axillary hair, and acne in this patient suggests the cause of puberty is an excess production of androgens. Other signs and symptoms of adrenal excess in girls include accelerated linear growth and hirsutism. Non-classical congenital adrenal hyperplasia is an important cause of precocious pseudopuberty in both boys and girls and occurs due to increased androgen production. Non-classical congenital adrenal hyperplasia is caused by a deficiency in 21-hydroxylase enzyme (CYP21A2) which is responsible for converting 17-hydroxyprogesterone to 11-deoxycortisol. Unlike classical congenital adrenal hyperplasia, enzyme deficiency in non-classical forms is mild and only leads to excess androgen production. The production of glucocorticoid and mineralocorticoid is maintained so salt-wasting does not occur in non-classical forms.

Answer 57

The patient most likely has metachromatic leukodystrophy due to a deficiency of arylsulfatase A. It is an inherited disorder that predominantly affects the central nervous system (CNS) white matter tracts, and it's cellular components. This leads to the accumulation of sulfatides, which result in the dysfunction and destruction of the CNS and peripheral nervous system (PNS) myelin sheaths and overall neurocognitive function and neurodevelopment deterioration. Symptomatic supportive care is needed to address the neurocognitive and neurodevelopment defects as no curative treatments are available.

Answer 58

Poor coordination, gynecomastia, small testes, and penis are signs suggestive of Klinefelter syndrome. Klinefelter syndrome is diagnosed by chromosomal analysis (karyotype). The majority of patients with Klinefelter syndrome are diagnosed around the age of puberty. Low androgens with high FSH and LH levels are suggestive of Klinefelter syndrome.

Answer 59

The silent carrier state for alpha thalassemia causes only microcytosis and hypochromia without anemia. Codocytes (target cells) are a common finding in all the thalassemic states. The condition is clinically silent and does not require treatment. Humans have two alpha-globin genes located on each chromosome 16, resulting in 4 a-gene loci (aa/aa). Adult hemoglobin is a mixture of HbA1, HbA2, and HbF. All of these hemoglobins are composed of 2 alpha-globin chains and 2 non-alpha-globin chains (delta in HbA2 and gamma in HbF). The alpha thalassemia carrier state is the result of deletion or inactivation of only one alpha-globin gene (-a/aa). Hemoglobin electrophoresis is normal in adults with the alpha thalassemia carrier state. Confirmation of the diagnosis requires molecular analysis. The condition is also referred to as alpha thalassemia minima.

Answer 60

Phocomelia is defined as a truncation of the intercalating segments of the upper or lower extremity, with hands or feet attached directly to the trunk. About 10% of patients with phocomelia have an underlying clinical syndrome, most commonly Robert syndrome. Robert syndrome is caused by an autosomal recessive mutation of the ESCO2 (establishment of cohesion 1 homolog 2) gene, resulting in syndromic facies and limb truncation defects. Phocomelia most commonly affects one limb, typically the upper left limb.

Answer 61

Galloway-Mowat syndrome (GMS) is an autosomal recessive disorder. It is characterized by microcephaly with various central nervous system anomalies and early-onset nephrotic syndrome. Physical findings include microcephaly, microphthalmos, epicanthic folds, a narrow slopping forehead, a highly arched palate, large low-set floppy ears, a small midface, and a beaked nose, thin lips, clenched hands, and arachnodactyly. The gene for Galloway-Mowat syndrome is not known. Denys-Drash syndrome (DDS) is characterized by male pseudo-hermaphroditism, Wilms tumor, and early-onset nephrotic syndrome that progresses rapidly to end-stage renal disease. Frasier syndrome (FS) is characterized by progressive glomerulopathy, male pseudo-hermaphroditism, and gonadoblastomas. Pierson syndrome is characterized by congenital nephrotic syndrome/diffuse mesangial sclerosis, microcoria (small pupils), impairment of vision, and muscular hypotonia.

Answer 62

Autosomal dominant causes of hearing loss can be summarized in the acronym WANT CBS (Waardenburg, Apert, neurofibromatosis, Treacher-Collins, Crouzon, brachio-oto-renal, and Stickler). This patient has Pendred syndrome, which is autosomal recessive. The patient presents with the constellation of bilateral hearing loss, euthyroid goiter, and bilateral vestibular aqueducts consistent with Pendred Syndrome. Pendred Syndrome is inherited in an autosomal recessive manner. X-linked recessive causes of hearing loss include Alport syndrome and Mohr-Tranebiaerg syndrome. This patient has Pendred syndrome, which is autosomal recessive. There are no Y-linked causes of hearing loss.

Answer 63

Rotor syndrome is an autosomal recessive disease and a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia. The disease is characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin. Rotor syndrome is an autosomal recessive disorder caused by homozygous mutations in both the SLCO1B1 and SLCO1B3 genes on chromosome 12. These genes provide instructions for making organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). These proteins are found in liver cells and mediate sodium-independent cellular uptake of compounds, including bilirubin glucuronide, bile acids, and steroid and thyroid hormones, as well as numerous drugs, toxins, and their conjugates. In rotor syndrome, the OATP1B1 and OATP1B3 proteins are abnormally short; therefore, the bilirubin is less efficiently taken up by the liver and removed from the body, causing a buildup of bilirubin in the blood and urine, which results in jaundice and dark urine.

Answer 64

Birdshot chorioretinopathy is a white dot syndrome with bilateral eye involvement that typically affects more women than men. Birdshot chorioretinopathy is highly correlated with the presence of the HLA-A29 haplotype. Correlation is so high that the absence of HLA-A29 should raise suspicion for an alternative diagnosis. The classic chorioretinal lesions of birdshot chorioretinopathy are multiple ovoid cream-colored lesions scattered in a birdshot pattern, often radially from the optic nerve with a nasal predominance. Patients with birdshot chorioretinopathy often present with visual symptoms out of proportion to measured visual acuity. Initial symptoms typically include photopsia, poor night vision (nyctalopia), alterations in color perception, and floaters.

Answer 65

Apert syndrome presents with premature fusion of the coronal suture. These patients have with midface hypoplasia, hypertelorism, syndactyly of hands and feet, hearing loss, and cervical vertebral fusion. Pfeiffer syndrome features brachycephaly (premature fusion of bicoronal sutures), hypertelorism, maxillary hypoplasia, broad thumbs, great toe, syndactyly, brachydactyly, and hearing loss. Muenke affects the coronal suture unilaterally or bilateral and features midface hypoplasia, hypertelorism, macrocephaly, and hearing loss. The only option stated that features syndactyly of the hands and feet with unilateral coronal suture fusion is Apert.

Answer 66

Chromosome 5q is linked to the development of atopy, but 3p, 1p, and 11p are not. Chromosome 5q encodes for IL-4, IL-5, and IL-13, CD14, and beta2 adrenergic receptors. IL-4 and IL-13 promote IgE switching, and IL-5 promotes the growth of eosinophils. CD14 is an LPS receptor component, via interaction with TLR4 and may influence the balance between Th1 and Th2 responses to antigens. Beta2-adrenergic receptor regulates bronchial smooth muscle contraction.

Answer 67

Chromosome 5q is linked to the development of atopy, but 3p, 1p, and 11p are not. Chromosome 5q encodes for IL-4, IL-5, and IL-13, CD14, and beta2 adrenergic receptors. IL-4 and IL-13 promote IgE switching, and IL-5 promotes the growth of eosinophils. CD14 is an LPS receptor component, via interaction with TLR4 and may influence the balance between Th1 and Th2 responses to antigens. Beta2-adrenergic receptor regulates bronchial smooth muscle contraction.

Answer 68

The most common chromosomal mutation of all meningiomas is chromosome 22, specifically with merlin tumor suppressor gene, SIS oncogene, and INI1. The most prevalent subtype of intraventricular meningioma is a fibrous meningioma. On immunostaining, fibrous meningiomas typically present with epithelial membrane antigen/vimentin/S100 positive. S100 protein positivity is more common in fibrous meningiomas, compared to other subtypes. 1p19q is seen in oligodendrogliomas, IDH wildtype is seen in primary glioblastomas, and chromosome 17 is associated with the development of neurofibromas.

Answer 69

B Chediak–Higashi syndrome is a rare autosomal recessive disorder. It arises from a mutation of a lysosomal trafficking regulator protein. This leads to decreased phagocytic activity and decreased immunity. Clinical manifestation includes recurrent pyogenic infections, albinism, and peripheral neuropathy. Clotting dysfunction is a feature of Chediak-Higashi syndrome. In addition to bruising, dermatological presentations include blonde hair and patches of non-pigmented skin.

Answer 70

This patient has thyroxine-binding globulin (TBG) deficiency based on a normal TSH, free T4, and low total T4, and the protein that is responsible for this is thyroxine binding globulin on TBG. TBG is encoded by a gene called SERPINA 7. TBG is encoded by SERPINA 7, is a serine protease inhibitor, and is found on the X-chromosome. Mutations in the SERPINA 7 gene can cause alterations in the level of TBG, which in turn can cause a decrease in total T4 but not in the free T4 as TBG is bound to T4. As such, patients do not experience symptoms since there is no change in the level of free T4. TTR is responsible for making transthyretin, another major transport protein for thyroid hormones, but this does not result in TBG deficiency. The SERPINA 6 gene is responsible for making corticosteroid-binding globulin, and MAP3K1 is a gene that plays multiple roles in signaling pathways. These two genes are not implicated in TBG deficiency.

Answer 71

The patient presents with a long history of anosmia and progressive deafness, both of which are symptoms of Refsum disease. The laboratory testing of the patient's serum shows elevated levels of phytanic acid, a breakdown product of chlorophyll in the diet of animals and humans. The PHYH gene encodes the enzyme phytanyl CoA hydroxylase (alpha-hydroxylase), which is required for the alpha oxidation of phytanic acids. Deficiency of this enzyme in peroxisomes leads to Refsum disease. ABCD1 gene mutation is present in patients with X-linked Adrenoleukodystrophy. PEX1 gene mutation is responsible for Zellweger syndrome. Mutations in RET are associated with multiple endocrine neoplasia type II.

Answer 72

Isoleucine is an essential nutrient because it is not synthesized in the body, but it is synthesized via several steps in plants and microorganisms, starting from pyruvate and alpha-ketobutyrate. Enzymes involved in this process include acetolactate synthase, acetohydroxy acid isomeroreductase, dihydroxy acid dehydratase, and valine aminotransferase. Isoleucine is a glucogenic and ketogenic amino acid, and methylene-cyclopropyl acetyl-CoA is derived from the hypoglycin plant toxin and inhibits the ß-oxidation and the catabolism of branched-chain amino acids. Maple syrup urine disease (MSUD) with late-onset includes neurologic symptoms such as inappropriate, extreme, or erratic behavior and moods, hallucinations, oscillating hypertonia and hypotonia, ataxia, seizures, opisthotonos, and coma.

Answer 73

This patient with severe depression and signs of facial muscle twitching that does not resolve on antidepressants and altering antipsychotics, respectively, with no account of family history, and an MRI of a boxcar appearance is most likely a case of Huntington chorea. It is caused by the atrophy of the caudate and putamen. The classic clinical triad in Huntington disease is (1) progressive movement disorder, most commonly chorea; (2) progressive cognitive disturbance culminating in dementia; and (3) various behavioral disturbances that often precede diagnosis and can vary depending on the state of disease. The enlargement of the frontal horns often gives a "box" like configuration. This can be quantified by a number of measurements 1. frontal horn width to intercaudate distance ratio (FH/CC) 2. intercaudate distance to inner table width ratio (CC/IT). Excess dopamine suppression due to antipsychotics can cause acute dystonia. However, stopping the antipsychotics and treating with benztropine should treat this. Cerebellar atrophy is seen in spinocerebellar ataxia. This presents with ataxia primarily along with other symptoms like slowing of ocular saccades, paralysis, etc. Atrophy of the subthalamic nucleus causes hemiballismus, which causes wild flailing of limbs, rather than facial chorea in Huntington chorea.

Answer 74

The patient has a sensitivity to aminoglycosides given the onset of hearing after starting gentamicin. Aminoglycoside-induced deafness is inherited in a mitochondrial manner, meaning only the mother can pass on those genes. Since he is a male, he would pass on the gene to 0% of his offspring. Hearing loss can present in 25% of children of parents who both have an autosomal recessive gene for hearing loss. Aminoglycoside sensitivity is inherited in a mitochondrial manner. Hearing loss can present in 50% of children of parents if one of them carries an autosomal dominant gene for hearing loss. Aminoglycoside sensitivity is inherited in a mitochondrial manner. Aminoglycoside sensitivity is inherited in a mitochondrial manner. If the patient had been female, the rate would be 100%.

Answer 75

Renal manifestations of tuberous sclerosis include angiomyolipomas and renal cysts. Angiomyolipomas are seen in 80% of patients and are composed of smooth muscle, adipose tissue, and connective tissue. Renal failure does occur from bleeding angiomyolipomas and is a common cause of death in these patients. Rarely, large lesions undergo differentiation to renal cell cancers.

Answer 76

The mass present in the newborn is most likely a lymphangioma. Congenital lymphangiomas form due to blockage of the lymphatic system during fetal development, though the cause remains unknown. Cystic lymphangiomas are associated with genetic disorders, including trisomies 13, 18, and 21, Noonan syndrome, Turner syndrome, and Down syndrome. Lymphangiomas are soft, with varying sizes and shapes, and will typically grow if not surgically excised. When posterior neck lesions are present, there may be an association with Turner syndrome, hydrops fetalis, or other congenital abnormalities. Lymphangiomas result from congenital or acquired abnormalities of the lymphatic system. The congenital form typically occurs before the age of 5 years. Acquired lymphangiomas occur as a sequela of any interruption of previously normal lymphatic drainage such as surgery, trauma, malignancy, and radiation therapy.

Answer 77

Oculocutanous albinism is a recessive disorder that affects melanin production without affecting melanocyte numbers or distribution in the skin. The relative lack of pigment leads to paler skin, hair, and eyes. The ocular findings of this condition can be debilitating and are divided into refractive and nonrefractive errors. Vitiligo and piebaldism are hypopigmentation skin conditions caused by autoimmune destruction and patchy absence of melanocytes, respectively Crouzon syndrome is an autosomal dominant branchial arch syndrome affecting the pharyngeal arch that develops into the maxilla and mandible, and is not a hypopigmentation syndrome.

Answer 78

Up to 5% of cases of hypothalamic hamartomas are associated with Pallister-Hall syndrome. Hypothalamic hamartomas are non-neoplastic tumors of the hypothalamic region consisting of normal neural and glial cells. Gelastic seizures are uncontrolled bouts of laughter that occur with hypothalamic lesions. Pallister-Hall syndrome is also associated with other abnormalities such as hypopituitarism, growth hormone deficiency, bifid epiglottis, and genital hypoplasia. Pallister-Hall syndrome is typically diagnosed in early childhood presenting with seizures, central precocious puberty due to hypothalamic hamartomas, and polydactyly. Not all have seizures. Pallister-Hall syndrome has an autosomal dominant inheritance pattern. It is caused by mutations in the GLI3 gene in chromosome 7. It is a dysmorphology syndrome involving the hands, feet (polydactyly and syndactyly), larynx, anus, and hypothalamus.

Answer 79

Cardiac-valvular Ehlers-Danlos syndrome (EDS) involves an autosomal recessive inheritance pattern and is associated with mutations in the COL1A2 and NMD genes, which code for type 1 collagen. Major clinical criteria include skin hyperextensibility, atrophic scarring, easy bruisability, restricted or generalized joint hypermobility, and progressive cardiac-valvular problems. Classical EDS involves an autosomal dominant inheritance pattern, and associated mutated genes include COL5A1 and COL1A1, which code for type 5 and type 1 collagen, respectively. Genetic testing of Marfan syndrome can reveal a mutation in the fibrillin 1 protein, which does not occur in EDS. Elbow involvement is generally spared, and marfanoid habitus is usually more evident in Marfan syndrome, with an arm span-to-height ratio greater than 1.05. Genetic analysis of a patient with cutis laxa will often identify mutations in the fibulin-5 gene. The skin of patients with cutis laxa is characteristically known to slowly return to its original form from distention, unlike EDS.

Answer 80

Werner syndrome patients appear unaffected at birth and develop normally until the adolescent period or second decade of life, when they start to exhibit signs and symptoms of accelerated aging. Patients develop skin ulcers, cataracts, graying, or even loss of their hair, hypogonadism, and can develop a malignancy. Up to 50% of the malignancies reported are soft tissue sarcomas, such as schwannoma, rhabdomyosarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, and osteosarcoma of the upper extremities. Patients have also been reported to develop meningiomas, malignant melanoma, and thyroid carcinomas. Werner syndrome patients are at an increased risk of tumor formation, with up to 10% of patients developing a malignancy. However, the types of tumors that develop are unusual compared to the aging population. If a Werner syndrome patient develops a malignancy, they should be referred to the appropriate specialist for the staging of the tumor. The life expectancy of a patient with Werner syndrome is around 50 years. Patients usually die from malignancy or cardiovascular complications.

Answer 81

Adrenoleukodystrophy (ALD) is an X-linked disease with a mutation in the ABCD1 gene. This gene codes for ALD, a peroxisomal membrane transporter protein. It is associated with high serum very-long-chain fatty acids. Several different phenotypes and ages of onset of adrenoleukodystrophy exist, and presentation is variable even within the same family. A progressive adrenal gland dysfunction and loss of myelin are characteristic of this illness. Symptoms include symptoms of adrenal insufficiency, behavioral changes, poor memory, gait disturbances, and progressive dementia.

Answer 82

Zellweger syndrome, also known as cerebrohepatorenal syndrome, is a very rare inherited disorder characterized by the absence or reduction of functional peroxisomes in cells. It is an autosomal recessive disorder and is one of the disorders included under disorders of peroxisome biogenesis. Zellweger syndrome is caused by mutations in various genes required for peroxisome biogenesis. The peroxisome is a single membrane-bounded organelle that is involved in degradation (beta-oxidation) of very-long-chain fatty acids (VLCFAs), and catabolism (alpha oxidation) of branched-chain fatty acids, catabolism of amino acids and ethanol, biosynthesis of bile acids, steroid hormones and plasminogen formation which are important in the cell membrane and myelin. It is also involved in the degradation of cytotoxic Hydrogen peroxide. Zellweger syndrome is thus characterized by abnormal accumulation of very-long-chain fatty acids (VLCFA) as the normal peroxisomal function is markedly reduced or absent. There is an increased accumulation of VLCFA with 26 carbons, an increased ratio of C26 to C22 very-long-chain fatty acids in plasma, fibroblasts, and amniocytes. Zellweger syndrome is the most common peroxisomal disorder that presents in early infants with an incidence of 1 in 50,000 to 100,000 live births. The overall incidence of peroxisomal disorders is about 1 in 5 to 10,000 live births.

Answer 83

Both actinic prurigo (AP) and polymorphous light eruption (PMLE) can present with similar papular pruritic lesions and are thought to be due to a delayed hypersensitivity reaction induced by UV radiation. There is a strong associated with actinic prurigo with the HLA-DR4 allele, specifically the DRB1*0407 subtype. The human leukocyte antigen DR4 allele variant is present in 90% of cases of AP, but PMLE has no association with the DR4 allele. AP has a strong genetic component while PMLE does not.

Answer 84

Dyskeratosis congenita (DKC), which is also known as Zinsser-Engman-Cole syndrome, is a genodermatosis. It is an uncommon syndrome classically associated with the triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Nail dystrophy is one of the first integumentary system signs of dyskeratosis congenital. Usually, dystrophic nails appear between 5 to 13 years and show longitudinal fissures. Reticulated hyperpigmentation and telangiectasias are common findings in dyskeratosis congenital, but these changes do not usually occur until after nail findings have been established. XL inheritance and causes low telomere length, which can lead to bone marrow failure or cancers

Answer 85

Birdshot Uveitis has the strongest human class I MHC correlation with any disease, with 80-98% of patients being HLA-A29 positive, only 7% in the general population. Diagnostic criteria involve more than 3 peripapillary birdshot lesions or cream-colored, irregular or elongated choroidal lesions with long axis radiating from the optic disc: less than 1+ anterior vitreous cells and less than 2+ vitreous haze in both eyes. Supportive findings include positive serum marker HLA-A29 individuals. HLA-DR2 is associated with pars planitis. HLA-B27 is associated with ankylosing spondylitis and other spondylarthropathies. HLA-A17 is not generally associated with ocular conditions.

Answer 86

Since this mutation is heterozygous, every acute myeloid leukemia (AML) blast will have only one of the two homologous chromosomes coding for NPM1 mutated (chromosome 5). Thus, of all the chromosome 5’s residing in the patient’s AML cells, half are mutated. With 30% of the cells being AML blasts and half of those cells’ chromosomes being mutated, that means 15% of the patient’s DNA fragments sequenced should be mutated. Since this mutation is heterozygous, every AML blast will have only one of the two homologous chromosomes coding for NPM1 mutated (chromosome 5). Thus, of all the chromosome 5’s residing in the patient’s AML cells, half are mutated. With 30% of the cells being AML blasts and half of those cells’ chromosomes being mutated, that means 15% of the patient’s DNA fragments sequenced should be mutated. Since this mutation is heterozygous, every AML blast will have only one of the two homologous chromosomes coding for NPM1 mutated (chromosome 5). Thus, of all the chromosome 5’s residing in the patient’s AML cells, half are mutated. With 30% of the cells being AML blasts and half of those cells’ chromosomes being mutated, that means 15% of the patient’s DNA fragments sequenced should be mutated. If this mutation were homozygous, then this answer would be correct. Since this mutation is heterozygous, every AML blast will have only one of the two homologous chromosomes coding for NPM1 mutated (chromosome 5). Thus, of all the chromosome 5’s residing in the patient’s AML cells, half are mutated. With 30% of the cells being AML blasts and half of those cells’ chromosomes being mutated, that means 15% of the patient’s DNA fragments sequenced should be mutated.

Answer 87

The etiology of MRKH (Mayer-Rokitansky-Kuster-Hauser) syndrome is previously thought to be sporadic, but familial cases support genetic etiology. Although the precise gene has not yet been identified. MRKH syndrome is appeared to be transmitted in an autosomal dominant fashion. MRKH syndrome causes the uterus or vagina to be underdeveloped or absent, although external genitalia and lower vagina are normal. Affected women don't have menstrual periods due to an absent uterus. Women with MRKH syndrome have a female chromosome pattern and normally functioning ovaries.

Answer 88

CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome is inherited in an X-linked dominant pattern, and therefore a preponderance of those affected are female (19:1 female:male). The clinical manifestations are ipsilateral hypoplasia of the limbs, facial hemidysplasia, and hypoplasia of various organ systems. The classic epidermal findings in CHILD syndrome include striking unilateral erythematous scales with clear midline demarcation that tend to improve with age. Stippled calcification of the epiphysis, a unique bone finding, can be found early in infancy and can help clinicians in making the diagnosis.

Answer 89

Pelizaeus-Merzbacher-like disease (PMLD) is a leukodystrophy that presents in a very similar manner to Pelizaeus-Merzbacher disease (PMD). It is an autosomal recessive disorder, unlike PMD, which is X-linked recessive. PMLD is due to a mutation at the level of the GJC2 gene. Clinical features include spasticity, delayed milestones, cognitive and motor impairment, titubation, and others. Clinical features are almost identical to PMD. Radiological findings include demyelination of most of the brain structures on MRI in both PMD and PMLD along with T2 hyperintensity. However, the involvement of the pontine area is more suggestive of PMLD. PLP1 mutation leads to PMD, L1CAM mutation leads to metachromatic leukodystrophy, and SOX10 mutation leads to Waardenburg syndrome.

Answer 90

Abacavir is a drug used in antiretroviral HIV regimens as an adjunct to treatment. Abacavir mediated hypersensitivity is a type IV hypersensitivity reaction in susceptible patients. The presence of the HLA B 5701 allele is a contraindication to abacavir treatment. Symptoms present within 2 weeks of drug initiation and occur as a result of a T-cell mediated cytokine reaction. Symptoms most commonly include rash, fever, fatigue, and GI disturbances. Hypersensitivity to abacavir occurs in 5-8% of patients who receive treatment and has therefore warranted genetic screening prior to initiation. Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) and exerts its action chain termination following incorporation into viral DNA.

Answer 91

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders caused by different gene mutations that share the same histological findings. The clinical manifestations are widely variable and gene-dependent. To date, many different gene mutations that cause ADTKD have been detected: uromodulin (UMOD), renin (REN), mucin-1 (MUC1), hepatocyte nuclear factor 1-beta (HNF1B), and recently SEC. 61A1 mutation was identified as a novel cause of this disease. In ADTKD-HNF1B, the HNF1B gene is essential in early embryonic development. It is also known as transcription factor-2 (TCF2). This gene is located on chromosome 17q12, which codes for protein hepatocyte nuclear factor 1 homeobox B. Since HNF1B is expressed in the body's variable tissues like the kidney, liver, pancreas, and genitourinary tract, this may explain the variable clinical presentations of the HNF1B-related disorders. It was found that loss of HNF1b could induce epithelial-mesenchymal transition. This type of transition will ultimately lead to kidney fibrosis by up-regulation of the expression of transforming growth factor-beta ligands in renal epithelial cells. ADTKD-HNF1B is caused by a mutation in the TCF2 gene. The homeodomain-containing transcription factors hepatocyte nuclear factor 1 alpha and 1 beta are expressed both in the kidney and the pancreas. It has been identified that mutations in this gene may cause the maturity-onset diabetes of youth (MODY), but further studies explicate that mutations in this gene may also lead to renal manifestations. The varied clinical manifestations and the fact that these clinical manifestations are not present consistently in all affected family members made diagnosing this condition difficult. The non-renal manifestations may include maturity-onset diabetes in youth, abnormal liver function tests of unclear etiology, genitourinary tract malformations, hyperuricemia with gout in adolescence, and hypomagnesemia may occur in some individuals. The renal manifestations are common in adulthood and often involve numerous renal cysts, congenital solitary kidney, congenital anomalies of the kidney and urinary tract system, renal dysplasia, and hypoplastic kidneys. For ADTKD-HNF1B, there is no specific therapy for this disease. The treatment is mainly supportive of chronic kidney disease. Allopurinol or febuxostat should be considered for patients with early-onset gout to prevent tophus development and urate accumulation. Screening for abnormal liver function tests, hyperglycemia, hypomagnesemia, and hyperuricemia is an essential part of the management to prevent further complications. To evaluate the renal morphologic abnormalities, renal ultrasound should be performed.

Answer 92

The CT image demonstrates a large right renal mass and a smaller left renal mass. Based on the patient's family history and his own personal history of renal malignancy, the patient is likely the carrier for the autosomal dominant mutation of the VHL tumor suppressor gene(Von Hippel Lindau Syndrome). Von Hippel Lindau Syndrome is characterized by renal cell carcinomas typically of the clear cell subtype. There is a high incidence of renal cancer in VHL patients (up to a 70% lifetime risk). Renal cysts are also commonly seen and renal angiomyolipomas are also frequently incidentally discovered on imaging. Other tumors include pancreatic neuroendocrine tumors, pheochromocytomas, and pancreatic adenocarcinoma. More often the pancreas is affected by cystic replacement (pancreatic cystosis) or serous cystic neoplasms. Von Hippel Lindau Syndrome patients often also acquire CNS hemangioblastomas, most commonly within the cerebellum. Hemangioblastomas of the spinal cord and brainstem can also occur, although less commonly noted. Choroid plexus papilloma, while also being associated with VHL patients, are less common than hemangioblastomas.

Answer 93

Dentatorubral pallidoluysian atrophy (DRPLA) is classified as a microsatellite repeat disorder, which shows genetic anticipation with earlier onset and worse disease severity as it passes to the next generation. Studies show that functional impairment is an indirect measure of disease severity, given that it is inversely related to the CAG repeat length. DRPLA patients require structured physical and occupational therapy to preserve, motor mobility, and functional activities of daily living as much as possible. Structured and individualized educational programs for affected children are other important considerations. An extensive neuropsychological and psychiatric assessment is instrumental in evaluating progressive memory and mood disorders. Managing them early will preserve more cognitive domains and increase the quality of life. Life expectancy ranges from 8–16 years from symptom onset. The length of the CAG repeat expansion in ATN1 is positively correlated with age of onset, clinical phenotype, and life expectancy, with longer repeats being linked to earlier onset, severe disease phenotype, and a shorter lifespan. The most feared complications are status epilepticus, aspiration pneumonia, and recurrent seizures, which are all linked with increased mortality.

Answer 94

Hereditary fructose intolerance is a disease where patients are unable to process fructose. Management requires strict dietary measures. Fanconi syndrome is a possible renal manifestation of this disease. Other manifestations include failure to thrive, jaundice, and hepatomegaly.

Answer 95

Von Gierke disease due to a mutation in glucose-6-phosphatase, an important enzyme in glycogenolysis in the liver responsible for dephosphorylated glucose-6-phosphate so that glucose can be exported out of the cell. A mutation in glucose-6-phosphate leads to hypoglycemia since the liver cannot make glucose to be transported into blood to maintain normal glucose levels. Patients with Von Gierke disease can be treated with multiple feedings because this avoids relying on glycogen degradation as a source of fuel. Patients with Von Gierke disease can manifest doll-like faces due to fat deposits and hyperlipidemia. Other findings in these patients include hyperuricemia and high lactic acid.

Answer 96

The patient described has chronic granulomatous disease (CGD). The presentation of this disease is variable, and the diagnosis should be suspected in patients with recurrent lymphadenitis, multiple-site osteomyelitis, cutaneous abscesses, and hepatic abscesses. A family history of recurrent infections or unusual infections with catalase-positive organisms such as Staphylococcus aureus, Aspergillus, or Burkholderia cepacia is seen in these patients. Patients with this disorder have a deficiency of NADPH oxidase enzyme, which is necessary for respiratory burst. The strong family history of male involvement on the maternal side indicates an X-linked hereditary condition and suggests CGD as the likely diagnosis in this patient. Chronic granulomatous disease is caused by mutations in genes encoding proteins involved in generating a respiratory burst. In CGD, there is an impairment in the killing because of defects in the NADPH oxidase enzyme system and the failure to generate superoxide. Catalase negative organisms like pneumococci and streptococci can generate hydrogen peroxide and are killed.

Answer 97

Low platelet count in a child due to deficient megakaryocytes in the bone marrow is called congenital amegakaryocytic thrombocytopenia. The main pathophysiology of this disease is a genetic defect in the thrombopoietin receptor on the megakaryocytes (called the MPL receptor). The main treatment for congenital amegakaryocytic thrombocytopenia is hematopoietic stem cell transplant. Another treatment is experimental gene therapy targeting the MPL receptor itself. The other mentioned genes are not involved in congenital amegakaryocytic thrombocytopenia. MYH7 gene is the acronym for myosin heavy chain 7 in muscles. MLPH is the acronym for melanophilin involved in melanin synthesis in melanocytes. BRAF gene is a proto-oncogene involved in several malignancies and their treatment.

Answer 98

The long arm of chromosome 19 carries the gene for myotonic dystrophy type 1. The gene for myotonic dystrophy type 2 is found on chromosome 3. It is an autosomal dominant disease with associated cataracts, heart disease, dementia, alopecia, and testicular atrophy. Duchenne muscular dystrophy is a mutation on the X chromosome. Chromosome 4 carries the gene for facioscapulohumeral dystrophy. In infants, the best way for dx is CK level, which will be elevated, especially if a family mutation is not known. Del/dup is next best with MLPA.

Answer 99

This 15-year-old patient with ataxia, and ocular saccades, with a family history in her paternal uncle and brother, suggesting an autosomal dominant inheritance, is most likely a case of spinocerebellar ataxia (SCA) type 2. SCA-2 is an autosomal dominant trinucleotide repeat disorder. It presents with cerebellar ataxia and early-onset slow ocular saccades, along with areflexia. SCA is caused due to a pathological expansion of a CAG sequence in the introns. This is transmitted by a paternal transmission of pathological repeats. When a maternal transmission occurs, a contraction in the repeat size occurs, reducing the expansion below the threshold. Hence the first generation expression of the disease is likely transmitted from the father. Maternal transmission of CGG repeats causes fragile X syndrome that presents with macroorchidism, mild mental retardation, and fragile X facies. CTG repeats caused by maternal transmission causes myotonic dystrophy, which causes myotonia, male pattern baldness, and infertility, among other symptoms rather than ataxia and slow ocular saccades. GAA repeat expansion by paternal transmission causes Friedreich ataxia, which presents with ataxia and cardiomyopathy, but is also transmitted in an autosomal recessive pattern.

Answer 100

A young boy with adult-onset proximal muscle weakness, waddling gait, and pseudohypertrophy of calf muscles with raised creatine kinase (CK) likely has Becker muscular dystrophy (BMD). BMD is caused by a mutation in a protein called 'dystrophin.' The defective gene is located in the Xp21.2 chromosome, and the defect is inherited as an X-linked recessive trait. Genetic analysis is usually sufficient for diagnosis. Raised creatine kinase level indicates muscle degeneration, attaining a maximum of around 10-15 years of age. Creatinine level is raised five times or more above the normal. Detection of deletions and duplications on genetic analysis is done by several methods such as multiplex ligation-dependant probe amplification (MLPA) fluorescence in situ hybridization and polymerase chain reaction(PCR). MLPA is the mainstay of methods that are mostly used for diagnosis.

Answer 101

C May-Hegglin anomaly is characterized by a mutated MYH9 gene that is present on chromosome 22q12-13 and encodes the nonmuscle myosin heavy chain class IIA (NMMHC-IIA). At least 33 mutations of the MYH9 gene have been identified. NMMHC-IIA is a cytoplasmic protein that is present in many tissues, including platelets. The MYH9 gene mutation causes abnormal production of NMMHC-IIA. This leads to macrothrombocytopenia secondary to defective megakaryocytic maturation and fragmentation. May-Hegglin anomaly shows crescent-shaped Dohle-like inclusion bodies in white blood cells on the peripheral blood smear. These inclusion bodies represent precipitates of MHC within the cytoplasm of neutrophils, eosinophils, basophils, and monocytes. Neutrophil and platelet function is considered to be normal in the May-Hegglin anomaly.

Answer 102

accelerated aging, dermal atrophy, increased SQ fat, cataracts defect in DNA repair

Answer 103

CADASIL should be suspected in patients with a strong family history of early strokes and dementia. The most common symptoms are migraine headaches, cognitive deficits, ischemic episodes, and psychiatric disorders. The average age of onset is around 30 years. If genetic testing is negative and still highly suspected, gold standard is skin biopsy as this disorder affects small blood vessels such as those in skin and muscle.

Answer 104

Type I: severe lack of gyrus and sulcus formation; seizures, floppy/hypotonia, regression/no gain of milestones, hypsarrhythmia on EEG, frog-like posture due to hypotonia Type II: cobblestone appearance/nodular cortex. Walker-Warburg syndrome patients are most severely affected with profound hypotonia, severe ocular abnormalities, and neurological impairment. Fukuyama syndrome is intermediate in severity, and muscle-eye-brain disease is least severe with patients exhibiting only mild hypotonia, mild ocular anomalies, and developmental delay

Answer 105

Fanconi anemia, AR inheritance, causes aplastic anemia and death A complete blood count (CBC) will show decreased leukocytes, red blood cells, and platelets in a child with Fanconi's anemia. Radial club hand, as seen below, is associated with a number of congenital anomalies, including Fanconi's anemia, thrombocytopenia absent radius syndrome, and vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL/VATER) syndromes

Answer 106

Notochord secretes sonic hedgehog (shh) in a morphogenic gradient pattern (highest concentration is near the notochord with diffusion outward), which binds to receptors on target cells to induce specification and differentiation events in the neural plate, somites, and ectoderm. The somite will provide muscle and bone to the vertebral column. The endoderm will pattern itself into the foregut, midgut, and the hindgut with foregut cells expressing Hex, Sox2, and Foxa2. And the hindgut expressing different homeobox genes Cdx1, Cdx2, as well as Cdx4. The lung bud is derived from the endodermal tissues of the foregut. The cells of the epiblast stretch to form a semi-sphere known as the amniotic cavity, while the cells of the hypoblast extend to surround the yolk sack. The responsibility of the yolk sac is to provide nutrients, proteins, stem cells for sex cell development, and to fill in the space between the foregut and hindgut (provides cells for the midgut). The ectoderm is the outer layer of the embryo, which gives rise to the external ectoderm (epidermis, hair, nails) and the neuroectoderm (neural crest and neural tube-brain and spinal cord), along with the lens of the eyes and the inner ear.

Answer 107

D Surveillance recommendations in Peutz-Jeghers syndrome include: - Baseline screening upper GI endoscopy at 12 years old. If polyps are found, the endoscopy should be repeated annually. In the absence of polyps, endoscopy should be repeated every 2 to 3 years into adulthood. - Testicular surveillance should be considered with annual examination and yearly ultrasound beginning at age 10. - Baseline screening colonoscopy is indicated beginning at 12 years old or earlier if reported symptoms, and if polyps found repeat annually. In the absence of polyps should be repeated at 1 to 3 year intervals. - Pancreatic surveillance should be obtained with magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound. It should be started, at 25 to 30 years old, and to be repeated every 1 to 2 years.

Answer 108

fumarate hydratase The pathophysiology of the relationship between heterozygous fumarate hydratase deficiency and the production of leiomyomas remains unknown, but it is suspected that fumarate hydratase may function to some degree as a tumor suppressor.

Answer 109

C Hereditary hemorrhagic telangiectasia increases the risk for pulmonary arteriovenous malformations by 20% to 30%. A venous thrombus can embolize and pass through a pulmonary arteriovenous malformation and lodge in the intracranial vessels. Transthoracic echocardiogram with agitated saline or contrast can be used to evaluate for intracardiac shunts or pulmonary arteriovenous malformations. A positive test for pulmonary arteriovenous thromboembolism using contrast echocardiography is defined as the visualization of bubbles in the systemic circulation at least 3 cardiac cycles after first seeing them in the right atrium. The purpose of waiting for more than 3 cardiac cycles, as 3 cycles or less means possible patent foramen ovale.

Answer 110

AD inheritance Autoinflammatory pathologies due to the dysregulation of the NLRP3 inflammasome, a proinflammatory protein complex Sporadic episodes of pain, photophobia, conjunctival injection, and visual disturbances Sporadic inflammatory episodes cause corneal edema in the stroma. A misshapen stroma may cause light to not focus directly on the retina. This blurry vision may persist for some time after the pain and red eye resolve.

Answer 111

Purely clinical diagnosis, no genetic testing recommended Poor wound healing, dislocated joints, strong associated with POTS 1. Beighton score: >6 for pre-pubertal >5 for those under 50 >4 over 50 2. Exclusion of other dx (connective tissue, autoimmune, unusual skin fragility 3. 5 other features such as soft/velvet skin, straie, herniations, dental crowding/high palate, arm span to height >1.05, MVP, aortic root dilation, etc + family hx + chronic pain and dislocated joints

Answer 112

Normal blood pressure with high serum bicarbonate rules out renal tubular acidosis. Conn syndrome presents with high aldosterone level and low renin levels. Increased sodium and low potassium levels are seen with increased aldosterone levels. If the patient is hypertensive and plasma renin levels are high, renin secreting tumors including Wilm should be ruled out by imaging. In Bartter syndrome, hyperplasia of juxtaglomerular apparatus leads to high renin levels and secondary hyperaldosteronism. It is secondary to chronic volume depletion caused by autosomal recessive defect that interferes with salt reabsorption in the loop of Henle. Polyuria and weakness are associated with chronic hypokalemia.

Answer 113

Familial chilblain lupus (FCL) is a rare form of cutaneous lupus erythematosus. Familial chilblain lupus (FCL) is mostly due to TREX1 mutations. Familial chilblain lupus (FCL) has an autosomal dominant inheritance. The TREX1 gene consists of a single exon and it is located on chromosome 3.

Answer 114

Methionine (met to met) at the non-mutated allele at codon 129 is linked to a more aggressive form of fatal familial insomnia with a shorter duration of disease. Valine at the non-mutated allele is seen in patients with familial Creutzfeldt-Jakob Disease (fCJD). Genetic prion diseases exhibit varying degrees of clinical phenotypes based on genetics. Fatal familial insomnia is invariantly linked to a mutation at the codon 178 of the PRNP gene.

Answer 115

Retinoblastoma is the most commonly encountered primary intraocular malignancy of childhood and accounts for 3% of cases of all childhood cancers. It is also the second most prevalent intraocular malignant tumor after uveal melanoma. The most common presentation is an asymmetric red reflex. Patients with heritable disease are at considerable risk of nonocular cancers such as pineoblastoma, osteosarcoma, soft tissue sarcomas, and melanomas. Retinoblastoma is highly associated with osteosarcoma specifically. External beam radiotherapy increases the risk of a second malignancy five times.

Answer 116

A Turcot syndrome type 1: Biallelic loss (homozygous mutation) of MMR gene or hMLH1 gene causing glioblastoma multiforme Turcot syndrome type 2: homozygous mutation of the APC gene causing medulloblastoma and BENIGN polyps FAP: Heterozygous mutation of the APC gene

Answer 117

A diagnosis of factor V deficiency is supported by a prolonged partial thromboplastin time, prothrombin time, and a normal platelet count. This is not consistent with hemophilia A or B, as the PT is prolonged. Factor V deficiency is inherited in an autosomal recessive pattern; therefore, males and females are equally affected. This is unlike hemophilia A and B, which are X-linked recessive and present in males. The maternal history of easy bruising and menorrhagia suggests the patient has the disease. The familial inheritance is further supported by the grandfather experiencing frequent epistaxis. The boyfriend is asymptomatic without any family history of bleeding disorders and therefore not a carrier.

Answer 118

CLCN1 gene AD or AR

Answer 119

The patient has von Hippel Lindau disease characterized by hemangioblastomas, renal cell carcinoma, and pheochromocytoma. It has an autosomal dominant inheritance and is caused by a mutation in the VHL gene. The VHL gene normally inhibits the hypoxia-inducible factor 1a. Cancer cells release hypoxia-inducible factors (HIF1 alpha and HIF2 alpha) that exert several physiological effects mediating their survival. HIF1a upregulates glycolytic enzymes, and at lower concentrations of MYC, inhibits MYC-associated cell proliferation. It promotes angiogenesis of surrounding vascular tissue through increased vascular endothelial growth factor (VEGF) expression. It also activates lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase (PDK1), preventing the conversion of pyruvate to acetyl-CoA. HIF2a has been shown to induce epithelial-mesenchymal transition (EMT) in normal cells as well as cancer cells. It stabilizes the MAX/MYC complex overcoming HIF1a's MYC-inhibiting effect at high MYC concentrations and under hypoxic conditions.

Answer 120

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder that involves a mutation of the proteolipid protein gene 1 (PLP1) located on the long arm of the X-chromosome. It is a progressive type of leukodystrophy that can manifest with varying degrees of severity according to the type of PLP1 mutation. The most severe type presents as early as 1 to 2 weeks postnatal as nystagmus and significant hypotonia. Respiratory complications, mainly stridor, as in this infant, are very common and characteristic of PMD, given the association with neurologic symptoms. MRI reveals significant demyelination in various areas of the brain, including the brain and cerebellum. Myelination of the cerebellum usually occurs at the age of 3 months. Hence, the persistence of demyelination at this age points towards PMD.

Answer 121

Metachromatic leukodystrophy usually does not present with nystagmus and occurs due to mutation of the arylsulfatase-A gene three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD; age of onset in a family is similar Weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria Spasticity, pain, seizures, and compromised vision and hearing

Answer 122

mutation of the cell adhesion molecule gene (L1CAM); also known as hereditary spastic paraplegia (HSP) Causes lower extremity spasticity and /or weakness, can look like CP Lower-extremity hyperreflexia and extensor plantar responses Often, mildly impaired vibration sensation in the distal lower extremities

Answer 123

The absence or reduction of LAMP2 protein leads to disruption of intracytoplasmic trafficking. The disruption in intracytoplasmic trafficking leads to accumulation of autophagic material and glycogen in cardiac muscle and skeletal muscle cells. This may cause SOB/pain on exertion, cardiac arrhythmias, and other muscle pain. The cytoplasmic tail of the LAMP-2A isoform serves as a receptor for the uptake of proteins which are required for lysosomal degradation. This process is known as autophagy. The role of each specific LAMP-2 isoform is unclear, although it is noted that LAMP-2A is ubiquitously expressed while LAMP-2B is present in a higher proportion in cardiac tissue, skeletal muscle, and the brain.

Answer 124

Retinoblastoma Li Fraumeni syndrome Rothmund-Thomson syndrome Bloom syndrome Werner syndrome

Answer 125

DNA is negatively charged, while histones are positively charged because of high lysine and arginine content. DNA becoming more positive while the histones becoming more negative causes the charge differences to become least different. At the location of oncogenes, this would result in greater expression and cause an increased risk of developing a tumor.

Answer 126

CDKN1B gene mutation has been termed as MEN4. It accounts for 1% to 2% of MEN1 like syndrome without MEN1 mutation. It includes hyperparathyroidism, adrenal masses, pituitary adenoma, functional adenoma, carcinoid tumor, and Zollinger-Ellison syndrome with duodenal and pancreatic masses.

Answer 127

Subaarchnoid hemorrhage This patient presents with bilateral flank pain and masses, hypertension, microscopic hematuria, deranged renal function test, and a family history of sudden death. This is suggestive of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutation of the PKD1 or PKD2 genes that encode for polycystin. This leads to cystic structural degeneration of the kidney and impaired vascular integrity. Renal complications include renal cyst rupture, hypertension, nephrogenic diabetes insipidus, nephrolithiasis, and chronic kidney disease. Berry aneurysm of the cerebral arteries is seen in up to 20% of patients with autosomal dominant polycystic kidney disease (ADPKD). Extrarenal complications include intracranial berry aneurysms (which can lead to subarachnoid hemorrhage and sudden death), hepatic cysts, and colonic diverticula. Other vascular associations with ADPKD include aortic root dilatation, bicuspid aortic valves, aortic regurgitation, mitral regurgitation, aortic coarctation, and abdominal aortic aneurysm. These associations are significantly less common with ADPKD than berry aneurysms. Cerebral berry aneurysms are of the greatest concern due to the risk of rupture and hemorrhage. Berry aneurysms also are associated with Ehlers-Danlos syndrome, neurofibromatosis I, Marfan syndrome, aortic coarctation, and renal artery fibromuscular dysplasia. Renal cell carcinoma can cause paraneoplastic symptoms such as Cushing syndrome (due to ACTH production) or hypercalcemia (due to PTHrp production). It presents with unilateral (not bilateral) flank mass and appears as a single solid/partially cystic mass in ultrasound. Neuroblastoma can present with an abdominal mass in a child about 2 years of age and cause epidural invasion leading to spinal cord compression.

Answer 128

Classic Vohwinkel syndrome is inherited in an autosomal dominant (AD) fashion. It is associated with “starfish” keratoses on the knuckles, a palmoplantar keratoderma (PPK) in a “honeycomb” pattern, hearing impairment, and mutilating digital constriction bands (pseudoainhum) that often lead to autoamputation of the affected digit(s).

Answer 129

There can be steatorrhea but most symptoms are secondary to poor absorption of vitamins. RBCs show acanthocytosis or spiking while there is degeneration of the spinocerebellar attract and posterior column. Retinitis pigmentosa. The genetic defect is of the microsomal triglyceride transfer protein. AR inherited, MTTP gene, which codes for microsomal triglyceride protein (MTP) that mediates intracellular chylomicron or VLDL assembly and transport in the intestinal mucosa and hepatocytes. Marked by low or absent levels of plasma cholesterol, low-density lipoproteins (LDLs), and very low-density lipoproteins (VLDLs)

Answer 130

Nail-patella syndrome (NPS) is a rare, autosomal dominant genetic disorder with high penetration caused by mutations of the LMX1B gene. A single frontal view of the pelvis shows bilateral symmetric posterior exostosis of the iliac bones, known as iliac horns. The LMX1B gene is a transcription factor protein Renal abnormalities may include asymptomatic proteinuria or age-accelerated renal failure, which is a significant contributor to those with NPS. Abnormalities of the nails and patellae are two of the more common features

Answer 131

Hepatocellular carcinoma caused by the deficiency of enzyme fumarylacetoacetate hydrolase (FAH). This results in the accumulation of fumarylacetoacetate (FAA), a metabolite with a short half-life. FAA is then quickly degraded to succinyl acetoacetate (SAA) and succinylacetone (SA). State newborn screening test for HT1 relies on detecting SA levels in the blood. Clinically patients with HT1 present with signs and symptoms of liver failure and renal Fanconi syndrome. Other features described are failure to thrive, hypertrophic cardiomyopathy, peripheral neuropathy, and respiratory failure. There is also an increased risk of hepatocellular carcinoma in these patients, attributed to elevated FAA levels. Early treatment with nitisinone has been shown to reduce the risk of liver malignancy in these patients. Patients who fail to respond to nitisinone will need liver transplantation. Patients diagnosed with HT1 need serial monitoring with serum alpha-fetoprotein and liver imaging to screen for hepatocellular carcinoma.

Answer 132

Type-4 Waardenburg syndrome is the association of Waardenburg syndrome with congenital aganglionic megacolon (Hirschsprung disease) because of the involvement of neural crest cell abnormalities. Type 4 Waardenburg syndrome is also called Shah Waardenburg syndrome, and is due to the mutation in the endothelin-B receptor gene. It has an autosomal recessive mode of inheritance. Hirschsprung disease affects one neonate per 5000 births.

Answer 133

Wide-spaced eyes and a broad nasal bridge. Pale eyes, heterochromia, white forelock, leukodermia (white patches of skin), and early graying

Answer 134

Moderate to severe hearing loss. Pale eyes, heterochromia, white forelock, leukodermia (white patches of skin), and early graying

Answer 135

Klein-Waardenburg syndrome: Hearing loss, skin pigmentation changes and bone growth abnormalities of your hands and arms. Pale eyes, heterochromia, white forelock, leukodermia (white patches of skin), and early graying

Answer 136

Patients with neurofibromatosis type 1 have increased risk of plexiform neurofibromas. Ten percent of plexiform neurofibromas become malignant. They also have an increased incidence of leukemia, brain tumors, and neurofibrosarcomas. Plexiform neurofibromas feel like a "bag of worms."

Answer 137

A mutation causes all forms of autosomal recessive polycystic kidney disease (ARPKD) in the PKHD1 gene on chromosome 6p12. In ARPKD, there is a cystic dilatation of the collecting duct. It can manifest in utero, resulting in decreased urine production, oligohydramnios, pulmonary hypoplasia, and multiple facial and limb abnormalities. It generally has a poor prognosis. Neonatal mortality is reported at 30% and is usually due to pulmonary issues from underdeveloped lungs. Later in life renal failure develops. Other presentation types apart from perinatal, the most common, are neonatal and infantile types which have minimal to moderate hepatic/periportal fibrosis. The juvenile type has gross hepatic fibrosis and features of portal hypertension like hepatosplenomegaly and portosystemic varices with less severe renal disease.

Answer 138

The patient presents with signs and symptoms of chronic myeloid leukemia (CML). These patients usually present with malaise, fatigue, night sweat, abdominal discomfort, and early satiety secondary to splenomegaly. Patients can experience weight loss due to that, as seen in this patient. The diagnosis is confirmed by demonstrating the Philadelphia chromosome, BCR-ABL1 fusion gene (9;22). T(15;17) chromosomal translocation is found in patients with acute promyelocytic leukemia, not CML. Smudge cells on peripheral smear are suggestive of chronic lymphocytic leukemia. Demonstration of toxic granulation in the neutrophils and high leukocyte alkaline phosphatase (LAP score) is consistent with leukemoid reaction. Leukemoid reaction is defined by the elevation of a leukocyte count of 50,000 or more from reasons other than leukemia. Infections are the most common underlying cause. The peripheral smear typically shows toxic granulation and a high LAP score.

Answer 139

This patient presents with a banded pattern of hair shafts characteristic of pili annulati (PA). Hair also typically has a characteristic dry and speckled appearance, and patients may present with co-existing alopecia areata. Transmission electron microscopy of affected hairs shows a normal medulla with clusters of intermittent air-filled cavities within the cortex of the hair shafts. Inheritance of PA is via an autosomal dominant pattern with variable expressivity. The locus responsible for PA was mapped on the end of the telomeric region of chromosome 12q (24.32–24.33), but the gene responsible for the disease is not yet completely identified.

Answer 140

When there is suspicion for Angelman syndrome (AS), the workup should start with methylation studies. Normally, the SNRPN exon 1 region/promoter is differentially methylated; the paternal allele is unmethylated, and the maternal allele is methylated. AS is typically caused by a de novo mutation, rather than inheritance, on the maternal gene UBE3A. If methylation studies are positive, consider deletion, uniparental disomy, or imprinting defect. If the patient has a negative methylation study, but the suspicion for AS is high, DNA sequencing can be done. It rules out any mutation in UBE3A, which can be missed in methylation studies. Fluorescence in situ hybridization is also done after methylation studies. It detects any deletions in the maternal chromosome 15. The karyotype will be normal for this patient if no concomitant chromosomal abnormalities are present.

Answer 141

Biotinidase deficiency is an autosomal recessive disorder due to a missense mutation at 3p25. It is directly proportional to consanguinity. Profound cases of biotinidase deficiency occur in early infancy and present as a neurocutaneous disorder. Neurological symptoms include seizures, developmental delay, hypotonia, vision, hearing loss, and spastic paresis. Cutaneous manifestations include alopecia, rash, fungal infections, and seborrheic dermatitis. Screening is done at birth in some countries, and a 5 mg to 20 mg daily dose of biotin is started as a treatment to prevent complications.

Answer 142

The patient most likely hypohidrotic ectodermal dysplasia. Ectodermal dysplasias are single-gene disorders with a variable mode of inheritance. Mutations in the processes of cell signaling involved in the induction and development of ectodermal structures as well as there interactions with mesodermal structures are central to the clinical manifestations of ectodermal dysplasias. X-linked hypohidrotic ED presents with a constellation of hair and tooth anomalies along with an inability to sweat. The affected neonates present with collodion like membrane along with prominent scaling. The scalp hair is sparse or absent with light-brown pigmentation. Affected infants clinically present with pyrexia of unknown origin and hyperthermia as early as the first few hours of life. Periorbital wrinkling, sebaceous hyperplasia of the face, saddle nose, fully everted lips, and prominent frontal bossing characterize the facial appearance. Cutaneous manifestations in the form of erythroderma, seborrheic dermatitis, and intertrigo are common. Nails remain unaffected in hypohidrotic ED. The most common mode of inheritance of hypohidrotic ED is X-linked recessive, even though AR and AD have been observed in very rare cases.

Answer 143

A subset of HOX genes expression in a linear fashion on Mullerian duct correlates with the differentiation of Mullerian duct into oviducts, uterus, cervix, and vagina in a female embryo. WNT7A gene activates the expression of Hoxa10 and Hoxa11 genes in females that are responsible for Mullerian duct development. In males, the same gene activates the expression of the Anti-Mullerian hormone receptor in Mullerian duct in males responsible for the regression of the Mullerian duct in males. HOXA 13 mutation is found in Hand foot and genital syndrome, which is characterized by digit anomalies as well as female genital tract anomalies such as the bicornuate uterus. Sex hormones have also been known to play a role in HOX gene expression as seen in T shaped uterine anomalies with exposure to diethylstilbestrol.

Answer 144

Trimethoprim-sulfamethoxazole and itraconazole

Answer 145

The phenotype described in the question matches I-cell disease. Children with I-cell disease often die within the first decade of life. I-cell disease is an autosomal recessive mucolipidosis characterized by abnormal protein targeting. The necessary proteins and enzymes are inappropriately shuttled out of the cell rather than to the appropriate organelle. Some clinical abnormalities of I-cell disease include low birth weights, bone abnormalities, gum hypertrophy, and developmental delay. Common causes of death include respiratory infections/distress and heart failure. Accumulating glycogen in the lysosome is a feature of glycogen storage disease type II (Pompe disease). The dynein arm in cilia is defective in Kartagener syndrome. Cystic fibrosis is an autosomal recessive disease characterized by a defect in the CFTR gene, which codes for an ATP-gated chloride channel.

Answer 146

C Neonates affected by harlequin ichthyosis require NICU admission and supportive treatment. The complications that are commonly seen in the neonatal period include fulminant sepsis, respiratory failure, ectropion, eclabium, transepidermal water loss (TEWL), electrolyte imbalances, contractures, constricting skin bands leading to limb and or digital ischemic necrosis. These neonates require a multidisciplinary team approach which includes dermatology, neonatology, plastic surgery, genetics, ophthalmology, otolaryngology, physical therapy, occupational therapy, nutritionist, and social work. ICU management is mainly supportive. The most common cause of death is fulminant sepsis from the complications preceding the compromise of the protective skin barrier followed by acute respiratory failure due to the large plaques on the anterior chest wall inhibiting proper chest wall expansion. Patients may require airway protection. Infants that become hemodynamically unstable require management with IV antibiotics and proper fluid resuscitation.

Answer 147

Young syndrome is characterized by recurrent and persistent sino-pulmonary infections, azoospermia, and bronchiectasis. Patients with Young syndrome are infertile, as the semen does not mix with the seminal fluid due to obstruction. Ruling out cystic fibrosis points the diagnosis towards Young syndrome. Mutations in the CFTR gene are present in up to four-fifth of men with CBAVD, and a significantly lower percentage of 20% of men with congenital unilateral absence of the vas deferens (CUAVD). Moreover, up to 21% of men with idiopathic epididymal obstruction have positive genetic testing for CFTR. Abdominal imaging should be requested in men who presented with vasal agenesis irrespective of the CFTR status. Cystic fibrosis shares many similar signs and symptoms characteristics of Young syndrome. The patients with non-obstructive azoospermia (NOA) have small volume testes, a higher level of FSH, along normal semen volume. NOA will typically relate to the impaired sperm production. On the contrary, a normal testicular length of above 4.6 cm, FSH level of lower than 7.6, and/or semen volume of lower than 0.5 or 1.0 mL are most likely present in the obstructive azoospermia (OA). The mentioned laboratory tests are highly predicted in the OA, especially when the physical examination is significant for enlarged proximal epididymis or the absence of vasa deferentia. Bronchiectasis is a critical component of Young syndrome. Hypospadias is not a common finding in patients with OA, while it might be a component of hypospadias, cryptorchidism, and testosterone deficiency spectrum, as one of the several conditions attributed to male infertility. Men with severe oligospermia (lower than 5 M/mL), including patients with NOA, should be evaluated with karyotype testing and Y microdeletion evaluations. The most prevalent abnormal karyotypic pattern is Klinefelter syndrome, which refers to the presence of an extra X chromosome.

Answer 148

Familial melanoma is associated with a point mutation in the CDKN2A locus at 9p21.

Answer 149

XXY and +21

Answer 150

Hypothalamus This patient likely has Prader-Willi syndrome (PWS). PWS is a rare and complex genetic disease, with numerous implications of the metabolic, endocrine, neurologic systems, with behavior and intellectual difficulties. Many patients with PWS manifest short stature due to growth hormone deficiency. These individuals also present with hypothalamic dysfunction, leading to several endocrinopathies such as hypogonadism, hypothyroidism, central adrenal insufficiency, with reduced bone mineral density.

Answer 151

MEN I: pituitary adenoma, parathyroid hyperplasia, pancreatic neuroendocrine tumor (PNET). Women may be at higher risk for breast cancer. MEN1 gene, 11q13. MEN IIA: chromaffin cell-derived pheochromocytoma and C-cell derived medullary thyroid carcinoma and parathyroid hyperplasia or adenoma. Mutations of the RET protooncogene, a transmembrane receptor of the tyrosine kinase family, are responsible for MEN-2 syndromes. The germline RET mutations (AD, 10q11.2) in MEN2 result in a gain of function of the tyrosine kinase receptor. Hirschsprung disease (congenital megacolon) and a variety of neural crest tumors (e.g., glioma) are also seen in patients with MEN-2A. MEN IIB: mucosal neuromas, Marfanoid habitus, medullary thyroid carcinoma, and pheochromocytoma

Answer 152

The patient in the vignette has hereditary tyrosinemia type I (HT1), which is diagnosed by elevated succinylacetone (SA) levels in blood or urine. Newborn screening can detect elevated SA levels in patients with HT1. Gene FAH on chromosome 15. The disease can manifest in the neonatal period with signs of liver dysfunction and renal Fanconi syndrome. Untreated patients can progress to acute or chronic liver failure, hepatocellular carcinoma, and hypophosphatemic rickets. Prognosis is improved by early diagnosis and treatment. Patients started on a tyrosine-restricted diet and nitisinone within 28 days of life have the most favorable outcome. Corneal ulceration and skin hyperkeratosis are seen in hereditary tyrosinemia type ii, which can be detected on newborn screening with elevated blood tyrosine levels.

Answer 153

"Cherry red spots" are seen in GM1 gangliosidoses, Farber disease, Tay-Sachs disease, Sandhoff disease, Niemann-Pick type A, and in a few other neurodegenerative conditions.

Answer 154

Dent disease is a rare, X-linked recessive hereditary disorder that primarily affects the proximal renal tubules resulting in hypercalciuria and proteinuria starting in childhood. It may progress from there, leading to osteomalacia, short stature, nephrocalcinosis, nephrolithiasis, hypophosphatemia and eventually renal failure. Up to 80% of affected males will develop end-stage renal failure by age 50. There are various clinical manifestations of Dent disease, but all the cases of Dent disease reported until now have a constant feature of low molecular weight proteinuria. Treatment is based on controlling hypercalciuria and preserving renal function. While this can be done with thiazide diuretics, the hypercalciuria almost always responds to dietary therapy.

Answer 155

The patient has Tangier disease, which occurs due to the accumulation of cholesterol eaters in many organs within the body, particularly the reticuloendothelial systems. These organs will appear yellow-orange in color and larger in size. The high-density lipoprotein (HDL) life cycle starts inside the cell when very small discoidal pre-beta-1, HDL picks up free cholesterol from cells with the help of ABCA transporter, defect in this stage will result in Tangier disease. Patients with this disease will have a cholesterol deposition manifestation in multiple tissues like in tonsils, which are considered the most characteristic feature. Cholesterol depositions will appear yellow or orange, hugely enlarged in children and young adults; usually, the first observed presentation. The diagnosis of Tangier disease requires a high index of suspicion. Besides clinical findings which could appear earlier in the first decades or wait until the second or third decades. Blood values remain the mainstay diagnostic tools to make a diagnosis. The patients regularly present with low HDL (less than 5 mg/dl ), a low Apo-a1 level below 5, besides low total plasma cholesterol (less than 150mg/dl).

Answer 156

The patient in the clinical scenario presents with alkaptonuria, for which there is no effective treatment. Therefore, management remains palliative. Additionally, the main focus of the treatment is to reduce the deposition of homogentisic acid (HGA). Ascorbic acid, also known as vitamin C is recommended in patients with alkaptonuria because it reduces the conversion of homogentisic acid to benzoquinone acetic acid by oxidation. Treatment with ascorbic acid does not affect the urinary excretion of homogentisic acid. Knee and hip surgery are quite common in these patients at a young age.

Answer 157

Canavan disease is an autosomal recessive disorder mostly seen in Ashkenazi Jews. There is a deficiency of aspartoacylase that leads to accumulation in the brain of N-acetylaspartic acid and spongiform leukodystrophy. Symptoms start in early infancy with loss of motor skills, intellectual disability, megalocephaly, and abnormal muscle tone. There can be seizures, blindness, and paralysis.

Answer 158

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease that presents with eczema, thrombocytopenia, and immune deficiency. It sometimes is called an eczema-thrombocytopenia-immunodeficiency syndrome. WAS-related X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similarly, but less severe symptoms are caused by mutations in the identical gene. Eczema and bacterial infections develop by three months. Enlargement of the spleen is a common finding. The majority of WAS children develop at least one autoimmune disorder, and lymphoma and leukemia develop in up to a third of patients. Immunoglobulin M levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to low blood platelet counts, 30% of afflicted individuals develop eosinophilia. The management of Wiskott-Aldrich syndrome mainly depends on conventional and supportive care, which includes broad-spectrum antibiotics for bacterial infections, antivirals/antifungals for viral and fungal infections, respectively. Patients also require platelet transfusions to prevent bleeding. Topical steroids are used to treat eczema. Skin immunologic testing may reveal hyposensitivity. Not all patients have a family history; new mutations do occur. Often, leukemia is suspected based on infections and low platelets, and a bone marrow biopsy may confirm the diagnosis. Decreased levels of Wiskott-Aldrich syndrome protein and/or a causative mutation provide the most definitive diagnosis.

Answer 159

The diagnostic criteria for small-duct primary sclerosing cholangitis (PSC) included biochemical features of chronic cholestasis with unknown etiology, normal cholangiogram, and liver histology compatible with PSC.HLA-DRB1*13:01 alleles in small duct PSC did not show a correlation with IBD status. HLA-DRB1*13:01 and B*08 alleles were significantly associated with small duct PSC. The similarity in its HLA association between small duct PSC with inflammatory bowel disease (IBD) and large duct PSC may confirm that small duct PSC is in early stages or mild variants of large duct disease. Despite large duct PSC, HLA-DRB1*13:01 alleles in small duct PSC did not show a correlation with IBD status. It may indicate that small duct PSC is a different entity.

Answer 160

Hyperkalemic periodic paralysis is diagnosed by genetic testing for a mutation in the SCN4A gene. Hyperkalemic periodic paralysis is inherited in an autosomal dominant pattern. Elevated serum potassium levels often accompany acute attacks. Exercise, potassium-rich foods, and fasting may trigger acute attacks.

Answer 161

Low platelet count in a child due to deficient megakaryocytes in the bone marrow is called congenital amegakaryocytic thrombocytopenia. The main pathophysiology of this disease is a genetic defect in the thrombopoietin receptor on the megakaryocytes (called the MPL receptor). The main treatment for congenital amegakaryocytic thrombocytopenia is hematopoietic stem cell transplant. Another treatment is experimental gene therapy targeting the MPL receptor itself. The other mentioned genes are not involved in congenital amegakaryocytic thrombocytopenia. MYH7 gene is the acronym for myosin heavy chain 7 in muscles. MLPH is the acronym for melanophilin involved in melanin synthesis in melanocytes. BRAF gene is a proto-oncogene involved in several malignancies and their treatment.

Answer 162

This is a classic presentation of Lowe syndrome, resulting from a mutation in the OCRL gene. This syndrome impacts multiple organ systems and can result in bilateral cataracts, bilateral glaucoma, nervous system dysfunction, and renal disease. The mutated gene, OCRL, is located on chromosome Xq25-26. It encodes an inositol 5-phosphatase enzyme. Since this is a disease with X-linked recessive inheritance, genetic counseling is essential for parents that have children with Lowe syndrome. Females may be asymptomatic carriers of the mutated OCRL gene, which can impact future offspring. Fanconi anemia has been associated with FANCC gene mutation. Nance-Horan syndrome is caused by mutations of the NHS gene, also located on the X chromosome. CYP1B1 gene mutations have been associated with early-onset glaucoma.

Answer 163

This patient likely has Adams-Oliver syndrome (AOS). AOS is an extremely rare developmental disorder characterized by the presence of aplasia cutis congenita of the scalp vertex, terminal limb-reduction defects, central nervous system anomalies, congenital heart defects, and vascular anomalies such as cutis marmorata telangiectatica congenita. AOS is caused by mutations in six genes (EOGT, DOCK6, ARHGAP31, RBP, NOTCH1, and DLL4). It can be transmitted in an autosomal dominant or autosomal recessive fashion. Genotype-phenotype correlations have been described in patients with AOS.

Answer 164

The child has Pfeiffer syndrome (PS), which is most commonly caused by mutations in the FGFR2 gene (on chromosome 10q26.13). Mutations in the FGFR1 gene on chromosome 8p11.23 cause a small percentage of cases of type I PS only. PS type II and type III are associated with mutations in FGFR2. PS type I is associated with mutations in FGFR1 and FGFR2.

Answer 165

Congenital pseudoarthrosis (CPT) of the tibia is a rare congenital anomaly occurring 1 in 190,000 live births characterized by deossification, bending, pathological fracture, and inability to form a normal callus at the fracture site. It is one of the rare causes of limb shortening. 50% of cases of pseudoarthrosis are associated with NF1, and 6% of patients with NF-1 develop CPT. Other rare causes of CPT are intrauterine trauma, birth fracture, generalized metabolic disorder, vascular malformation, and hereditary. Fibula is affected in one-third of patients. CPT is a complicated condition with failure of normal bone formation and subsequent angulation leading to fracture. The characteristic feature of this condition is the formation of dense cellular fibrous tissue with few vessels without normal callus formation. All other three conditions are not associated with NF1 and can be excluded by characteristic X-ray finding of bony discontinuity with tapering ends of tibia and fibula in CPT.

Answer 166

Patients with Klinefelter syndrome are at higher risk for breast cancer, extragonadal germ cell tumor, and non-Hodgkin lymphoma. Despite the increased risks of certain cancers, the overall frequency is still quite low and routine screening is not recommended. In patients with Klinefelter syndrome, breast cancer most commonly occurs in adulthood, extragonadal germ cell tumors peak in adolescence and present as precocious puberty in boys less than 10 years old, and as cough, dyspnea, or chest pain in adolescents or adults, given the most common location is in the mediastinum. Childhood leukemias are still the most common malignancies in children with Klinefelter syndrome, though they are not more likely than children without Klinefelter syndrome.

Answer 167

Pseudohypoparathyroidism results from end-organ resistance to the actions of the parathyroid hormone (PTH). In pseudohypoparathyroidism, PTH levels will be appropriately increased in response to low calcium levels in the blood, but the body does not recognize the effects of PTH, resulting in high phosphate levels and low calcium levels. Pseudohypoparathyroidism is a result of abnormal genetics with three different main variants. Type Ia, also known as Albright hereditary osteodystrophy, is inherited in an autosomal dominant manner and characterized by short stature, round face, and short bones of the hands. Type Ib shows resistance to PTH only in the kidneys and does not have the same presentation as type Ia. Type II also shows high blood phosphate levels and hypocalcemia but does not have the same physical phenotype as the other 1a, and its inheritance pattern is unknown. The problem in the kidney’s response to PTH is the basis of pseudohypoparathyroidism. The resistance to PTH appears to take place in the proximal tubule, leaving the actions of PTH in the thick ascending tubule unaffected. Treatment for pseudohypoparathyroidism is the administration of oral calcium and vitamin D.

Answer 168

The most common mutations found in essential thrombocytosis are in the JAK2, CALR, and MPL genes. The presence of these gene mutations helps in the diagnosis of essential thrombocytosis. The complications of essential thrombocytosis include thrombosis and hemorrhage. Thrombosis complications include stroke, deep venous thrombosis, and transient ischemic injury.

Answer 169

This patient has congenital protein C deficiency. Protein C deficiency can range in symptom severity from asymptomatic to recurrent thromboses leading to post-thrombotic syndrome. In addition to VTE and pulmonary embolism (PE), these patients may develop sequelae including ischemic arterial stroke and pregnancy-associated thrombosis. Protein C deficiency is an autosomal dominant disease. Mutations in a single copy in heterozygous individuals cause mild protein C deficiency, whereas individuals with homozygous mutations present with severe protein C deficiency.

Answer 170

Parathyroid hormone resistance (pseudohypoparathyroidism) is characterized by hypocalcemia, hyperphosphatemia, and a high PTH level. The most common cause of pseudohypoparathyroidism is a mutation of the G alpha subunit of the parathyroid hormone receptor. Patients with pseudohypoparathyroidism are treated the same as those with PTH deficiency with calcium and calcitriol. Patients with pseudohypoparathyroidism often have an unusual phenotype characterized by short stature, round face, and shortened fourth metacarpal bones termed Albright osteodystrophy.

Answer 171

Congenital amegakaryocytic thrombocytopenia is a rare condition characterized by severely low platelets in neonates and young children due to a genetic mutation of the thrombopoietin receptor (MPL) on the megakaryocytes, causing almost absent megakaryocytes in the bone marrow. It should be suspected in patients with thrombocytopenia after excluding all common causes and failing treatment for immune thrombocytopenic purpura (ITP). Thrombopoietin is produced at a constant rate by the liver and removed from circulation by MPL receptor-mediated uptake and destruction. Impaired expression of MPL in congenital amegakaryocytic thrombocytopenia leads to decreased receptor-mediated thrombopoietin destruction. Therefore, circulating levels of thrombopoietin increase to as much as 10-fold above normal controls. The clinical picture of congenital amegakaryocytic thrombocytopenia includes bleeding and bruising. Some studies have noted neurological defects like psychomotor disabilities, strabismus, cerebellar agenesis, hypoplasia of the corpus callosum and brainstem, facial malformations, and cortical dysplasia. Pancytopenia usually follows in at least 90% of patients. Congenital amegakaryocytic thrombocytopenia, a genetic platelet production defect, is not associated with hepatosplenomegaly. One should look for hepatosplenomegaly to help rule out other causes of thrombocytopenia, such as indolent leukemia, infiltrative storage diseases, and splenic sequestration.

Answer 172

This patient presents with intellectual disability, long ears, a narrow face, and an arched palate, suggesting a diagnosis of fragile X syndrome (FXS). Fragile X syndrome, also called Martin-Bell syndrome, is a non-Mendelian trinucleotide repeat disorder. Physical features include a long and narrow face with a prominent jaw, flexible fingers, large ears, and enlarged testicles in males. About a third of these children have features of autism and delayed speech that is present from an early age. Hyperactivity and seizures are common. ADHD is present in approximately 80% of patients. In patients with fragile X Syndrome, antidepressants may treat comorbid anxiety, obsessive-compulsive behaviors, and mood disorders, and antipsychotics are an option if self-injurious or aggressive behaviors are present. Anticonvulsants help to control seizures.

Answer 173

The clinical features of this 10-year-old child with microtia, esotropia, facial asymmetry, and a limbal mass suggest the diagnosis of Goldenhar syndrome or OAVS (oculo-auriculo-vertebral spectrum). Commonly described clinical features of OAVS include epibulbar and lipo-dermoid, auricular abnormalities like microtia (minimum diagnostic criterion), hemifacial microsomia, preauricular tags, appendages and fistula, and vertebral anomalies. Ocular features include limbal dermoid, lipodermoid, eyelid coloboma, strabismus like Duane retraction syndrome, ptosis, and microphthalmia. OAVS is most commonly sporadic, with family history reported in only 2 to 12% of cases. The most common chromosomal abnormality observed is 5p15.33-pter deletion. Others include deletion of the 12p13.33 region, involving the WNT5B gene, and microduplications on 14q23.1. SALL-1 gene is involved in Townes–Brocks syndrome, characterized by dysplastic ears (overfolded superior helices and preauricular tags), hearing impairment, thumb malformations, renal impairment, anal anomalies. The SIX-5 gene mutation is found in branchio-oto-renal spectrum disorders. These patients have malformations of the outer, middle, and inner ear, hearing impairment, branchial fistulae and cysts, renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis, branchial fistulae, and cysts. The phenotypic spectrum associated with mutations in EFTUD2 presents with acrofacial dysostosis, thumb anomalies, intellectual disability, zygomatic anomalies, microcephaly, and esophageal atresia.

Answer 174

This clinical vignette is describing Beckwith-Wiedemann Syndrome (BWS). It is estimated that about 80% of patients with BWS have a known molecular defect at 11p15. The most common mechanism of disease (found in ~50% of patients) is due to loss of methylation at DMR2 (IC2) on the maternal chromosome. This causes derepression of KCNQ1OT1 and downregulation of CDKN1C on the maternal allele. Additional common mechanisms of disease are paternal isodisomy at 11p15 and a gain of methylation at DMR1 (IC1) on the maternal chromosome Loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals Paternal uniparental disomy for chromosome 11p15 in 20% Gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Methylation alterations associated with deletions or duplications in this region have high heritability.

Answer 175

Recommended screening for BWS patients due to loss of methylation at DMR2 (IC2) on the maternal chromosome: -Full abdominal ultrasound every 3 months until 4 yrs of age -Renal-bladder ultrasound every 3 months from 4-7 yrs - AFP screening every 3 months until 4 yrs.

Answer 176

The most common mechanism of Russell-Silver Syndrome is loss of methylation at the paternal IC1 (H19/IGF2) on chromosome 11p15 (same area on chromosome as BWS but maternally inherited). The disorder is characterized by prenatal onset of growth delay, as well as postnatal growth failure and short stature.

Answer 177

Bloom syndrome

Answer 178

Hypophospotasia

Answer 179

This patient most likely has Friedreich ataxia, an autosomal recessive disease. This is due to a GAA trinucleotide repeat on chromosome 9. Patients often present with kyphoscoliosis, pes cavus, hypertrophic cardiomyopathy, and diabetes mellitus. Dysarthria, muscle weakness, spasticity, particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Friedreich ataxia affects the lateral corticospinal tracts, dorsal columns, and spinocerebellar tracts. Hypertrophic cardiomyopathy is the most common cause of death in patients with Friedreich ataxia. There is considerable evidence to suggest that Friedreich ataxia is the result of the accumulation of iron in mitochondria leading to excess production of free radicals, which results in cellular damage and death. There is no treatment to alter the natural course of the disease.

Answer 180

The most likely cause is transfusion-associated acute lung injury (TRALI) as a consequence of allogeneic blood transfusion. The patient usually presents with fever, shortness of breath, and hypotension within 6 hours of transfusion. TRALI occurs due to donor-specific anti-HLA antibodies directed against HLA antigens on recipient pulmonary interstitial cells or leukocytes. TRALI work-up should include HLA typing. Both HLA class I and class II antigens have been attributed in the majority of cases of TRALI.

Answer 181

NOTCH3 is the causative mutation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL causes early-onset cardiovascular disease including ischemic strokes. There is no disease-modifying therapy for CADASIL. Treatment is focused on cardiovascular risk reduction.

Answer 182

NOTCH1 gene have been found to cause Adams-Oliver syndrome, a condition characterized by areas of missing skin (aplasia cutis congenita), usually on the scalp, and malformations of the hands and feet. (remember patient with bicuspid aorta and aortic aneurysm VUS)

Answer 183

NOTCH2 gene mutations can cause of Alagille syndrome, a condition that can affect the liver, heart, and other parts of the body. NOTCH2 gene have been associated with Hajdu-Cheney syndrome, a rare disorder that can affect many parts of the body, particularly the bones. Affected individuals have acro-osteolysis, which is a loss of bone tissue that affects the hands and feet most severely. Most people with this condition also have osteoporosis, which causes the bones to be brittle and prone to fracture; distinctive facial features; spinal abnormalities; and short stature. Additionally, Hajdu-Cheney syndrome can affect the joints, teeth, heart, kidneys, and other parts of the body. Lymphomas, gain of function

Answer 184

A Radial dysplasia is characterized by a congenital radial deviation of the hand and wrist, as well as a shortened or absent radius. Fanconi anemia is a condition known to be associated with radial dysplasia. It may be diagnosed with a complete blood count (CBC), peripheral blood smear, and chromosomal breakage studies. Fanconi anemia is a potentially lethal condition if not recognized early. When it is recognized before bone marrow failure, then a life-saving bone marrow transplant may be performed. Fanconi anemia is inherited in an autosomal recessive pattern.

Answer 185

Patients with Turcot Syndrome can rarely present with an astrocytoma. Given her age, unknown family history and biopsy result, it would be prudent for her to undergo a colonoscopy to rule out Turcot. Diagnosing Turcot syndrome is helpful because making correlations between brain tumors and colorectal cancer can help guide preventative action for either condition. It also provides anticipatory guidance–to know and expect brain vs. colon cancer in patients that exhibit either clinical presentation; early diagnosis leads to early treatment. Turcot syndrome (TS) is the association of primary brain tumors to colorectal cancer. Another correct answer that may have been appropriate for her could have been to check for evidence of APC or MMR gene mutations.

Answer 186

Complex karyotype with greater than five abnormalities predicts poor prognosis independent of TP53 or IgVH status. In cases of 3 to 4 chromosomal abnormalities, the prognosis depends on TP53 mutational status. A low platelet count does mean the patient has advanced disease. However, cytogenetics has more importance as compared to thrombocytopenia. Also, thrombocytopenia could be immune-mediated. In that case, it does not have any impact on the prognosis. TP53 gene is frequently mutated in patients with a complex karyotype. However, this patient did not have a mutation in the TP53 gene. Immunoglobulin heavy chain gene status would have relevance if the patient had normal cytogenetics and an unmutated TP53 gene.

Answer 187

incontinentia pigmenti (IP), which is caused by a mutation in IKBKG, which encodes for NF-kB essential modulator (NEMO). 80% are usually resultant in a gene deletion NEMO is involved in activating NF-kB, a transcription factor that protects against TNF-alpha-induced apoptosis. Gene is located on the X chromosome, making the mutation lethal in XY males. IP typically presents at birth or soon after birth with linear, inflammatory, vesiculobullous papules and plaques in a Blaschkoid distribution that then with time progresses through various stages of skin lesions, including vesicular, verrucous, hyperpigmented, atrophic, or hypopigmented stages. Other ectodermal abnormalities are expected, including alopecia of the vertex of the scalp, nail dystrophy, and dental abnormalities. CNS and eye abnormalities can also be noted.

Answer 188

Type I. Mildest and most common type. About 50% of all affected children have this type. There are few fractures and deformities Type II. Most severe type. A baby has very short arms and legs, a small chest, and soft skull. He or she may be born with fractured bones. He or she may also have a low birth weight and lungs that are not well developed. A baby with type II OI usually dies within weeks of birth Type III. Most severe type in babies who don’t die as newborns. At birth, a baby may have slightly shorter arms and legs than normal and arm, leg, and rib fractures. A baby may also have a larger than normal head, a triangle-shaped face, a deformed chest and spine, and breathing and swallowing problems. These symptoms are different in each baby. Type IV. Symptoms are between mild and severe. A baby with type IV may be diagnosed at birth. He or she may not have any fractures until crawling or walking. The bones of the arms and legs may not be straight. He or she may not grow normally. Type V. Similar to type IV. Symptoms may be medium to severe. It is common to have enlarged thickened areas (hypertrophic calluses) in the areas where large bones are fractured Type VI. Very rare. Symptoms are medium. Similar to type IV. Type VII. May be like type IV or type II. It is common to have shorter than normal height. Also common to have shorter than normal upper arm and thighbones. Type VIII. Similar to types II and III. Very soft bones and severe growth problems.

Answer 189

The familial form of infantile cortical hyperostosis (ICH) is associated with a COL1A1 point gene mutation. The mutation is located on chromosome 17q21. This missense mutation results in an arginine to cysteine substitution in the triple helix of the alpha-1 chain of type 1 collagen. Proposed mechanisms between this mutation and the ICH findings include the inability of chromosome interactions with proteins, defective cross-linking, and decreased thermal stability of collagen.

Answer 190

The type of point mutation in SCD is called a missense mutation in which a single nucleotide substitution results in changed amino acid. In SCD specifically, an A to T mutation (GTG>GAG) at the sixth codon of the beta-globin gene occurs, leading to the production of a defective form of Hb.

Answer 191

Pentalogy of Cantrell is a collection of five congenital anomalies that present a distinctive challenge for physicians and surgeons. Those five defects are of the heart, pericardium, diaphragm, sternum, and abdominal wall. A ventral septal defect is commonly associated with the pentalogy of Cantrell. It presents as a pansystolic murmur on cardiac auscultation of the left lower sternal area. Echocardiography can reveal the size, location, and severity of the defect. History can vary dramatically from patient to patient. Patients with partial defects may have an incomplete expression of the disorder. Patent ductus arteriosus presents as a continuous machine like a murmur best heard at the upper left sternal border and in the interscapular region. An atrial septal defect is less commonly associated with the pentalogy of Cantrell and presents as a fixed split in second heart sound (S2).

Answer 192

Alport syndrome can present with haematuria and hearing loss. Importantly, hearing is usually normal at birth. They have underlying glomerulonephritis and end-stage kidney failure. It is generally inherited in an X-linked fashion. The gene involved is COL4A5.

Answer 193

Usher syndrome involves a hearing loss with retinitis pigmentosa.

Answer 194

Spinal muscular atrophy is an autosomal recessive disease that involves the anterior horn cells in the spinal cord and motor nuclei of the brainstem. There are 4 main types of SMA (SMA 1, SMA 2, SMA 3, and SMA 4) which are based on the age at which the disease presents (from pre/perinatal to adulthood) and the maximum motor function achieved. Clinical features include symmetric proximal muscle weakness and atrophy, tongue fasciculations, and decreased to absent reflexes. These patients are also at increased risk of aspirations and failure to thrive. The weakness usually progresses to respiratory insufficiency and eventually death. A multidisciplinary approach is adopted in the management of these patients. The involvement of pulmonologists, gastroenterologists, and orthopedics is crucial. There are numerous ongoing trials for pharmacological and gene-based therapies that aim at increasing the expression of the SMN gene.

Answer 195

Jervell and Lange-Nielsen syndrome is a rare type of long QT syndrome associated with severe sensorineural hearing loss.

Answer 196

About two-thirds of patients with aniridia follow an autosomal dominant pattern. Sporadic cases account for one-third of patients. A rare autosomal recessive variant (Gillespie syndrome) is associated with aniridia, cerebellar ataxia, and intellectual disability. The implicated gene abnormality is 11p13. Sporadic aniridia may be associated with WAGR syndrome (Wilm tumor, aniridia, genitourinary anomalies, and mental retardation). In sporadic congenital aniridia, the Wilm tumor must be ruled out by ultrasonography of the abdomen.

Answer 197

Together, the different forms of Charcot-Marie-Tooth diseases (CMTs) are the most common among the inherited neuromuscular disorders, with an estimated frequency of 1 in 2500 people. Most of the patients have an onset within the first two decades of life. CMT is slightly more prevalent in men than in women. The majority of CMTs are benign and have an insidious onset and slow progression. However, the clinical features and the course vary depending on the underlying genetic variation.

Answer 198

Alport syndrome is a genetic condition characterized by kidney disease, loss of hearing, and eye abnormalities. It occurs due to an abnormality of a gene that codes for type 4 collagen and usually presents in patients with hematuria, edema, and hypertension. In 80% of cases, Alport syndrome is inherited in an X-linked pattern and caused by COL4A5 gene mutations, although other inheritance patterns exist. It can be inherited as an autosomal recessive or dominant pattern by mutations in COL4A3 or COL4A4 gene. Type 4 collagen involves the basement membrane of the kidney and commonly affecting the cochlea and eye. Females can be affected despite the X linked inheritance with onset of ESRD and failure in 60s. Most patients require dialysis and/or renal transplantation.

Answer 199

The patient is having an absent septum pellucidum, which is evidenced by the ultrasound finding of squared frontal horns that are pointing inferiorly. The associated features seen in magnetic resonance imaging (MRI) include the vertically oriented Sylvian fissures, dorsal cyst in the dorsocaudal aspect of the diencephalon, and hypoplasia of corpus callosum suggesting a final diagnosis of syntelencephaly (a middle interhemispheric variant of holoprosencephaly). The gene most likely to be mutated in syntelencephaly is the ZIC2 gene. ZIC2 gene is located on chromosome 13q32. Patients need reassurance that cavum septum pellucidum is a normal anatomical variation and requires no surgical intervention and is unlikely to progress. Only if the size is >1 cm or if symptomatic, enlarged CSP requires further evaluation and management.

Answer 200

Phacomatosis pigmentokeratotica is characterized by a nevus sebaceous in combination with a papular nevus spilus. In infancy and early childhood, the nevus spilus component of this syndrome may be characterized by a light brown patch that does not develop the papules until several years later. Phacomatosis pigmentokeratotica is most frequently associated with a post-zygotic RAS mutation. Neurologic deficits are usually observed in this syndrome. Interestingly, a propensity to develop hypophosphatemic rickets is observed with greater frequency in this condition in comparison to schimmelpenning syndrome. Phacomatosis pigmentokeratotica is associated with the development of neurologic, skeletal, and endocrinologic findings.

Answer 201

Ocular features of pseudoxanthoma elasticum include angioid streaks, peau d' orange appearance of the fundus, optic nerve head drusen or hyaline bodies, and macular pattern dystrophy. Angioid streaks are breaks in the degenerated and mineralized Bruch membrane. Angioid streaks typically form around the optic disc and radiate from the optic disc. The Bruch membrane in such cases with pseudoxanthoma elasticum (PXE) is calcified and fragile. This causes the rupture of the Bruch membrane or choroidal rupture after trauma leading to subretinal hemorrhage. Such subretinal hemorrhages usually do not show evidence of choroidal new vessels and usually resolve spontaneously. An acute posterior vitreous detachment can cause vitreous hemorrhage, which is very frequently associated with retinal breaks.

Answer 202

Stevens-Johnson syndrome/toxic epidermal necrolysis due to antiepileptic drugs, including carbamazepine, phenytoin, and lamotrigine, is reported to be significantly more common in Asian patients than in Europeans. The HLA-B*1502 allele in Han Chinese and other ethnicities has been associated with a markedly increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis from carbamazepine. Other HLA alleles that are known to be associated with a greater likelihood of severe cutaneous adverse reactions to drugs include HLA-B*5801 (allopurinol) and HLA-A*3101 in Europeans (carbamazepine). Cytochrome P450 genetic polymorphisms (not haplotypes) are known to result in variations in plasma levels of various drugs, including carbamazepine.

Answer 203

Patients with Wilson disease are very sensitive to increases in total body copper levels. Wilson disease is an autosomal recessive disorder caused by a mutation in the ATP7B gene on chromosome 13, leading to impaired copper excretion into bile, leading to excess copper accumulation within hepatocytes and subsequently extrahepatic copper deposition. The copper IUD is routinely used as an emergency contraception method. Removal of sources of excess copper and subsequent chelation with a first-line agent such as penicillamine should be pursued.

Answer 204

Crouzon syndrome is characterized by facial deformations at or near birth. The physical findings include a wide face secondary to the obliteration of the coronal and sagittal sutures. Findings include hypertelorism, wide and high forehead, malocclusion, short stature, and the absence of physiologic spinal curvature. Acanthosis nigricans of the axillary fossa is seen in those with FGFR3 mutations.

Answer 205

Familial Mediterranean fever is most common in Armenians, Arabs, Turks, and Sephardic Jews. It is characterized by fever, serositis, monoarthritis, and sometimes rashes on the lower extremity. Patients can develop amyloidosis late in the course of the illness. Colchicine can decrease the frequency and severity of attacks.

Answer 206

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease. Prognosis and symptoms are worse in smokers, so people with this syndrome are encouraged not to smoke. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, and spontaneous pneumothorax. BHDS patients may present with spontaneous pneumothorax. There is always a lower lung predominance for pulmonary cysts since there is more lung tissue in the lower lung. A ruptured cyst can cause a pneumothorax.

Answer 207

Hereditary hemorrhagic telangiectasia increases the risk for pulmonary arteriovenous malformations by 20% to 30%. A venous thrombus can embolize and pass through a pulmonary arteriovenous malformation and lodge in the intracranial vessels. Transthoracic echocardiogram with agitated saline or contrast can be used to evaluate for intracardiac shunts or pulmonary arteriovenous malformations. A positive test for pulmonary arteriovenous thromboembolism using contrast echocardiography is defined as the visualization of bubbles in the systemic circulation at least 3 cardiac cycles after first seeing them in the right atrium. The purpose of waiting for more than 3 cardiac cycles, as 3 cycles or less means possible patent foramen ovale.

Answer 208

Glanzmann thrombasthenia is an inherited bleeding disorder caused by a quantitative or qualitative deficiency of alpha IIb beta3 integrin, the platelet fibrinogen receptor. Glanzmann thrombasthenia patients who have received platelet transfusions may develop antibodies, such as antiplatelet, anti-HLA, and/or anti-alpha IIb beta3 integrin. Patients who develop these antibodies may have an inadequate response to future platelet transfusion, leading to continued bleeding. These patients are considered to be platelet refractory. Recombinant activated factor VII is approved in the U.S. for patients with Glanzmann thrombasthenia and platelet refractoriness. Recombinant activated factor VII is generally effective for the perioperative management of patients with Glanzmann thrombasthenia and may be as or more effective as platelet transfusion in some patients.

Answer 209

BRAF mutations were detected in almost half of examined iris melanomas. Uveal melanomas in more than 80% carry activating mutations in either GNAQ or GNA11 genes. BAP1 mutations strongly correlate with metastatic behavior of uveal melanoma. KIT mutation is seen in conjunctival melanomas.

Answer 210

Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly. A mutation in the FLVCR2 gene in chromosome 14q24.3 occurs in the cases. Fowler syndrome presents with hydranencephaly-hydrocephalus. Involves ischemic lesions of the brain, brain stem, and spinal cord. Fowler syndrome is usually diagnosed by ultrasound between 26 and 33 weeks of gestation. Rarely, patients may survive, but they have severely impaired neurologic development. Other conditions associated with hydranencephaly are trisomy 13, aplastic renal dysplasia, polyhydramnios, arthrogryposis, and poly-valvular heart disease.

Answer 211

In FOP, heterotopic ossification occurs in various skeletal muscle groups. Certain skeletal muscle groups are not involved, including the diaphragm, extra-ocular muscles, and tongue.

Answer 212

Sturge-Weber syndrome (encephalotrigeminal angiomatosis) is a phakomatosis characterized by facial port-wine stains and pial angiomas. Common manifestations are seizures, developmental delay, and ophthalmic manifestations such as glaucoma and choroidal hemangioma. Diffuse choroidal hemangioma is seen in about 20% of patients with this condition. An ophthalmic examination is required to rule out glaucoma. Glaucoma is almost always ipsilateral to the facial port-wine stain. Sturge-Weber syndrome is a sporadic developmental disorder caused by somatic mosaic mutations in the GNAQ gene which is located on the long arm of chromosome 9. Patients with this condition may present with cerebral symptoms without facial findings. Management includes seizure control and medical and surgical management of glaucoma if present.

Answer 213

Nevus of Ota commonly affects face and eyes usually unilaterally, although rarely bilateral involvement can be seen. Nevus of Ota is characterized by patchy brown, slate-blue, or with grey-black pigmentation while deeper lesions appearing blue. Involvement of eyes may affect sclera, conjunctiva, cornea, iris, or choroid. Distribution of nevus of Ota is along the ophthalmic and maxillary divisions of the trigeminal nerve.

Answer 214

Type 1 is characterized by dystopia canthorum, narrow nose, short philtrum, and short retropositional maxilla. SOX3 mutation. Type 2 Waardenburg syndrome have normally located canthi and sensorineural deafness. Different colored iris are diagnostic for type 2. Type 3 Waardenburg syndrome (Klein-Waardenburg syndrome) has similar features to type 1 but is characterized by musculoskeletal abnormalities like aplasia of first and second ribs, and small carpal bones not differentiated fully. The underlying genetic mutation is most often SOX3 (the same gene most commonly affected in type I Waardenburg also). In the sacrum, there is cyst formation and abnormalities of the arms, hypoplasia of muscles, and syndactyly. Some cases of type 3 present with all features of disease plus mental retardation, microcephaly, and severe skeletal abnormalities. This is most frequently associated with a PAX3 mutation. Type 4 Waardenburg syndrome (Shah-Waardenburg syndrome) has similar features to type 2 Waardenburg syndrome but is associated with Hirschsprung disease, and can be seen with a variety of genetic mutations. One of the most common is SOX10, leading to Waardenburg syndrome type 4C.

Answer 215

Follicular adenomas are one subset of benign neoplasms that can occur in the thyroid gland or ectopic thyroid tissue. They typically present as a solitary thyroid nodule or in association with nodular hyperplasia or thyroiditis. Follicular adenomas exhibit rearrangement of the PAX8-PPAR gamma 1. PAX8 helps follicular cell differentiation by encoding a nuclear protein product necessary for the transcription of thyroid-specific factors. Genetic rearrangement of the PAX8-PPAR gamma 1 gene causes loss of follicular growth inhibition, thus facilitating the development of follicular neoplasms. PAX8-PPAR gamma 1 has a high predictive value for differentiated thyroid cancer.

Answer 216

Rett syndrome is a degenerative disorder that affects females, caused by a mutation in the MECP2 gene found on the X chromosome. Rett syndrome is characterized by a sporadic inheritance pattern and is associated with a significantly decreased life expectancy. Rett syndrome is fatal in males and will lead to mortality either during gestation or shortly after birth. Symptoms of Rett syndrome include apraxia (hand-wringing), speech and motor development regression, eye contact avoidance, calmness, and gastrointestinal symptoms. Symptoms typically begin between one and four years of age.

Answer 217

Holt-Oram syndrome also referred to as the heart-hand syndrome, is an autosomal dominant disorder that is distinguished by upper limb abnormalities in association with congenital heart lesions. A heterozygous mutation in the TBX5 gene on chromosome 12q24.1 causes Holt-Oram syndrome. This gene is responsible for encoding a transcription factor, T-box5, which regulates the expression of other genes in the development of the heart and limbs. Specifically, the gene is an important factor in cardiac septation and the development of bones in the arm and hand. More than 85% percent of individuals diagnosed with Holt-Oram syndrome carry the mutated TBX5 gene. Both physical features and family history can help establish the diagnosis of Holt-Oram syndrome. Specifically, a family history of congenital heart malformations should warrant further investigation with an electrocardiogram and echocardiogram. In addition, upper limb x-rays can demonstrate various abnormalities. Finally, genetic testing looking for TBX5 mutations should be a consideration. The treatment of Holt-Oram syndrome is individualized and based on specific symptoms. In some cases, many providers are involved, including pediatricians, cardiologists, surgeons, and orthopedists. Patients undergoing any surgical procedure, including tooth extraction, should be given prophylactic antibiotics for bacterial endocarditis.

Answer 218

AR - PKHD1 AD - PKD1 (85%)/PKD2 (15%)

Answer 219

The patient gives a classical history of childhood hyperphagia with features of metabolic syndrome signifying childhood-onset obesity. The most commonly mutated gene for obesity is MC4R. GWAS has established that the rs17782313 near MC4R is strongly associated with obesity. rs17782313 T allele mutation can cause promoter hypermethylation and decreased expression of MC4R. MeQTL and eQTL analysis can be applied to explore the effect of rs17782313 MC4R expression and its link to childhood or pediatric obesity. LEPR and PPARG are other common genes associated with obesity.

Answer 220

Proto-oncogene RET

Answer 221

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder that presents in infancy. The usual presentation includes skeletal abnormalities, neutropenia, bone marrow dysfunction, and exocrine pancreatic insufficiency. Fibrosing colonopathy is a condition in which there is a narrowing of the lumen of a long segment of the colon. This occurs due to submucosal widening secondary to the deposition of mature collagen. It most commonly is seen in children with cystic fibrosis, as they require long-term, high-dose pancreatic enzyme replacement. It may present with symptoms, signs, and imaging very similar to Crohn disease. As bone marrow dysfunction is a feature of SDS, febrile neutropenia frequently is associated with the condition. Patients present with fever associated with other signs of infection. The recommendation for children above 4 years of age is a maximum of 10,000 units/kg/day if lipase orally or less than 4,000 lipase units per gram of dietary fat per day. Chronic high-dose pancreatic enzyme replacement has been shown to cause colonic strictures and fibrosing colonopathy.

Answer 222

A child with multiple cafe-au-lait macules (CALMs), short stature, and a murmur consistent with pulmonic stenosis likely has Watson syndrome. Other characteristics of Watson syndrome include mild intellectual disability, macrocephaly, Lisch nodules, and neurofibromas. Watson syndrome should be included in the differential diagnosis when evaluating a patient for neurofibromatosis type 1. Watson syndrome is an autosomal dominant disorder. It is one of several syndromes characterized as a RASopathy, with germline mutations in genes related to the Ras/mitogen-activated protein kinase pathway.

Answer 223

Manitoba oculotrichoanal syndrome inherits autosomal recessively with mutation of the FREM1 gene. Manitoba oculotrichoanal syndrome presents with eyelid coloboma or cryptophthalmos, ipsilateral aberrant anterior hairline pattern, and anal anomalies.

Answer 224

A nonenhancing, infiltrating, calcified frontal lobe mass in an adult is favored to represent a glial neoplasm, and more specifically, an oligodendroglioma. Oligodendroglioma is characterized by a 1p/19q codeletion, with this being a primary diagnostic and prognostic factor in differentiating it from the other glial neoplasms in the latest World Health Organization (WHO) 2016 guidelines. Oligodendroglioma is one of the subsets of glial neoplasms that demonstrate a mutated IDH, but other glial neoplasms, such as astrocytoma, also carry this mutation. Histology is not a reliable method to differentiate glial neoplasms, an oligodendroglioma can be positive or negative for GFAP, a primarily astrocytic cell marker, and can be negative for myelin basic protein, found in normally functioning oligodendrocytes.

Answer 225

Treacher Collins - TCOF1 Stickler - normocephaly, hearing, marfanoid habitus (COL2A1), slipped epiphysis or Legg-Perthes-like disease Emanual syndrome - microcephaly, severe ID, FTT, ear anomalies 22q11.2 del Cornelia de Lange 56% associated with syndromes

Answer 226

tombstone T waves/inverted T wave/ coved T wave SCN5A, sodium channel most common, AD Can have calcium and potassium channelopathies ICD = treatment

Answer 227

Cardio-facio-cutaneous syndrome - BRAF, KRAS; ALL Costello - HRAS; bladder, neuroblastomas, rhabdomyosarcoma Noonan - myeloproliferative disorders and leukemias

Answer 228

TBX5 85% de novo, AD malformation of the carpal bones (thumb aplasia or hypoplasia) + CHD in 75%

Answer 229

PTPN11, loss of function (gain of function in Noonan) L = lentigines E = EKG changes O = ocular hypertelorism P = pulmonary stenosis A = abnormal genitalia R = retadation of growth D = sensorineural hearing deafness HCOM

Answer 230

Small pons Very small cerebellum

Answer 231

Abnormal fat pads Strabismus MRI: small pons and cerebellum (almost absent)

Answer 232

C X-linked ichthyosis is the second most common form of ichthyosis. Ichthyosis Vulgaris is the most common disorder of cornification in the ichthyosis family of diseases. The medical management of X-linked ichthyosis is directed at reducing scales, decreasing skin dryness, and improving skin appearance. This can be accomplished with regular bathing, and the use of emollients and keratolytic agents. Ocular findings are asymptomatic. Ophthalmology examination is generally unnecessary for affected males since the punctuate corneal opacities are asymptomatic with x-linked ichthyosis. The opacities are the most common eye finding (present in up to 50% of affected males and 25% of female carriers). X-linked ichthyosis has been reported to be associated with corneal opacities, a 20-fold increase in cryptorchidism, increased risk for testicular cancer and hypogonadism; also a higher prevalence of attention deficit hyperactivity disorder. The defect in X-linked ichthyosis is steroid sulfatase, which affects fatty aldehyde dehydrogenase. A falsely low unconjugated serum estriol (uE3) level will result in false-positives in second-trimester Down syndrome screening tests. Because of this, X-linked ichthyosis may be diagnosed prenatally as an unexpected finding in women undergoing elective genetic screening tests during the second trimester of pregnancy.

Answer 233

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders caused by different gene mutations that share the same histological findings. Therefore, the clinical manifestations are widely variable and gene-dependent. To date, many different gene mutations that cause ADTKD have been detected, such as uromodulin (UMOD), renin (REN), mucin-1 (MUC1), hepatocyte nuclear factor 1-beta (HNF1B), and SEC.61A1. ADTKD-UMOD was known historically as familial juvenile hyperuricemic nephropathy type 1 (FJHN1), uromodulin-associated kidney disease (UMOD-associated kidney disease), and medullary cystic kidney disease type 2 (MCKD2). The clinical manifestation is slowly progressive chronic renal failure, usually noticed in the teen years, and progresses to end-stage renal disease between the fourth and seventh decades of life. Other important clinical features are gout and hyperuricemia, resulting from inappropriately decreased fractional urate excretion that usually occurs as early as the teenage years. In ADTKD-UMOD, the diagnosis may be made based on the appropriate, relevant clinical scenario in addition to the knowledge that another family member has been identified with a UMOD mutation on genetic testing. However, uromodulin genetic analysis is readily available at commercial clinical laboratories. Regarding ADTKD-UMOD, allopurinol or febuxostat are the best treatment options for gout and hyperuricemia. To prevent further gout attacks and gouty tophi, patients should be encouraged to take one of these medications as soon as gout develops.

Answer 234

The CT skull in the patient shows multiple skull osteomas in the patient. Multiple osteomas may be a component of Gardner syndrome, which comprises skull osteomas, soft tissue tumors, and colonic polyps. There is a high predilection of familial adenomatous polyposis in these patients. A colonoscopy helps in the early screening and management of these polyps prior to the malignant transformation. The excision of the benign skull osteoma is only advocated for giant lesions or aesthetic purposes only.

Answer 235

he diagnostic criteria for small-duct primary sclerosing cholangitis (PSC) included biochemical features of chronic cholestasis with unknown etiology, normal cholangiogram, and liver histology compatible with PSC.HLA-DRB1*13:01 alleles in small duct PSC did not show a correlation with IBD status. HLA-DRB1*13:01 and B*08 alleles were significantly associated with small duct PSC. The similarity in its HLA association between small duct PSC with inflammatory bowel disease (IBD) and large duct PSC may confirm that small duct PSC is in early stages or mild variants of large duct disease. Despite large duct PSC, HLA-DRB1*13:01 alleles in small duct PSC did not show a correlation with IBD status. It may indicate that small duct PSC is a different entity.

Answer 236

SS genotype is not as likely to have COPD as ZZ. ZZ is more consistent with this early age of onset and the severity at this age. MM is the normal genotype. MZ is predisposed to COPD with occupational exposure, smoking, and biomass burning, but with minimal tobacco use and the age, ZZ would be more likely the answer.

Answer 237

ankyloblepharon-ectodermal defects (AEC)-cleft lip/palate syndrome, also known as Hay-Wells syndrome. Clinical features are evident from birth. A classic erythrodermic presentation with peeling skin and underlying erosions is common, resulting in potentially fatal infections due to acute skin failure. The scalp is invariably involved in the form of chronic oozing erosive dermatitis, patchy alopecia, and wiry hair. Congenital strands of tissue, also known as ankyloblepharon adnatum filiforme, are observed between the eyelids, which might require surgical correction or resolve spontaneously. Lacrimal duct atresia may occur. External ear malformation may be observed. Hypospadias is observed in 80% of male patients with AEC. Other features such as ectopic breast tissue, reticulated hyperpigmentation of intertriginous areas, and syndactyly are also observed, but they are not as common.

Answer 238

about 30-40% of children with pleuropulmonary blastoma (PPB), there are other childhood cancers or abnormalities in their immediate or extended family. DICER-1 gene mutation causes an increased risk for PPB and a variety of other conditions such as lung /kidney cysts or tumors, ovarian tumors in children or adults, thyroid nodules or cancers, brain tumors, and tumors in the eye or nose/sinuses.

Answer 239

Hereditary angioneurotic edema is usually caused by mutations in the SERPING1 gene, which reduces the amount of functional C1-INH protein. Type I hereditary angioneurotic edema is thought to be due to less C1-INH production, while type II hereditary angioneurotic edema is due to the non-functioning. Many patients with hereditary angioneurotic edema have five times the lower level of plasma C1-INH levels normal people.

Answer 240

The macular “cherry-red” spot is seen in Tay-Sachs (as in this case), Nieman-Pick disease, and central retinal artery occlusion. In lipid storage disorders, there is a buildup of the substrate in the retinal layers. As the macula and fovea are thin and devoid of these cellular layers, the relative transparency of the choroidal capillaries persists resulting in the “cherry-red” spot appearance. In Tay-Sachs disease, the accumulated substrate is GM2 ganglioside. While the presentation is very similar to Niemann-Pick, they can be discerned as Tay-Sachs presents with hyperreflexia and no hepatosplenomegaly, while Niemann-Pick presents with hyporeflexia and hepatosplenomegaly.

Answer 241

In such cases with discordant clinical and laboratory findings, when the clinical suspicion is high, PSAP gene C subunit mutations should be sought. PSAP gene codes for a protein called prosaposin. It is composed of four subunits, A, B, C, and D encoded by specific points on the PSAP gene. The subunits are called saposins and function as enzyme activators for sphingolipid metabolism. Saposin C is an activator for the enzyme glucocerebrosidase. A deficiency of saposin C will render the enzyme inactive in vivo. It leads to the accumulation of the sphingolipid glucocerebrosidase and causes Gaucher's disease. Invitro enzyme testing uses synthetic substrates that function without an activator and will show normal levels. There is no mutation in the GBA gene that encodes the enzyme. The activator is defective because of a mutation in the PSAP gene C subunit. PSAP B subunit mutations produce metachromatic leukodystrophy.

Answer 242

The Philadelphia chromosome is seen in 95% of patients with chronic myeloid leukemia (CML), which is detected by traditional karyotyping. Five percent of patients with CML are positive for cryptic BCR-ABL1 fusion gene, which is detected by fluorescence in situ hybridization or reverse transcriptase-polymerase chain reaction. The Philadelphia chromosome also is found in B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL).

Answer 243

Menkes disease, also known as ''kinky hair disease'', which is a rare X-linked neurodegenerative disorder of copper metabolism caused by a mutation in the ATP7A gene. The clinical features are due to a deficiency of copper-dependent enzymes. Neurodegeneration and connective tissue abnormalities are the two most important manifestations of this disease. Menkes disease patients typically start developing symptoms by 2 months of age. Hypopigmented skin and sparse, fine hair are typically due to tyrosinase deficiency. Developmental regression and seizures are usually the first symptoms starting around 2 to 3 months. Infection or a febrile state triggers the onset of seizures. Disease onset can also manifest in other ways, such as nonconvulsive seizures and recurrent episodes of apnea. Recurrent infections and pneumonia are reported to be the most common causes of morbidity and mortality in Menkes disease. It can be due to defective free radical clearance and diffuse pan lobular emphysema and cystic changes with abnormal pulmonary vascular development.

Answer 244

X-linked ichthyosis female cases are extremely rare and all of these patients are offspring of an affected father and a carrier mother. X-linked ichthyosis is equally reported in all ethnic groups and races worldwide. As the name of the disease suggests, X-linked ichthyosis almost exclusively affects males. The incidence of X-linked ichthyosis is reported as 1 out of 2500 to 1 out of 6000 males. Female carriers of the STS gene do not exhibit any manifestations because the gene is localized to a region of the X-chromosome that does not undergo X-inactivation.

Answer 245

The presence of hamartomas along with signs and symptoms and MRI findings consistent with Lhermitte–Duclos disease are suggestive of Cowden disease. In addition, the patient has macrocephaly, which is also one of the major criteria for the diagnosis of Cowden disease. Autosomally dominant inherited mutations in the tumor suppressor gene PTEN are responsible for Cowden disease. The protein encoded by the PTEN gene contributes to the control of apoptosis and the cell cycle. Specifically, the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is down-regulated by the PTEN gene product, resulting in decreased cellular proliferation and survival. When heterozygosity for the PTEN gene is lost by a "second hit" mutation, the resulting phenotype of multiple hamartomas and neoplasms is produced. Most commonly, patients experience macrocephaly along with mucocutaneous lesions such as oral papillomas, tricholemmomas, and acral keratoses.

Answer 246

1 has wasting of facial muscles and distal limb muscle weakness 2 has proximal muscle weakness Myotonia associated with both has failure of hands to relax

Answer 247

Triad: irritability, swelling, and bone lesions DDx: hypervitamin A, osteo, bone tumor, scurvy, battered baby syndrome

Answer 248

Ham test CD59 CD55

Answer 249

Dx with MCHC/MCV ratio as osmotic fragility is not specific in neonates MCHC is very high and MCV is very low Index of greater than 0.36

Answer 250

Bilateral egg yolk like lesions (usually sub retinal) Electrooculogram is abnormal and specific for the disease Mutation in CMD2 or BEST1 at 11q12-q13

Answer 251

Triad of redness, warmth, and burning pain affecting lower extremities SCNA9A If CBC showed thrombocytosis or polycythemia Vera, it is caused by JAK2

Answer 252

Burning sensations of hands and feet Small red and purple papules over lower abdomen and thighs Corneal opacities XLR but females can have symptoms due to lyonization

Answer 253

BRCAPro was developed to predict the likelihood of BRCA1/2 mutation and can be used in women with or without a personal history of breast cancer. The Chompret criterion is helpful in determining the likelihood of TP53 mutations. The Claus tables are designed to determine the risk of breast cancer in healthy women based on their family history of breast cancer. The Gail model is also for healthy women (over age 35) to predict risk of breast cancer. The NCCN guidelines suggest TP53 testing for any woman diagnosed with breast cancer under age 35 if BRCA1/2 is negative.

Answer 254

1/4 of males with hydrocephalus with aqueductal stenosis have the X linked form and karyotype can be normal. To calculate recurrence risk: 1/4 x 1/2 male x 1/2 chance of inheritance = 1/16 or ~6%

Answer 255

ex. Population frequency = 1:400 Allele frequency would be 1/20 Thus carrier frequency would be 1/10

Answer 256

21-Hydroxylase deficiency causes ~95% of cases of CAH. Aromatase deficiency causes inability to synthesize estrogen and affected females have ambiguous genetalia and primary amenorrhea 5-α-Reductase deficiency converts testosterone into the more potent dihydrotestosterone. Affected males can have pseudovaginal perineoscrotal hypospadias Androgen receptor deficiency causes androgen insensitivity and feminization of affected males.

Answer 257

an enlarged NL at the second standard deviation increases the relative risk for aneuplopidy but will be encountered most commonly in chromosomally normal pregnancies

Answer 258

ALL - hypodiploid variety have TP53 mutations. Almost 50% are germline are in nature and represent Li Fraumeni Syndrome.Distractors ETV6 is associated with hyperdiploid ALL and myeloid leukemia GATA2 is associated with various types of mutations causing myelodysplasia, acute or chronic leukemias RUNX1 is associated with predisposition to thrombocytopenia and AML PAX5 is associated with ALL and abnormalities of chromosome 9.

Answer 259

Normal karyotype is most common. Other higher risk HLH include Turner, Down syndrome, and Smith Lemli Opitz

Answer 260

Miscarriage Hemangiomas appears to be concentrated in transcervical CVS

Answer 261

caused by a gene inversion of Factor VIII

Answer 262

Mutations causing deficiency of G proteins occur in Albright osteodystrophy while activating mutations in the same gene cause McCune-Albright.

Answer 263

Smith-Lemli-Opitz, prenatalCholesterol is a precursor for the synthesis of steroid hormones and many fetuses affected with SLOS are associated with low maternal serum estriol.

Answer 264

The most common lesions in DNA caused by UV damage are pyrimidine dimers

Answer 265

Gyrate atrophy of the retina is caused by deficiency of ornithine aminotransferase (OAT). It is diagnosed by finding elevated ornithine on plasma amino acids.

Answer 266

Soft cystic masses in the auricle which develop into hypertrophic cartilage

Answer 267

Lysosomal storage disease 2/2 cathepsin K deficiency

Answer 268

female genitalia in XY karyotype short limbs

Genetics Board Stat Pearls Flashcards

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