Genodermatoses Flashcards

Question

25- A patient presents to your clinic for evaluation of "eczema." In addition to widespread ill- defined erythematous finely scaly patches, you notice coarse facies, cold subcutaneous fluctuant nodules, and retained primary teeth. Lab testing reveals an elevated IgE level and peripheral eosinophilia. Which of the following is most likely mutated in this patient? A. WASP B. SPINK5 C. AIRE D. LYST E. STAT3

Answer 1

E. STAT3 Explanation: The stem describes many findings characteristic of Hyper-IgE syndrome (Job syndrome). Two types of inheritance patterns exist: Autosomal dominant mutation in STAT3, and autosomal recessive mutation in DOCK8. WASP is mutated in Wiskott-Aldrich syndrome. SPINK5 is mutated in Netherton syndrome. AIRE is mutated in autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED). Lastly, LYST is mutated in Chediak-Higashi syndrome.

Answer 2

A. Odontogenic keratocysts Explanation: Nevoid basal cell syndrome (Gorlin syndrome) is an inherited condition with a defect in the PTCH gene. The dental findings are odontogenic keratocysts. Destructive periodontitis can occur in Langerhans cell histiocytosis and Papillon-Lefevre syndrome. Hypodontia can occur in X-linked hypohidrotic ectodermal dysplasia, Hypomelanosis of Ito, Incontientia pigmentosa, and Anhidrotic Ectodermal Dysplasia. Gingival fibromas can occur in Tuberous sclerosis. Retention of primary teeth can occur in Hyperimmunoglobulin E syndrome (Job syndrome).

Answer 3

A. Sjogren-Larsson syndrome Explanation: Sjogren-Larsson syndrome is an autosomal recessive disorder caused by mutations in the ALDH3A2 gene that encodes the enzyme fatty aldehyde dehydrogenase. This disorder is characterized by ichthyosis with pruritus, spastic diplegia or quadriplegia, mental retardation, epilepsy, glistening dot retinal pigmentation, and dental enamel dysplasia. The other listed syndromes do not include spastic diplegia.

Answer 4

B. It is an X-linked recessive disorder Explanation: Incontinentia Pigmenti is an X-linked dominant disorder (NOT X-linked recessive). Incontinentia Pigmenti is caused by a mutation in the NEMO gene. Females only present at birth with linear lesions of inflammation and blistering (stage 1), followed by hyperkeratotic verrucous areas (stage 2), hyperpigmentation (stage 3), and then atrophy and hypopigmentation (stage 4). Systemic findings include psychomotor retardation, microcephaly, seizures, cerebellar ataxia, coloboma, and retinal detachment.

Answer 5

E. First clinical sign is neurologic Explanation: First sign is ataxia. Telangiectasias occur later in puberty. Carriers show an increased risk of breast cancer. Telangiectasias occur later in puberty. Carriers show an increased risk of breast cancer. The condition is autosomal recessive.

Answer 6

E. They are commonly related to trauma and require no further work up Explanation: Angiokeratomas are dilated vesels in the dermis. They are related to injury and are benign. Options B and C refer to Fabry disease, which present with angiokeratoma corporis diffusum in a bathing suit distribution. There are 5 different types of angiokeratomas: solitary angiokeratoma as in this case; angiokeratoma of mibelli seen on dorsal fingers and toes in adolescence, angiokeratoma corporis diffusim which are predominantly seen on lower torso and thighs and is seen in Fabry's disease; angiokeratoma of fordyce on the scrotum or vulva, and angiokeratoma circumscriptum which develop on the lower limb and can be assocaited with Cobb syndrome and Klippel-Trenaunay-Weber Syndrome.

Answer 7

A. Plexiform variant Explanation: The plexiform variant is composed of neurofibroma with hypertrophied nerves in a plexiform pattern. This is pathognomonic of neurofibromatosis type I. Diffuse neurofibroma is a variant seen in a proportion of neurofibromatosis type I patients. It extends into the subcutaneous tissue with honey combing this variant has typical Wagner-Meissner bodies that resemble Meissner's corpuscles.

Answer 8

A. Dyskerin Explanation: The dyskerin gene, whose product is involved in ribosomal RNA synthesis, is mutated in X-linked recessive dyskeratosis congenita. TERC is linked with autosomal domininant transmission of the syndrome. CDKN2A is involved in familial dysplastic nevi/melanoma syndrome, PTEN in Cowden syndrome and Menin in MEN type I.

Answer 9

A. The number of melanocytes in the patient's skin is unchanged. Explanation: Oculocutaneous albinism is a rare, inheritied disorder in melanin synthesis. Therefore the number of melanocytes is normal and unchanged in these patients. This is an inheritied condition, not sporadic. Patients typically present with hypo or depigmentation from birth, not progressively throughout their lifetime. Subtypes OCA1a (absence of tyrosinase) and OCA1b (reduced tyrosinase) have mutations in tyrosinase. OCA2 has a mutation in the P gene and 1% of these cases also present with Prader-Willi or Angelman's syndromes. OCA3 results from a mutation in Tyrosinase-Related Protein 1 (TYRP1). OCA4 results from a mutation in Membrane-Associated Transport Protein (MATP).

Answer 10

C. Premature atherosclerosis Explanation: Werner syndrome or adult progeria is caused by autosomal recessive mutations in WRN (Recql2) gene, which encodes DNA helicase. This defect leads to defects in DNA repair and replication. Patients prematurely age and essentially experience many diseases of aging early in childhood and teen years. They exhibit tight atrophic skin, relatively large heads for body size, leg ulcers and cannities. Patients experience early, accelerated atherosclerosis leading to death by myocardial infarction. In addition, type II diabetes, cataracts, osteoarthritis, osteoporosis and hypogonadism are features. The alternative answers are not features of Werner syndrome regarding heart problems with the condition.

Answer 11

B. Tricho-rhino-phalangeal Syndrome Explanation: Tricho-rhino-phalangeal Syndrome is characterized by sparse hair, a pear-shaped broad nose and cone-shaped epiphyses.The other listed syndromes do not fit this clinical scenario.

Answer 12

E. p63 Explanation: The ectodermal-clefting syndromes are caused by a defect in the p63 gene. Specifically, AEC or Hay-Wells syndrome is comprised of ankyloblepharon filiforme adnatum (fusion of the eyelids), ectodermal dysplasia and clefting. The other listed gene mutations are not commonly associated with ankyloblepharon filiforme adnatum.

Answer 13

A. p63 Explanation: Patients with Hay-wells syndrome have mutations in P63. They have wiry, sparse hair, ankyloblepharon, PPK, partial anhidrosis, cleft lip/palate, and absent/dystrophic nails. TP73L mutation occurs in Rapp-Hodgkin Syndrome. DLX3 mutation occurs in Trichodentoosseous Syndrome. PORCN mutation occurs in Focal Dermal Hypoplasia (Goltz syndrome). Arylsulfatase mutation occurs in Chondrodysplasis Punctata and X-linked ichthyosis.

Answer 14

B. Hidrotic ectodermal dysplasia Explanation: Hidrotic ectodermal dysplasia (Clouston syndrome) is caused by mutations in connexin 30, which is a gap junction protein. Rothmund-Thompson syndrome is caused by a mutation in the RECQL4 gene, which encodes a helicase. Anhidrotic (hypohidrotic) ectodermal dysplasia can be caused by mutations in the EDA, EDAR, and EDARADD genes. Netherton syndrome is caused by mutations in the SPINK5 gene, encoding a serine proteinase inhibitor. Naxos syndrome is caused by a mutation in plakoglobin, which is component of desmosomes and adherens junctions structures.

Answer 15

E. Peutz-Jeghers Syndrome Explanation: Peutz-Jeghers Syndrome is an autosomal dominant syndrome. 50% of patients have mutations in the STK11 gene, which encodes a serine threonine kinase. It presents with periorificial and mucosal lentigines beginning in infancy, as well as hamartomatous intestinal polyps with intussusception and bleeding; there is an increased risk of gallbladder, pancreatic, breast, ovarian, and testicular cancers. Muir-Torre Syndrome results from mutations in MLH1, MSH2, or MSH6 (DNA mismatch repair genes). Bannayan-Riley-Ruvalcaba Syndrome occurs due to a mutation in PTEN. Birt-Hogg-Dubbe Syndrome results from a FLCN (folliculin) mutation. Lastly, Cronkhite-Canada Syndrome is rare, acquired, nonhereditary syndrome; no specific gene mutation has yet been found to cause this syndrome.

Answer 16

E. hyperpigmentation Explanation: Hyperpigmentation. POEMS syndrome, also known as Crow-Fukase syndrome, is an acronym for polyneuropathy, organomegaly, endocrinopathy (most common being hypogonadism), M-protein (IgG and IgA light chains), and skin changes. Of the cutaneous signs, hyperpigmentation is the most common, occurring in up to 90% of affected patients. The remaining cutaneous findings are findings in POEMS syndrome however are less frequent in occurrence.

Answer 17

A. Distal-less homeobox-3 gene (DLX3) Explanation: Distal-less homeobox-3 gene (DLX3) mutations cause trichodentoosseous syndrome, which is characterized by curly hair that straightens in the 2nd-3rd decades, enamel hypoplasia, dental pits, and increased bone density. Vascular-endothelial growth factor receptor 3 is mutated in Milroy disease. SLURP 1 is mutated in Mal de Maleda. SPINK 5 is mutated in Netherton syndrome

Answer 18

A. Turns Ras to its inactive form Explanation: Neurofibromin is a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. Thus neurofibromin acts as a tumor suppressor by reducing Ras activity. In NF1, decreased neurofibromin results in unrestricted Ras activity in the RAS/MAPK and leads to the tumor growth seen in this disease.The other answer choices do not accurately describe the function of neurofibromin.

Answer 19

B. Deafness Explanation: This patient likely has LEOPARD syndrome, an autosomal dominant disease caused by a gene mutation in PTPN11, which encodes Shp2 (tyrosine phosphatase). Other findings in LEOPARD syndrome include multiple lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retarded growth, and deafness. LEOPARD syndrome is allelic to Noonan syndrome.The remaining answer choices are not seen in LEOPARD syndrome.

Answer 20

C. Hay-Wells Syndrome Explanation: Hay-Wells Syndrome, also known as AEC (Ankyloblepharon-Ectodermal dysplasia- Clefting) is characterized by wiry, sparse hair or alopecia, ankyloblepharon, PPK, partial anhidrosis, cleft lip, palate, absent, and dystrophic nails.The other listed syndromes do not fit this clinical presentation.

Answer 21

Correct choice: C. C Explanation: This is xeroderma pigmentosum. XPC is the most common subtype in the US. In this subtype there are no neurologic symptoms. In XPA, which is the most common subtype in Japan, there are often severe neurologic symptoms. Xeroderma pigmentosum (XP) is a very rare skin disorder where a person is highly sensitive to sunlight, has premature skin aging and is prone to developing skin cancers. Xeroderma pigmentosum is caused by cellular hypersensitivity to ultraviolet (UV) radiation, as a result of a defect in the DNA repair system. Xeroderma pigmentosum has also been called DeSanctis-Cacchione syndrome. At least seven different gene abnormalities or complementation groups have been described in different families (XPA to XPG) resulting in varying disease severity. XPA and XPC are relatively common XPE is fairly rare XPG is severe XPF is mild.

Answer 22

Correct choice: E. All of the above are features of nevoid BCC syndrome Explanation: The 5 major diagnostic criteria for nevoid BCC syndrome include: 1. Development of >2 BCCs or 1 BCC before the age of 20 2. Odontogenic keratocysts of jaw 3. Palmar or plantar pits (3 or more) 4. Calcification of the falx cerebri 5. 1st degree relative with nevoid BCC syndrome .All the above features are major diagnostic criteria for nevoid BCC syndrome.

Answer 23

Correct choice: A. Transglutaminase 1 Explanation: This is lamellar ichthyosis which is in flexures and has thick scales on the palms and soles. It is most commonly due to a mutation in transglutaminase 1. BCIE is due to K1 and K10 mutation. Ichthyosis bullosa of Siemens is due to a keratin 2e mutation. Harlequin fetus is due to an ABCA12 mutation. Erythrokeratoderma variabilis is due to a GJB3 and GJB4 mutation. Autosomal recessive congenital ichthyosis Harlequin ichthyosis ABCA12 Lamellar ichthyosis TGM1 (transglutaminase 1 is an enzyme) and others Congenital ichthyosiform erythroderma ALOXE3 and others Autosomal recessive congenital ichthyosis-1(ARCI1):The baby is encased by collodion membrane at birth, which cracks and is then shed; 10% are self-healing Harlequin ichthyosis: severe collodion membrane, ectropion ( drooping lower eyelids), eclabium (out-turned lips) and contractures Lamellar ichthyosis: plate-like dark scaling over the whole body, including creases of arms and legs Bathing suit variant: localised to scalp and trunk (warmer sites of the body) Nonbullous congenital ichthyosiform erythroderma (NCIE): erythroderma and fine white, superficial, semiadherent scales Palmoplantar keratoderma varies with affected gene Biopsy reveals: Thick, hyperkeratotic stratum corneum, Reduced or absent granular cell layer and filaggrin in ichthyosis vulgaris, Lamellar body ‘ghosts’ in lamellar ichthyosis, Vacuolar degeneration of suprabasal keratinocytes and coarse keratohyalin granules in a thickened granular layer in keratinopathic ichthyosis.

Answer 24

Correct choice: E. Colon cancer Explanation: This pathologic image identifies a sebaceous adenoma (well circumscribed lobules of mature sebocytes). Sebaceous adenomas are frequently seen in Muir-Torre syndrome. Patients with Muir-Torre syndrome can present with gastrointestinal, genitourinary, breast cancers, and keratoacanthomas. Melanoma, thyroid cancer, lymphoma, and lung cancers are not the most common malignances seen in Muir Torre syndrome.

Answer 25

Correct choice: E. Natal teeth Explanation: This photo has a histologic image of steatocystoma – It is lined by a characteristic eosinophilic crenulated cuticle (shark tooth lining), sebum typically falls out during processing, and sebaceous glands attach to cyst wall on the outside. Steatocystoma multiplex can occur in Type II Pachyonychia congenita (Jackson-Lawler syndrome), which involves mutations in KRT17. It will have findings of natal teeth and less severe PPK than type I pachyonychia congenita. Trichodiscomas occur in Birt-Hogg-Dube syndrome which has fibrofolliculomas, trichodiscomas, achrochordons, lipomas, oral fibromas, renal cell carcinoma, medullary thyroid carcinoma, and colon cancer. Pilomatricomas occur in Gardner syndrome and Rubinstein-Taybi syndrome. Trichoepitheliomas occur in Rasmussen syndrome, Rombo syndrome, and Brooke-Spiegler syndrome. Hutchinson’s teeth are widely spaced, peg-shaped upper incisors that occur in congenital syphilis.

Answer 26

Correct choice: B. Urinary cytology Explanation: The question is describing a patient with Muir-Torre Syndrome (photo is depicting a keratoacanthoma). These patients have autosomal dominant mutations in MSH2, MLH1, MSH6 (DNA mismatch repair genes). Dermatologically, they are at risk for sebaceous adenomas, epitheliomas, and carcinomas;keratoacanthomas (esp. w/sebaceous differentiation). These patients are also at high risk for internal malignancies, including GI, genitourinary, and breast cancers. These patients need workup with upper and lower endoscopy, genitourinary surveillance, chest xray, CBC, and liver function tests. Kidney abnormalities are not a common feature of Muir Torre. Thyroid abnormalities are not a common feature of Muir Torre. PET Scan would be appropriate if initial screening shows suspicion for visceral malignancy. Brain abnormalities are not a typical feature of Muir Torre.

Answer 27

Correct choice: C. Lipoid proteinosis Explanation: This photo shows lichen sclerosis, which in 80% of cases has been associated with IgG1 autoantibodies against ECM-1. It presents with white, polygonal, and flat-topped papules or plaques surrounded by erythema. ECM-1 has also been found to be mutated in lipoid proteinosis. Piebaldism has been associated with mutations in the c-kit proto-oncogene. Cowden syndrome is associated with a PTEN mutation. Birt-Hogg-Dube syndrome is associated with a FLCN (folliculin) mutation. Familial cylindromatosis is associated with a CYLD mutation.

Answer 28

Correct choice: D. Schöpf-Schulz-Passarge Syndrome Explanation: This kodachrome depicts a hidrocystoma, which can occur in Schopf-Schulz-Passarge syndrome. It presents with a cyst lining composed of a double layer of cuboidal epithelial cells. It can occur with apocrine type decapitation secretion. Schopf-Schulz-Passarge syndrome is an autosomal recessive mutation of the WNT gene. It occurs with PPK, hidrocystoma, BCC, SCC, hypodontia, and eccrine tumors (eccrine syringofibradenoma). Cowden syndrome is an autosomal dominant mutation of the PTEN gene, which presents with trichilemmonas, oral papillomas, and sclerotic fibromas. Muir-Torre syndrome is an autosomal dominant mutation in the DNA mismatch repair genes, presenting with sebaceous adenomas, carcinomas, and keratoacanthomas. Birt-Hogg-Dube syndrome is an autosomal dominant syndrome presenting with fibrofolliculomas, trichodiscomas, lipomas, oral fibromas, and achrocordons. Lipoid proteinosis is an autosomal recessive mutation of the ECM1 gene, which presents with hyaline papules along the eyelid margins “string of pearls”.

Answer 29

Correct choice: B. Piebaldism Explanation: This photo depicts urticaria pigmentosa, which occurs due to a mutation in c-kit (CD117). This mutation has also been found in piebaldism.Cowden syndrome is associated with a PTEN mutation. Birt-Hogg-Dube syndrome is associated with a FLCN (folliculin) mutation. Familial cylindromatosis is associated with a CYLD mutation. Lipoid proteinosis is associated with an ECM-1 gene mutation.

Answer 30

► A Kaposiǁs varicelliform eruption is the condition in which viral infection occurs in a patient with a pre-existing chronic dermatitis. Darierǁs disease is an autosomal dominant genodermatosis caused by a mutation in ATP2A2 which encodes SERCA2. Cutaneous manifestations of warty, hyperkeratotic papules in a seborrheic dermatitis, which may be infected with HSV or bacteria.

Answer 31

► D Patients with Hyper IgE Syndrome (Job syndrome) have impaired regulation of the IgE function and increased susceptibility to infections. In addition to recurrent cutaneous infections including cold abscesses, patients have widespread eczematous dermatitis, recurrent sinopulmonary infections and typically have coarse facies with broad nasal bridge and a prominent nose.

Answer 32

► A Treatment is with a diet low in green vegetables, dairy and ruminant fats is the treatment of choice for Refsum syndrome. Avoidance of specific amino acids is not helpful.

Answer 33

►A The rupture of Bruch's membrane causes angioid streaks in pseudoxanthoma elasticum. Bruch's membrane is the innermost layer of choroid with a central layer of elastic fibers. The other findings are found in Ehlers-Danlos syndrome and are not related to Bruch's membrane.

Answer 34

►A Bloom's syndrome is an autosomal recessive disorder caused by mutations in the RecQL3 gene encoding a DNA helicase. Clinically, individuals with Bloom's syndrome have a photodistributed erythema with telangectasia on the malar eminences. The may also have decreased IgM and IgA levels, hypogonadism, and an increased risk for leukemia and lymphoma.

Answer 35

►D Incontinentia pigmenti (Bloch-Sulzberger syndrome) is an X-linked dominant disease that is lethal in males unless they are a mosaic. There are four stages: vesicular, verrucous, hyperpigmented and hypopigmented. Also seen are peg and conical teeth, eye abnormalities, CNS defects, and alopecia. This condition is caused by mutations in the NEMO gene.

Answer 36

►B Erythrokeratodermis variabilis is an autosomal dominant disease characterized by transient patches of geographic erythema and fixed hyperkeratotic plaques. The disease is due to gene defects in connexin 30.3 and 31.

Answer 37

►A Marfan syndrome is an autosomal dominant disordercharacterized by tall stature, arachnodactyly, pectus excavatum, high-arched palate, joint laxity, ectopia lentis, aortic dilatation, striae, and elastosis perforans serpiginosa. The syndrome is caused by a defect in fibrillin 1 or 2. Fibronectin is defected in Type 10 Ehlers-Danlos syndrome. Collagen 5 defects can cause Ehlers-Danlos types 1 or 2. ABCC6 is mutated in pseudoxanthoma elasticum. Cutis Laxa is caused by defects in fibulin 4

Answer 38

►A This patient has Menkes Disease that is an X-linked recessive disorder caused by a mutation of the ATP7A gene. This gene encodes copper-transporting ATPase. The disease is lethal in males. Girls develop variably depigmented lusterless hair. Polaroscopy reveals monilethrix, pili torti, trichorrhexis nodosa. In addition, there is diffuse cutaneous hypopigmentation, doughy skin and an exaggerated cupid bow.

Answer 39

►A Findings of the eyelid string of pearls and a hoarse cry during the first years of life (due to vocal cord infiltration) is characteristic of Lipoid Proteinosis (Urbach-Wiethe disease or Hyalinosis cutis et mucosae). It is an autosomal recessive condition with mutations in the extracellular matrix protein 1 gene. Other findings include calcifications of the temporal lobe and hippocampus, hairloss, atrophic scars and waxy papules on the face, verrucous nodules and a thick tongue. The other conditions could be considered on the differential for Lipoid Proteinosis, but do not have the findings described above.

Answer 40

►D Dyschromatosis symmetrica hereditaria (or acropigmentation symmetrica of Dohi) is an autosomal dominant disease with hypo and hyper pigmented macules and patches on the dorsal hands and feet associated with a low activity of double stranded RNA adenosine deaminase.

Answer 41

►B Lamellar ichthyosis which is characterized by collodian membrane in newborns and platelike scale in children and adults is an autosomal recessive syndrome. The gene defect is transglutaminase 1 (TGM1).

Answer 42

►E Nail-patella syndrome, also called hereditary osteo-onychodysplasia is a rare autosomal dominant condition caused by a defect in the LMX1B gene. It is characterized by triangular lunulae, palmoplantar hyperhidrosis, renal dysplasia, glomerulonephritis, and hyperpigmentation of the papillary margin of the iris, an ophthalmologic finding also known as Lester iris. Other nail findings include micronychia with hemionychia, anonychia, and longitudinal fissures. Bony findings include absent or hypoplastic patella, posterior iliac horns, radial head subluxation, thickened scapulae, and scoliosis. Nail findings in Darier's disease include red and white longitudinal bands, subungual hyperkeratosis and V-shaped nicking of the distal nail plate. Dystrophic nails with longitudinal ridges, pterygium, and atrophic or absent nails can be found in dyskeratosis congenita. Dystrophic changes of the nails can be seen in approximately 5-10% of patients with incontinentia pigmenti.

Answer 43

►E Adenosine deaminase deficiency is associated with severe combined immunodeficiency. The most common inheritance is x-linked recessive. It is a mixed group of disorders all sharing defects in cell-mediated and humoral immunity. Skin findings include: candidal infections, Mucocutaneous, bacterial pyodermas, seborrheic-like dermatitis/lichen planus-like Sclerodermatous changes, aplastic thymus and pneumonias. The other listed syndromes are not associated with adenosine deaminase deficiency.

Answer 44

►A This patient has nail-patella syndrome. The gene defect is an autosomally transmitted defect in LMX1B. This gene is involved in dorsal/ventral limb patterning and is in close proximit to the COL5A1 gene. EEC1 is defective in ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and LKB1 in Peutz Jeghers syndrome.

Answer 45

►D Pseudoxanthoma elasticum is caused by mutations in the ABCC6 gene, which is an ATP -using cell transporter. Elastin and lysyl oxidase mutations cause cutis laxa, fibrillin 1 mutations cause Marfan syndrome, and collagen 5 mutations cause Ehlers-Danlos syndrome.

Answer 46

►E Down syndrome is caused by nondisjunction and results in trisomy 21. Clinical features include single palmar crease, flat nipples, increased nuchal skin folds, syringomas, elastosis perforans serpiginosa, xerosis, epicanthic folds of eyes, protruding scrotal tongue and fissured thickened lips.

Answer 47

►D Pseudoxanthoma elasticum is an autosomal rescessive or autosomal domminant disease caused by a mutation in ABCC6 (adenosine triphosphate-binding cassette subfamily C member 6). Associated findings include gastric artery hemorrhage, angiod streaks, retinal hemorrhage, atherosclerotic disease, and a possible increased risk of first trimester miscarriage.

Answer 48

►A Fibrillin 2 defects are linked primarily with congenital contractural arachnodactyly. This syndrome is associated with long limbs, arachnodactyly, scoliosis and crumpled ears. Occasionally, fibrillin 2 can be associated with Marfan syndrome also. The other conditions are not linked to fibrillin mutations.

Answer 49

►A In-utero methimazole exposures has been linked to aplasia cutis congenita and should not be used in pregnant women. The FDA pregnancy class is D. The other listed options are not linked with maternal methimazole usage.

Answer 50

►A Spontaneous mutations are four times more likely to occur in TSC2. In familial TS half mutations are in TSC1 and half in TSC2.

Answer 51

A Moyahan syndrome is also known as Leopard syndrome and can have all the findings of lentigines, ECG conduction defects, ocular hypertelorism and pulmonic stenosis. They also get abnormal genitalia, retardation of growth and deafness.

Answer 52

►D Patients that are diagnosed with Peutz-Jeghers syndrome need to have a colonscopy every 2 years to assure that the hamartomatous polyps do not progress to carcinomas. It is an autosomal dominant disorder with hyperpigmented macules in the oral mucosa

Answer 53

►A Patients with Conradi-Hunermann-Happle syndrome has chondrodysplasia punctata that is X- linked dominant. They have ventricular septal defects and asymmetric limb shortening.

Answer 54

►E Cockayne’s syndrome is caused by a mutation in a DNA helicase gene, CSA or ERCC8. The condition is defined by growth deficiency, premature aging, and pigmentary retinal degeneration. 75% of patient have photosensitive eruptions and severe cataracts before the age of 3 are associated with poor prognosis.

Answer 55

►D Epidermolytic hyperkeratosis is caused by a genetic mutation in keratins 1 and 10. White sponge nevus is caused by a genetic mutation in keratins 4 and 13. Pachyonychia congenita is caused by a genetic mutation in keratins 6a and 16. Netherton syndrome and Sjogren-Larsson syndrome are not disorders of keratins.

Answer 56

►A Hailey-Hailey, or Familial Benign Pemphigus, is an autosomal dominant genodermatosis which is caused by a mutation in ATP2C1. Vesicles and erythematous plaques develop in the skin folds such as axillae and groin area. Darier's disease is an autosomal dominant genodermatosis due to a mutation in ATP2A2 and is often in a seborrheic distribution.

Answer 57

►C Naxos is associated with right sided cardiomyopathy. It is an AR, non epidermolytic PPK in which patients have congenital wooly hair and fragile desmosomes. These patients are at risk for heart failure and death.

Answer 58

►C Hepatolenticular degeneration or Wilson Disease is caused by a defect in biliary excretion of copper leading to accumulation in the liver, brain, cornea, pretibial hyperpigmentation, hepatomegaly and cirrhosis. The Kayser-Fleischer ring is the yellow-brown copper deposition in Descemet's membrane of the cornea. Other findings include ataxia, dysarthria and dementia. Hemochromatosis does not have an eye finding. Neurofibromatosis has Lisch nodules and Pseudoxanthoma elasticum has angioid streaks of the retina.

Answer 59

►C Familial cerebral cavernomas are due to a defect in the CCM gene which encodes the KRIT-1 protein. These patients often times have hyperkeratotic cutaneous capillary-venous malformations.

Answer 60

►A Hypomelanosis of Ito, or Incontinentia pigmenti achromians is a condition characterized by marble-cake hypopigmentation, epilepsy, alopecia, scoliosis and mental/motor retardation. The characteristic dental abnormality is anodontia. The remaining syndromes are not associated with anodontia.

Answer 61

►A The most likely diagnosis is Congenital ichthyosiform erythroderma. In neutral lipid storage disease, the peripheral blood smear would demonstrate lipid vacuoles in leukocytes and monocytes. Lamellar ichthyosis is characterized by plate-like scale in children/adults. Netherton syndrome is characterized by ichthyosis linearis circumflexa. Ichthyosis vulgaris does not typically present with collodian baby.

Answer 62

►D Albright hereditary osteodystrophy is caused by mutations in the Gs subunit of adenylate cyclase. There is calcification and ossification due to pseudohypoparathyroidism, absent 4th knuckle, and hypogonadism.

Answer 63

►A Patients that have Leopard syndrome have AV blocks, arrhythmias, bundle branch block, ventricular hypertrophy. The patient has ocular hypertelorism, pulmonic stenosis, abnormal genitals, and deafness.

Answer 64

►A This patient has MEN type IIA also known as "Sipple's Syndrome". It is an autosomal dominant disorder caused by the RET gene. Work up should include calcitonin, calcium, PTH and urine catecholamines.

Answer 65

►D Familial multiple cutaneous leiomyomatosis is an autosomal dominant condition caused by mutations in the fumarate hydratase gene. Clinically, there are multiple cutaneous leiomyomas, uterine leiomyomas and leiomyosarcomas, as well as renal cell carcinomas.

Answer 66

►B The patient scenario describes Reed's syndrome (multiple cutaneous and uterine leiomyomatosis) characterized by uterine and cutaneous leiomyomas, in addition to papillary renal cell cancer. This autosomal dominant disorder is due to mutations within the fumarate hydratase gene, which catalyses the conversion of fumarate to malate in the Kreb\'s cycle. It is also thought to act as a tumor suppressor gene. With regards to the other answer choices, telomere maintenance is disrupted in dyskeratosis congenita. The tuberous sclerosis genes hamartin (TSC1) and tuberin (TSC2) inhibit mTOR signalling. Mutations in the FLCN gene, with encodes folliculin (thought to act as a tumor suppressor), cause Birt Hogg Dube syndrome. The CYLD gene, a deubiquitinating enzyme, has been implicated in Brooke-Spiegler syndrome.

Answer 67

►B Epidermolysis bullosa with muscular dystrophy is caused by mutations in plectin.

Answer 68

►B Von Hippel-Lindau syndrome is an autosomal dominant condition caused by a defect in the VHL tumor suppressor gene. This disease is characterized by retinal hemangioblastomas, often resulting in visual impairment and blindness if left untreated. In addition, many tumors are seen including pheochromocytoma, renal cell carcinoma, and hemangioblastomas of the cerebellum, medulla, and spinal cord. Pancreatic and renal cysts are also a feature of this condition. Finally, polycythemia can occur as a result of erythropoietin production by renal cell carcinoma. Von Hippel-Lindau syndrome is a progressive, universally fatal condition which presents most often in the fourth decade of life.

Answer 69

►E Patients with hemochromatosis have increased intestinal iron absorption leading to systemic iron overload. Signs include a generalized metallic-grey hyperpigmentation, koilonychia, alopecia (especially pubic/axillary hair) cardiac failure/arrhythmias/heart block, hepatomegaly with cirrhosis, diabetes (bronze diabetes), polyarthritis with chondrocalcinosis and are susceptible to Vibrio vulnificus and Yersinia infections.

Answer 70

►A LAMB3 is the most common mutation, it is usually a nonsense mutation causing a premature stop codon resulting in the absence of laminin 332. Non herlitz type is due to a missense or splice site mutation resulting in rudimentary/decreased laminin 332. COL7A1 is mutated in dystrophic epidermolysis bullosa. NEMO gene is mutated in incontinnentia pigmenti. ATP2A2 gene is mutated in Dariers. ATP2C1 is mutated in Hailey Hailey.

Answer 71

►E All of the listed syndromes include atrophoderma vermiculatum as part of their constellation of symptoms. Atrophoderma vermiculatum is characterized by honeycomb pattern of atrophic scars on the face. Tuzun Syndrome also has scrotal tongue. ROMBO has BCCs, milia, peripheral vasodilation, trichoepitheliomas. Nicolau-Balus has eruptive syringomas and milia. Braun-Falco- Marghescu has keratosis pilaris and palmoplantar hyperkeratosis.

Answer 72

►A Keratin 6a/16 are defective in PC type I. K6b17 is defective in PC type II, K1/10 in Unna-Thost PPK and epidermolytic hyperkeratosis, K2e/10 in Ichthyosis bullosa of Siemens.

Answer 73

►A Focal dermal hypoplasia, or Goltz syndrome, is an x-linked dominant condition with a defect in the PORCN gene. It is characterized by linear atrophy in a Blasckoid distribution, alopecia, nail dystrophy, abnormal teeth, and colobomas.

Answer 74

►A Cutaneous meningiomas are sperated into 3 types. Type 1 are thought to be misplaced meningeal cells, or rudimentary mengioceles. Type II develop along the course of cranial nerves. Type III lesions represent cutaneous metastasis or an underlying primary meningioma. Cutaneous meningiomas have been associated with cranial developmental anomalies and in neurofibromatosis.

Answer 75

►C Erythrokeratoderma variabilis is also known as Mendes da Costa Syndrome. It is caused by a defect in connexin 31, a gap junction protein. EB simplex is caused by a mutation in keratins 5 & 14, Hailey-Hailey is caused by a mutation in calcium transporters, dyskeratosis congenita is caused by a defect in rRNA synthesis, and bullous icthyosis of Siemens is caused by mutations in keratin 2e.

Answer 76

►A The patient has Cockayne syndrome. It is autosomal recessive associated with a defect in nucleoside excision repair with a mutation in the XPG gene. It is similar to XP with photosensitivity, neurologic degeneration, deafness, retinal atrophy, basal ganglia calcifications and peripheral neuropathy.

Answer 77

►D The patient has Conradi-Hunermann Syndrome. This is a X-linked dominant disorder characterized by ichthyosiform erythroderma in Blaschko's lines in infancy which resolves with follicular atrophoderma, patchy alopecia, short stature, cataracts, scoliosis, assymetric limb shortening. Bone films will demonstrate stippled epiphyses. Ichthyosis and stippled epiphyses resolve after infancy.

Answer 78

►D Nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome, is an autosomal dominant disease, with abnormalities in the PTCH gene. It presents with multiple basal cell cancers early in life, frontal bossing, hypertelorism, odontogenic keratocysts, and bifid ribs. The presence of intracranial calcification of the falx cerebri is characteristic.

Answer 79

►B The patient described has trichothiodystrophy, with the hair finding of trichoschisis. These patients have photosensitivity but no increased risk of skin cancer. They also have intellectual impairment, decreased fertility, short stature, and progeria-like facies. Low sulfur content of the hair is found. Eyebrows and eyelashes are also affected. Dark bands in pili annulati, not trichoschisis, are air cavities.

Answer 80

►A Menkes kinky hair syndrome is transmitted in an X-linked recessive manner and is caused by a mutation in ATP7A, an ATP-dependent copper tranporter. This defect results in low serum levels of copper. These individuals will have hair abnormalities such as sparse, hypopigmented brittle hair, eyelashes and eyebrows, lax skin, a "cupid's bow" upper lip, CNS progressive deterioration, seizures, skeletal abnormalities and tortuous arteries. The other listed items are not associated with Menkes syndrome.

Answer 81

►A This child has Chanarin-Dorfman syndrome, also called neutral lipid storage disease. This is an autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. Patients generally have normal blood lipid levels and a finely scaling ichthyosis. They can also have extracutaneous involvement such as cataracts, decreased hearing, myopathy, and neurologic abnormalities.

Answer 82

►A Acute intermittent porphyria can cause hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion.

Answer 83

►A Patients with hereditary hemorrhagic telangiectasia or Osler-Weber Rendu have a mutation in Endoglin or Activin receptor like kinase -1 (ALK1, ACVRL1) gene that result in HHT1 and HHT2. Both genes play a role in the vascular system.

Answer 84

►B Darier's disease is autosomal dominant condition characterized by hyperkeratotic papules coalescing into warty plaques and cobblestoned papules on mucosal surfaces. The cutaneous manifestations may be exacerbated by lithium.

Answer 85

►A Alkaptonuria is an autosomal recessive disease with a deficiency in homogentistic acid oxidase. The osler sign is a blue black discoloration in the sclera near the insertion of the rectus muscles, oil droplet opacities in the cornea, pigmented pingucela, granules in episclera.

Answer 86

►D These syndromes are all mucopolysaccharidoses. These papules are characteristic of Hunter syndrome which is caused by a deficiency in iduronate sulfatase.

Answer 87

►A KIP2 can be mutated in 15% of cases of Beckwith-Wiedemann Syndrome. KIP2 is a cyclindependent kinase inhibitor gene which acts as a negative regulator of cell proliferation. These children have an increase risk of Wilms' tumor and organomegaly. In addition to the circular ear depression, they can also have a linear earlobe crease. The remaining genes are mutated in other syndromes with vascular disorders as a component: ATM in ataxia telangectasia, VHL in Von Hippel-Lindau, FLT4 in Hereditary lymphedema and FOXC2 in Lymphedema-distichiasis syndrome.

Answer 88

►E To date, three genetic etiologies of hyper IgE syndromes have been identified: STAT3, DOCK8, and Tyk2. All of these hyper IgE syndromes are characterized by eczema, sinopulmonary infections, and greatly elevated serum IgE. However, each has distinct clinical manifestations. Mutations in STAT3 cause autosomal dominant HIES (Job\'s syndrome), which is unique in its diversity of connective tissue, skeletal, and vascular abnormalities. DOCK8 deficiency is characterized by severe cutaneous viral infections such as warts, and a predisposition to malignancies at a young age. Hyper IgE syndrome associated with Tyk2 deficiency is characterized by nontuberculous mycobacterial infections.

Answer 89

►C A plectin mutation is linked with this subtype of epidermolysis bullosa simplex.

Answer 90

►A Patients with premature aging with thin hair, bird like face, early wrinkling, and atherosclerosis has progeria. THey also have dyspigmentation, atophy of the skin and decreased subcutaneous fat.

Answer 91

►A This case describes Howell-Evans syndrome. This AD syndrome characteristically has a PPK in areas of pressure, oral leukoplakia and esophageal carcinomas. Desmoplakin is defective in Carvajal syndrome and plakoglobin in Naxos syndrome. Connexin 31 and 30.3 are linked to erythrokeratoderma variabilis, which includes a PPK, but not esophageal carcinoma.

Answer 92

►E Rubenstein-Taybe syndrome is caused by a mutation in CREB-Binding protein and presents with brachyonychia, eruptive keloids, and multiple pilomatricomas. Nail-Patella syndrome is associated with anonychia, along with hypoplastic patellae, triangular lunulae, radial subluxation, Lester iris, iliac horns, and glomerulonephritis. The other disorders are not associated with brachyonychia.

Answer 93

►A Attached picture is Mal de Meleda (keratosis palmoplantaris transgrediens) which is an autosomal recessive form of diffuse PPK, associated with keratotic plaques that extend to the dorsal aspects of the hands and feet ("transgrediens") and may overlie joints . Hyperhidrosis, superinfection, and occasionally perioral erythema, brachydactyly, and nail abnormalities are associated. Mal de Meleda is due to mutations in ARSB, which encodes SLURP-1. The other choices represent gene defects for "non-transgrediens" forms of PPK (Plakoglobin in Naxos syndrome, TOC gene in Howel-Evans syndrome, K1 in non-epidermolytic PPK "Unna-Thost", and K9 in epidermolytic PPK "Vorner"

Answer 94

►D Patients with x-linked icthyosis have a 20% chance of having cryptorchidism and are more prone to both testicular cancer and acute lymphocytic leukemia.

Answer 95

►C Dyshcromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant pigmentary disease characterized by asymptomatic hypopigmented and hyperpigmented macules distributed on the face and dorsal extremities. It is most common in patients of Asian descent but has also been reported in patients of European and South American descent. The condition is typically limited to the skin but has been associated in rare instances with neurological deterioration and brain calcificiations. The lesions tend to appear in infancy and childhood and stabilize during adolescence. Mutations in the double-stranded RNA-specific adenosine deaminase gene (ADAR1 or DSRAD) underlie DSH. The ADAR1 protein catalyzes the deamination of adenosine to inosine in double-stranded RNA which is important for alternative splicing or alternations of codons for protein translation. However, the precise mechanism by which these mutations lead to actual disease remain unknown. There are two diseases that are phenoptypically similar to DSH and previously thought to be related. The first is dyschromatosis universalis hereditaria (DUH) which is characterized by a mixture of hyperpigmented and hypopigmented macules that are widespread. DSH can be distinguished from DUH by its localization to the face and distal acral sites. The second disease is acropigmentatio retiticularis (AR, also known as acropigmentation of Kitamura). AR is also characterized by hyperpigmentated macules on the dorsal hands and feet as well as palmar pits. However, in contrast to DSH, it is notably devoid of hypopigmented macules. Suzuki et al. sequenced 20 cases of patients presenting with DSH, DUH, and AR. All patients with DSH demonstrated mutations in ADAR1, however, none of the patients with DUH or AR demonstrated mutations. Based on these studies, they proposed that these diseases are in fact distinct and separate from DSH. There are no effective therapies for DSH. However, it is important to distinguish DSH from other more serious disorders that can present with pigment alterations such as dyskeratosis congenita and xeroderma pigmentosum. Both of these conditions present with photosensitivity and squamous cell carcinomas which are not present in DSH.

Answer 96

►A White sponge nevus is caused by a defect in keratins 4 & 13. The remaining entities have the corresponding defects: EB simplex→►►►keratins 5 & 14 EB simplex with myotonic dystrophy→►►►plectin Junctional EB with pyloric atresia→►►►Integrin ɑ-6, β4 Cloustonǁs syndrome (hidrotic ectodermal dysplasia)→►►►connexin 30

Answer 97

►C This patient may have a constellation of features associated with NAME syndrome, otherwise known as Carney complex or LAMB syndrome. This condition is inherited in an autosomal dominant pattern and is due to a defect in the PRKAR1A gene. This condition is characterized by the following features: blue Nevi, Atrial myxomas, cutaneous Myxomas, and Ephelides. In addition, testicular tumors are seen as well as sexual precocity. Finally, patients may have endocrine abnormalities including pigmented nodular adrenocorticoal disease and Cushing syndrome as well as pituitary adenomas. Deafness, pulmonary stenosis, GI malignancies, and mental retardation are not features of this condition.

Answer 98

►B Proteus syndrome is a sporadic condition due to mutation in AKT1. Clinical features include subcutaneous lymphovenous malformations, capillary malformations, lipomas, connective tissue nevi of palms/soles, hemihypertrophy, frontal bossing, hyperostoses of epiphyses & skull (especially external auditory canal), scoliosis, bilateral ovarian cystadenomas, and parotid monomorphic adenomas.

Answer 99

►C Blue rubber bleb nevus syndrome is characterized by multiple tender venous malformations of skin and gastrointestinal tract, which can lead to gastrointestinal bleeding.

Answer 100

►D Pappilon Lefevre Syndrome is an autosomal recessive syndrome characterized by transgredient PPK and periodontitis. There is a defect in cathepsin C. One sees dural calcification at the tentorium and choroid plexus. Tram track calcifications are seen in STurge-WEber. CAlcification of the falx cerebri and agenesis of the corpus callosum is seen in basal cell nevus syndrome. Hippocampal calcification is seen in lipoid proteinosis.

Answer 101

►A Patients with tuberous sclerosis have a mutation in the TSC1 and TSC2 gene. The encode for tumor suppressor proteins hamartin (TSC1) and tuberin (TSC2). Other skin findings include hypopigmented macules, facial angiofibromas, collagenomas, shagreen patch, periungual fibromas, Koenen's tumors and forehead plaques.

Answer 102

►A Angioid streaks are characteristic of pseudoxanthoma elasticum. They are caused by rupture of Bruch's membrane of the choroid. Choroid malformations are found in Sturge-Weber syndrome, eyelid papillomas in xeroderma pigmentosum, Lester iris in Nail-patella syndrome and salt & pepper retinitis pigmentosa in Refsum syndrome.

Answer 103

►C Kasabach-Merritt Syndrome results from platelet trapping. It occurs with tufted angiomas and kaposiform hemangioendotheliomas. Hematologic complications include thrombocytopenia, microangiopathic hemolytic anemia, DIC, and acute hemorrhage. The presence of large angiomas can lead to high output failure (CHF) and they can also compress on surrounding structures.

Answer 104

►A Bloom's syndrome is an autosomal recessive disorder caused by a mutation in DNA helicase. It is characterized by photodistributed erythema in a butterfly distribution, malar hypoplasia with a prominent nose, high pitched voice, and an increased risk for malignancy (acute leukemia, lymphoma, and GI adenocarcinoma.)

Answer 105

►E Right-ventricular cardiomyopathy is associated with Naxos syndrome, pseudoainhum is associated with Vohwinkel syndrome, esophageal cancer is associated with Howel-Evans syndrome, and eccrine syringofibradenomas are associated with Schopf-Schulz-Passarge syndrome. Periodontitis with tooth loss is associated with Papillon-Lefevre and Haim-Munk syndromes, which are caused by mutations in Cathepsin C.

Answer 106

►B Cowden's syndrome is an autosomally dominant inherited defect of PTEN. Patient may present with multiple trichilemmoma, hamartomatous tumors of the breast, thyroid and endometrium, acral keratoses and papillomatous papules. Breast cancer is the most common cancer to arise while thyroid carcinoma is the second most common.

Answer 107

►A This patient has basal cell nevus syndrome or Gorlin Syndrome. The mutation is in the PATCH gene that encodes PTC protein involved in the sonic hedge hog pathway. It leads to multiple basal cell carcinomas in the adulthood and also palmoplantar pits in nearly all patients.

Answer 108

►C Acrodermatitis enteropathica presents itself in infancy once breastfeeding has stopped. It can clinically mimic atopic dermatitis, seborrheic dermatitis and candidiasis. Clinical features include scaly red rash around mouth, eyes, and palms, diarrhea, stomatitis, glossitis, alopecia, and failure to thrive.

Answer 109

►A Chediak-Higashi syndrome is caused by an autosomal recessive mutation in a lysosomal transport gene (LYST, CHS1). This disorder is characterized by oculocutaneous albinism, ataxia, muscle weakness, and giant lysosomal granules. There is an accelerated phase characterized by lymphohistiocytic infiltration of reticuloendothelial system, pancytopenia and death.

Answer 110

►E Chronic granulomatous disease is inherited in an autosomal recessive and x-linked recessive manner. There are mutations 5 mutations total. If the mutation is present in CYBA (a cytochrome subunit), NCF1 & 2 (neutrophil cytosol factors 1 & 2 & 4) it is inherited in an autosomal recessive manner. The mutation in CYBB is X linked recessive.

Answer 111

►D Pachyonychia congentia is an autosomal dominant condition characterized by a constellation of findings affecting ectodermal structures. These include the presence of natal teeth, steatocystoma multiplex, follicular hyperkeratosis of the knees, elbows and extensor extremities, eruptive vellus hair cysts, and oral leukokeratosis which is not pre-malignant. In addition, nail findings include twenty-nail dystrophy, subungual hyperkeratosis with increase transverse curvature ("pincer nails") and candidal paronychia. There are two forms of pachyonychia congenital: Type 1(Jadassohn- Lewandowsky syndrome) caused by defects in keratin 6a and 16, and Type 2 (Jackson-Lawler type) caused by defects in keratins 6b and 17. Anhidrotic ectodermal dysplasia is associated with peg- shaped teeth, hypoanodontia, and a non-specific nail dystrophy. Likewise, incontientia pigmenti also is characterized by anodontia and peg-shaped teeth and dystrophic changes of the nail. Finally congenital syphilis is a well-recognized cause of pegged teeth. Limb deformities are the most serious sequelae of thalidomide exposure in utero.

Answer 112

►C Cronkhite-Canada syndrome is a sporadic gastrointestinal polyposis syndrome associated with nail atrophy, alopecia, generalized pigmentation of the skin, and melanotic macules on the fingers.

Answer 113

►E Non-bullous congenital erythroderma (NCIE)is an autosomal recessive disorder characterized by a collodion baby presentation at birth, and generalized erythroderma with fine white scale, palmoplantar keratoderma, and heat intolerance. NCIE may be caused by mutations in transglutaminase-1. gene (TGM1), the 12R-lipoxygenase gene (ALOX12B), and the lipoxygenase-3 gene (ALOXE3). Mutations in the keratinocyte TGM1 gene interferes with normal cross-linking of structural proteins and the lipid envelope, leading to defective cornification and desquamation. ALOXE3 functions as an epoxy alcohol synthase using the product of ALOX12B as the preferred substrate; either gene can be the site of mutations causing NCIE.

Answer 114

►D The patient described has Cockayne syndrome, an autosomal recessive disorder believed to be due to a mutation in either DNA helicase ERCC6 or defective ERCC8 which does nucleotide excision repair. UV irradiated cells have decreased DNA and RNA synthesis and increased chromosomal breaks. Clinical features include cachectic dwarfism with microcephaly, thin nose, large ears, photosensitive eruption, cataracts, salt & pepper retina, and diffuse demyelination.

Answer 115

►B The split seen in junctional epidermolysis bullosa is in the lamina lucida. The other locations can be involved in blistering disease, but not junctional epidermolysis bullosa.

Answer 116

►A CHILD Syndrome is a X-linked dominant disorder characterized by unilateral ichthyosiform erythroderma, ipsilateral limb deformity, and ipsilateral organ hypoplasia. The most commom gene defect is NSDHL which encodes 3-beta hydroxysteroid dehydrogenase. EBP gene defects which encode 3-beta-hydroxysteroid isomerase have been described, however this is the usual defect in Conradi-Hunermann Syndrome. Aryl sulfatase E is mutated in X-linked recessive chondrodysplasia punctata.

Answer 117

►D Basal cell nevus syndrome is an autosomal dominant syndrome caused by a mutation in PTC gene, which acts in the Sonic hedgehog pathway. Cutaneous manifestations of this genodermatosis include basal cell carcinomas, palmoplantar pits, epidermoids cysts. Other findings include odotogenic cysts, frontal bossing, bifid ribs, calcification of the falx cerebri and medulloblastomas.

Answer 118

►C RCC Birt-Hogg-Dube syndrome is characterized by multiple fibrofolliculomas, trichodiscomas, acrocollagenomas, lipomas, and oral fibromas. Patients develop renal cell carcinoma, colon cancer, and medullary thyroid carcinoma.

Answer 119

►A Sipple syndrome (MEN 2a) is caused by autosomal dominant mutations in the ret protooncogene. Patients develop parathyroid cancers, pheochromocytomas, and medullary cancer of the thyroid gland. Familial macular and lichen amyloidosis is also a feature of this syndrome.

Answer 120

►A Men with x-linked ichthyosis are at increased risk of testicular cancer and cryptorchidism. A testicular exam is simple to perform and a good screening exam for detecting testicular abnormalities. The remaining exams are not useful as these patients are not at higher risk for other types of cancer.

Answer 121

►A Nail patella syndrome is also known as hereditary osteonychodysplasia (HOOD) and is inherited in an autosomal dominant fashion. The defect is in the gene LMX1B. The ocular abnormality is Lester iris seen in 45% of patients.

Answer 122

►B Ichthyosis hystrix or extensive epidermal nevi occurs secondary to a somatic mosaicism for keratins 1 and 10. If the mosaicism occurs on gonadal cells, offspring may have full blown epidermolytic hyperkeratosis (EHK).

Answer 123

►A A double row of eyelashes is defined as distichiasis and is associated with the Lymphedema- distichiasis syndrome. This syndrome is transmitted in an autosomal dominant fashion and is related to a mutation in FOXC2. Findings include late onset lymphedema, distichiasis, corneal irritation, ectropion, webbed neck and congenital heart defects. The remaining syndromes do not include distichiasis as a feature.

Answer 124

►A Peg/conical teeth are not part of the Carney complex. This is found in incontinentia pigmenti and anhidrotic ectodermal dysplasia. The remaining skin findings are part of this complex sometimes known as NAME syndrome. It consists of multiple, diffuse mucocutaneous lentigines, cardiac and subcutaneous myxomas and endocrine abnormalities may be present. Other findings include: testicular tumors, thyroid disease, primary pigmented nodular adrenocortical disease, psammomatous melanotic schwannomas and hormone-secreting pituitary adenomas.

Answer 125

►A This patient has all the clinical signs of blue rubber bleb nevus syndrome. These patient can also have melena that occurs with gastrointestinal hemangioma rupture. Other involvement are in the lung, eye and CNS.

Answer 126

►A Arylsulfatase E is also known as steroid sulfatase and is mutated in X-linked ichthyosis. This condition is inherited in a X-linked recessive pattern. Clinical findings include: brown scale sparing palms, soles and flexures, comma-shaped corneal opacities, failure of labor progression and cryptorchidism. It is also mutated in X-linked recessive type chondrodysplasia punctata.

Answer 127

►A KID syndrome is described above. It is an autosomal dominant mutation in connexin 26. Vohwinkel syndrome is also a connexin 26 mutation, but is characterized by diffuse honeycombed palmoplantar keratoderma, pseudoainhum, starfish-shaped keratotic plaques over joints and deafness. Erythrokeratoderma variabilis is an autosomal dominant mutation in connexin 31 and 30.3 characterized by erythematous migratory patches, fixed hyperkeratotic plaques and a palmoplantar keratoderma. CHILD syndrome is an X-linked dominant mutation condition due to a mutation in NAD(P)H Steroid dehydrogenas-like protein, lethal in males. Unilateral ichthyosiform erythroderma, limb/visceral hypoplasias are characteristic. Refsum syndrome is an autosomal recessive condition with a mutation in phytanoyl coenzyme A hydroxylase characterized by mild ichthyosis, cerebellar ataxia, peripheral neuropathy, retinitis pigmentosa (salt & pepper) and deafness.

Answer 128

►D Noonans syndrome is similar to cardiofaciocutaneous syndrome as they both have mutations in PTPN11. Noonan patients have short stature, ptosis, hypertelorism, low-set ears, thick lips and curly hair. Pulmonic valve stenosis is the most common cardiovascular defect, with atrial septal defects also seen.

Answer 129

►C Kasabach-Merritt syndrome is associated with hematologic abnormalities, such as thrombocytopenia, microangiopathic hemolytic anemia, disseminated intravascular coagulation. The condition develops from platelet-trapping within a large hemangioma, most commonly a kaposiform hemangioendothelioma in the retroperitoneal location.

Answer 130

►A Patients with hypohidrotic ectodermal dysplasia have longitudinal groove on electonmicroscopy. They also have peg teeth with problems with sweating.

Answer 131

►B Glaucoma is the most common associated eye finding in CMTC patients. Glaucoma is also seen in patients with neurofibromatosis type 1 and Sturge Weber patients.

Answer 132

►B Keratin hHb1/hHb6 is defective in monilethrix, which is described above. Keratin 1/10 defects are found in epidermolytic hyperkeratosis, K6/16 in inflamed skin and pachyonychia congenita type I, K6/17 in pachyonychia congenita type II and K2e in Ichythosis bullosa of Siemens.

Answer 133

►A Bloom syndrome is an autosomal recessive disorder due to a mutation in the BLM gene which codes for a DNA helicase. Patients have impaired DNA repair after UV exposure and increased photosensitivity. Clinical features include photodistributed erythema, cheilitis, high -pitched voice, hypogonadism, and increased risk for leukemia, lymphoma and GI adenocarcinoma. Laboratory evaluation reveals decreased IgA, IgM and IgG leading to increased risk of respiratory infections

Answer 134

►C Patients with Fabry disease have a defect in the alpha-galactosidase A enzyme, leading to an accumulation of glycosphingolipids in all tissues. Although patients are at increased risk for myocardial infrctions and strokes, the serum lipid levels are normal. Ischemic events occur as a result of glycosphingolipid accumulation in endothelial cells leading to swelling. In the brain, strokes occur from direct vessel occlusion or stretching and distention of branches of dolichoectatic parent vessels. Deposits in the kidneys leads to progressive renal failure with urine exam exhibiting proteinuria and birefringent lipid globules (―maltese crossesǁ) seen with polarizing light microscopy.

Answer 135

►D Focal dermal hypoplasia (Goltz syndrome) is an X-linked dominant disorder that is lethal in males. There is linear atrophy following Blaschko‘s lines with areas of fat herniation with underlying osteopathia striata, which is radiologically characterized by linear bony hyperdensity. Other features include mucocutaneous papillomas and pits, alopecia, nail dystrophy, tooth abnormalities, and colobomas.

Answer 136

►B Ectodysplasin (EDA) on Xq12-q13 is transmitted in an X-linked recessive fashion and is the most common cause of anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome or hypohidrotic ectodermal dysplasia). NEMO can be linked to this syndrome and is associated with immunodeficiency, but this is a rare association. ERCC2 is associated with trichothiodystrophy and ATP7A with Menkes kinky hair syndrome. They are not associated with anhidrotic ectodermal dysplasia.

Answer 137

►A Klippel-Trenaunay-Weber syndrome is a sporadic condition characterized by port-wine stains typically covering one lower extremity that is enlarged with underlying lymphatic and d eep venous insufficiency.

Answer 138

►A Maffucci syndrome comprises of superficial and deep venous malformations, enchondromas, and short stature. Enchondromas are the most common neoplasm, while chondrosarcomas are the most common malignancies.

Answer 139

►D Pseudoxanthoma elasticum is caused by a defect in connective tissue. Angioid streaks develop when a rupture occurs in Bruch's membrane.

Answer 140

►A PTPN11 gene is mutated in LEOPARD syndrome. This syndrome consists of the complex of Lentigines, EKG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth and Deafness. PRKAR1A is associated with the Carney complex of diseases. KIP2 is found in 15% of cases of Beckwith-Wiedermann syndrome. ATM is mutated in ataxia telangectasia syndrome and Neurofibromin in Neurofibromatosis type I.

Answer 141

►B Ectopia lentis (downward displacement) is seen in homocystinuria. Upward displacement is seen in Marfan syndrome. There are no changes in the lens in phenylketonuria or multiple carboxylase deficiency.

Answer 142

►A Tenascin-X defects are associated with EDS and with congenital adrenal hyperplasia. The phenotype is that of typical EDS with hyperextensible skin, hypermobile joints, and tissue fragility. Lysyl oxidase is defective in X-linked EDS (type V) and Occipital horn syndrome (type IX). Lysyl hydroxylase is defective in ocular-scoliotic (type VI) EDS.

Answer 143

►C Phenylketonuria is an autsomal recessive disorder caused by a mutation on the long arm of chromosome 12. A deficiency of phenylalanine hydroxylase or its cofactor tetrahydrobiopterin leads to accumulation of phenylalanine. Clinical features include generalized hypopigmentation, eczematous dermatitis, sclerodermoid changes, seizures, psychomotor delay, urine with ―mousyǁ odor, mental retardation.

Answer 144

►A Argininosuccinic aciduria is an autosomal recessive disorder caused by mutations in argininosuccinase. It is characterized by trichorrhexis nodosa, hyperammonemia, hepatomegaly and vomiting, seizures, lethargy, coma, ataxia, and mental retardation.

Answer 145

►A Schopf-Schulz-Passarge syndrome is characterized by multiple apocrine hydrocystomas (most commonly appearing on the eyelids) and syringofibroadenomas, in addition to hypodontia, hypotrichosis, onychodystrophy, and palmoplantar keratoderma. It is inherited as an autosomal recessive condition and is caused by mutations in WNT10A, which encodes a cutaneous signaling molecule involved in ectodermal appendageal development.

Answer 146

►A Patients with nail-patella syndrome can have glomerulonephritis and renal dysplasia leading to renal failure. Screening with a urinalysis is a reasonable first test. If this is abnormal, referral for a renal ultrasound could be useful. Fasting lipids and a CBC are not indicated.

Answer 147

►A The porphyrias are generally inherited in an autosomal dominant manner. Congenital erythropoietic porphyria is unique in being inherited in an autosomal recessive manner. Helpful mnemonic: all porphyrias are autosomal dominant exCEPt one.

Answer 148

►A Osteogenesis imperfect is a defect in collagen I which leads to thin skin, easy bruising, blue sclera, and multiple fractures. Mitral valve prolapse is seen especially in Type I.

Answer 149

►A Epidermodysplasia verruciformis is a rare autosomal recessive disorder in which an impaired cellular immunity allows widespread infection with certain subtypes of the human papilloma virus (HPV). Some of these lesions have a tendency for malignant transformation, most commonly those verruca caused by HPV type 5.

Answer 150

►A Collagen III is mutated in all three types of EDS listed. Benign hypermobile type EDS is associated with hypermobile joints and is autosomal dominant (AD) in transmission. Vascular type EDS is associated with arterial and visceral rupture leading to early death, and visible venous patterns. It is transmitted autosomal recessive (AR) or AD. Periodontitis type EDS is associated with mild EDS symptoms and periodontitis.

Answer 151

►B Painful crises and whorled corneal opacities are found in Fabry disease which is caused by a defect in alpha-galactosidase A.

Answer 152

►C Patients with Acropigmentation of Dohi (dyschromatosis symmetrica hereditaria) are usually from Europe, India, or the Carribean. They develop pigmented and depigmented macules on dorsal distal extremities and face. This disorder is due to mutation in DSRAD gene. Reticulated pigmentation of the axillae, neck, and groin is seen in Dowling-Degos' disease. Linea palmar pits and pigmented macules on volar and dorsal hands an feet is seen in Reticulate acropigmentation of Kitamura. Hyperpigmented macules on oral mucosa and lips can be seen in Peutz-Jeghers, Cronkite-Canada, and Laugier-Hunziker syndromes. Flaccid, superficial pustules that burst and leave pigmented macules is seen in transient neonatal pustulosis.

Answer 153

►E Beckwith-Wiedemann syndrome is also known as EMG syndrome as it includes exomphalos, macroglossia, and gigantism. It is usually a sporadic condition but is sometimes caused by autosomal dominant mutations in p57. Clinical features include facial capillary malformations, macroglossia, visceromegaly with omphalocele, and hemihypertrophy associated with tumors (especially WilmÂ‘s tumors).

Answer 154

►C Muir-Torre syndrome is an autosomal dominant disorder caused by the HMSH2 and MLH1 DNA mismatch repair genes. Clinically, there are numerous sebaceous adenomas, epitheliomas and carcinomas and multiple keratoacanthomas associated with indolent colon and other visceral adenocarcinomas. Patients and first-degree relatives should be screened by colonoscopy as colonic adenocarcinomas may precede the development of cutaneous tumors.

Answer 155

►A There is an increased incidence of pulmonary arteriovenous fistulas in HHT type I. Type II has an increased incidence of hepatic arteriovenous malformations. Note ALK1 ACVRL1.

Answer 156

►D Pseudoxanthoma elasticum is usually an autosomally recessive inherited condition due to a defective transport protein, ABCC6. The clinical manifestations of the disease arise from fragmented and calcified fibers of the skin, eyes and arteries. Patients may have yellow papules, loose redundant skin, angioid streaks and hemorrhage. Histologically, the hallmark of pseudoxanthoma elasticum is calcified elastic fibers.

Answer 157

►D The patient has Vohwinkel syndrome. This is an autosomal dominant syndrome with 2 clinical variants. The variant described above with generalized ichthyosis is due to a loricrin mutation. In the classic form with nonprogressive hearing loss connexin 26 is mutated.

Answer 158

►C Progeria (Hutchinson-Gilford syndrome) is a sporadic condition characterized by lipoatrophy, sclerodermoid skin, alopecia, nail atrophy, craniomegaly with small face, muscle/bone wasting, and severe premature atherosclerosis resulting in early death.

Answer 159

►A Hereditary lymphedema (Nonne-Milroy disease) is an autosomal dominant condition caused by mutations in the FLT4 gene which encodes for VEGF receptor-3. There is congenital lymphedema and chylous ascites, scrotal swelling, intestinal tract protein loss, persistent bilateral pleural effusion, and hypoproteinemia.

Answer 160

►C Neurofibromatosis type II is an autosomal dominant disorder caused by mutations in schwannomin/ merlin. Clinical features include cutaneous schwannomas and neurofibromas, bilateral vestibular schwannomas, and juvenile posterior subcapsular lenticular opacities. Optic gliomas are usually seen in NF1.

Answer 161

►D Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is due to a defect in secreted mammilian Ly6/uPAR-related protein or SLURP-1.

Answer 162

►A Chediak-Higashi syndrome and Griscelli syndrome have similar features including silver-grey highlights of hair, immunodeficiency, mild albinism and an accelerated phase of disease. Examining a peripheral blood smear is helpful in distinguishing between these two syndromes. Patients with the LYST defect (a lysosomal storage transport gene) have Chediak-Higashi syndrome and will have giant lysosomal granules visible in white blood cells on a blood smear.

Answer 163

►A Marfan's syndrome is caused by a mutation in the fibrillin 1, it is a major component of intermediate fibrils found in the skeletal, ocular and cardiovascular system. The cardiac irregularities are aortic root aneurysms, rupture and dissection.

Answer 164

►A Menkes kinky hair syndrome is an x-linked recessive disorder caused by defects in ATP7A, an ATP- dependent copper transporter. It is characterized by pili torti, trichorrhexis nodosa, short, britle hair, lax skin, CNS deterioration, seizures, and tortuous arteries.

Answer 165

►B Carney complex is an autosomal dominant disorder caused by mutations in PRKAR1A (protein kinase A regulatory subunit 1-alpha). Key features include cardiac, cutaneous and mammary myxomas, pigmented skin lesions, endocrine abnormalities (pituitary, testicular, thyroid, etc), primary pigmented nodular adrenocortical disease, and psammomatous melanotic schwannomas.

Answer 166

►C Both subunits of integrin can have mutations causing this type of junctional epidermolysis bullosa. Plectin is associated with epidermolysis bullosa simplex with muscular dystrophy. Laminin 5 is mutated in Herlitz and non-Herlitz types of junctional epidermolysis bullosa.

Answer 167

►A Vascular Ehlers-Danlos (Type 4) is characterized by the skin findings discussed above, as well as the onset of severe complications of fragile blood vessels and organs in early adulthood. The disease is inherited in an autosomal dominant manner. Defects are seen in type III collagen. Tenascin-X mutations are seen in hypermobile Ehlers-Danlos (Type 3), type V collagen in classical Ehlers-Danlos (Type 1 and 2), lysyl hydroxylase in kyphoscoliosis Ehlers-Danlos (Type 6), and type I collagen in Ehlers-Danlos types 1, 2, and 7.

Answer 168

►B Eyebrow hair is most common site with hairs demonstrating trichorrhexis invaginata.

Answer 169

►B The patient in this scenario has piebaldism, an autosomal dominant disorder of pigmentation caused most commonly by dominant negative missense mutations in the KIT proto-oncogene. Piebaldism almost always has no progression of the depigmented patches, and is thought to be a static disoder. One exception was noted in a family with a novel Val620Ala (1859T>C) mutation in the KIT gene where development of new depigmented patches did occur. Regression of the white forelock has been noted in select cases. Piebaldism is thought to be unresponsive to systemic treatments or phototherapy. If the patient presented with either eye abnormalities or deafness, Waardenburg syndrome would be considered in the diagnosis.

Answer 170

►C Progeria (Hutchinson-Gilford syndrome) is a sporadic condition characterized by lipoatrophy, sclerodermoid skin, alopecia, nail atrophy, craniomegaly with small face, muscle/bone wasting, and severe premature atherosclerosis resulting in early death. Recent studies have shown that mutations in nuclear envelope protein lamin A is associated with progeria.

Answer 171

►D IgM is decreased in WAS. IgA, IgD and IgE levels are all elevated. IgG is not abnormal in WAS.

Answer 172

►A APC gene has been associated with defects in beta-catenin mediated transcription. The remaining genes are not associated with Gardner syndrome.

Answer 173

►E Marfan syndrome is an autosomal dominant disorder caused by mutations in fibrillin 1 and 2. Patients have tall stature, arachnodactyly, pectus excavatum, high-arched palate, joint laxity, ectopia lentis with upward dislocation, dilated aorta with rupture, mitral valve prolapse, striae, and elastosis perforans serpiginosa.

Answer 174

►A This patient has piebaldism, which is autosomal dominant caused by a defect in the porto oncogene c-KIT. The gene encodes tyrosine kinase receptor on melanocytes. It is associated with CNS abnormalities with motor coordination, cerebellar ataxia, mental retardation, and deafness.

Answer 175

►E The patient has elastosis perforans serpiginosa and is associated with medications and certain systemic conditions. It is associated with the medicine penicillamine, Marfan's syndrome, Down's, osteogenesis imperfecta, and Ehler's Danlos syndrome. It is often self limiting.

Answer 176

►A Uncombable hair syndrome has the characteristic findings of spun-glass hair or cheveux incoiffables. It is associated with pili trianguli et canaliculi

Answer 177

►C Refsum‘s syndrome is an autosomal recessive disorder caused by mutations in phytanoyl -CoA hydroxylase. Clinically, patients have mild icthyosis, cerebellar ataxia, polyneuropathy, salt and pepper retinitis pigmentosa, sensorineural deafness, and arrhythmias with heart block. They are not overly sensitive to UV radiation.

Answer 178

►B Klinefelter syndrome results from nondisjunction during meiosis, leading to the XXY genotype. Patients are characteristically tall (long lower extremities) with scant body and pubic hair. Klinefelter patients have numerous varicosities predisposing them to recurrent leg ulcers.

Answer 179

►E Mendes da COsta syndrome is also called Erythrokeratoderma Variabilis. It is an autosomal dominantly inherited due to a mutation in connexin 31 or connexin 30.3. It is characterized by transient geographic patches of erythema and hyperkeratotic plaques.

Answer 180

►C Accumulation of leukotriene B4 contributes to pruritus in Sjogren Larsson syndrome. Leukotriene inhibitors may be helpful in controlling symptoms.

Answer 181

►D The earliest and most common cutaneous manifestation of tuberous sclerosis are hypomelanotic macules (ash leaf spots), typically presenting at birth or early infancy. 3 or more of these lesions are considered a major criteria in diagnosis. Melanocyte numbers are normal. Confetti-like macules, on the other hand, are usually not apparent until the second decade of life. Facial angiofibromas occur in approximately 75% of patients, and tend to become more prominent with age. Periungual fibromas are considered a major feature for diagnosis, usually presenting around puberty to early adulthood.

Answer 182

►A Piebaldism is linked to a defect in the c-kit protooncogene. Hypomelanosis of Ito has whorled hypopigmentation, occasional CNS defects, scoliosis and anodontia, a sporadic mutation. Waardenburg syndrome has 4 types, 1-3 are AD, 4 is AR. Type 1 & 3 have defects in PAX-3, 2 in MITF, and 4 in Sox10, endothelin-3 ligand or receptor genes. Hermansky-Pudlak syndrome is AR and most commonly linked to defects in HPS, a lysosomal transport protein and AP3B1, a protein important in endocytic/exocytic sorting. Incontinentia pigmenti is an X-linked dominant syndrome with a defect in the NEMO gene.

Answer 183

►A Aplasia cutis congenita presents as well-demarcated erosions at birth with heal with atrophic, alopecic scars. It can be inherited in autosomal dominant, autosomal recessive, or sporadic forms. Aplasia cutis congenia can be caused by teratogens, particular methimazole.

Answer 184

►C Calcification of falx cerebri is seen in Gorlin's syndrome. CHILD syndrome and chondrodysplasia punctata both can exhibit stippled epiphyses. Polyostotic fibrous dysplasia is found in McCune- Albright syndrome, osteopoikilosis in seen in Buschke-Ollendorf syndrome. Sphenoid wing dysplasia is seen in neurofibromatosis type I.

Answer 185

►A This patient has Jobs syndrome. It is characterized with papulopustular rash that progresses to chronic impetiginized eczematous dermatitis and IgE levels that are 10x the normal level. It is also highly suggestive of autosomal dominant hyper IgE syndrome.

Answer 186

►E Hyper-Immunoglobulin E syndrome is an autosomal dominant condition with impaired regulation of IgE function and deficient neutrophil chemotaxis. There is increased susceptibilty to infections and increased IgE serum levels. Retained primary teeth and lack of development of secondary teeth are characteristic findings. The remaining conditions do not have this as a prominent finding.

Answer 187

►A Keratin 2e is mutated in ichythosis bullosa of Siemens. Keratin 5 and 14 are defective in epidermolysis bullosa simplex, 6a/16 in Pachyonychia congenital type I (JadassohnLewandowsky), 1/10 in epidermolytic hyperkeratosis and Unna-Thost PPK.

Answer 188

►A Rubinstein-Taybi syndrome is caused by a sporadically transmitted defect in transcriptional coactivator CREB-binding protein. This gene is responsible for encoding a nuclear protein which acts as a co-activator of cAMP regulated gene expression. Findings of this syndrome include: capillary malformation, short stature, broad thumbs, craniofacial abnormalities including beaked nose, mental retardation, strabismus, congenital heart defects and cryptorchidism. The other listed conditions are not related to this defect.

Answer 189

►D Patients with Cockayne syndrome do not have an increased risk of skin cancer.Â All the other findings are associated with Cockayne syndrome, as well as photosensitivity, deafness, cataracts, and sunken facies.Â Increased chromatid exchange is also seen in Bloom syndrome, dyskeratosis congenita, and Fanconi's anemia.

Answer 190

►B XP variant is DNA nucleotide excision repair proficient, but the defect is in post replication repair of DNA. Increased chromosomal breakage and sister chromatid exchanges is found in Bloom‘s syndrome, an autosomal recessive syndrome caused by a defect in BLM gene, whose product functions as a helicase. Clinical findings include: Telangiectasias, short stature, malar erythema, recurrent infection, increased frequency of leukemia and lymphoma, normal intelligence. Defective DNA nucleotide excision repair of actively transcribing genes is a feature of Cockayne‘s syndrome, an autosomal recessive syndrome with clinical findings including: Cachexia, short stature, pigmentary retinal degeneration, progressive deafness and no increase in neoplasms. Xeroderma pigmentosum has seven different complementation groups (A-G), each associated with a different form of impairment of DNA nucleotide excision repair.

Answer 191

►A Naxos disease is caused by a defect in the plakoglobin protein. It is characterized by woolly hair, keratoderma, and right-sided cardiomyopathy.

Answer 192

►B Lymphomatoid papulosis is a recurrant eruption of unclear etiology characterized by the appearance of red-brown papules and nodules which spontaneously disappear in 3 to 8 weeks. It is notable for histologic features which suggest a CD30 positive malignant lymphoma. There is controversy regarding whether lymphomatoid papulosis (LyP) is a malignant, premalignant or benign condition. The disease may last from months to years and in up to 20% of patients, it may be preceded by, followed by, or associated with another type of cutaneous malignancy. Generally, this is mycosis fungoides, a CD30-positive large T-cell lymphoma or Hodgkin's disease. Because of this potential risk, long-term follow-up of these patients is required.

Answer 193

►A Bazex-Christol-Dupre syndrome has the findings of follicular atrophoderma, hypohidrosis, hypotrichosis and multiple basal cell carcinomas (BCC). Rombo syndrome is associated with BCC and hypotrichosis, but not the other listed findings. The atrophoderma in Rombo syndrome is vermicular, not follicular. Rasmusen syndrome is not associated with BCC.

Answer 194

►A This patient has Gardner's syndrome with a mutation in the tumor suppressor APC gene. These patients with develop adenenomatous polyposis of the colon and rectum with 100% transformation to carcinoma by the age of 30.

Answer 195

►A The dyskerin gene, whose product is involved in ribosomal RNA synthesis, is mutated in Xlinked recessive dyskeratosis congenita. TERC is linked with autosomal domininant transmission of the syndrome. CDKN2A is involved in familial dysplastic nevi/melanoma syndrome, PTEN in Cowden syndrome and Menin in MEN type I.

Answer 196

►A Myosin Va or Rab27a are defective in Griscelli syndrome, an AR syndrome with mild albinism, pancytopenia, immunodeficiency, neurologic symptoms and an accelerated phase similar to Chediak-Higashi syndrome. LYST/CHS1 is defective in Chediak-Higashi syndrome. The P-gene is mutated in oculocutaneous albinism type 2 and TRP in oculocutaneous albinism type 3.

Answer 197

►D X-linked ichthyosis is a X-linked recessive disorder secondary to steroid sulfatase deficiency characterized by brown adherent scale. Additional findings include comma-shaped corneal opacities, cryptorchisdism, and failure to progress during labor.

Answer 198

►A Hypohidrotic ectodermal dysplasia with immune deficiency, is caused by mutations in the NEMO (IKK-gamma gene). As opposed to the X-linked dominant inheritance of Bloch- Sulzberger syndrome (incontinentia pigmenti), this is a X-linked recessive disorder. Hypomelanosis of Ito is sporadically inherited and is not linked with a gene defect. Tuberous sclerosis is autosomal dominant and has been linked to defects in tuberin and hamartin tumor suppressor genes. Waardenburg syndrome has four subtypes, linked with the PAX-3, MITF and SOX10/endothelin-3 receptor genes. Piebaldism is linked to defects in the c-kit protooncogene.

Answer 199

►B Autosomal dominant means that a mutation in a gene on one of the two chromosomes in any autosomal chromosome pair results in disease. Autosomal recessive means that mutations in the same gene on both of the chromosomes in the pair must occur for the disease to occur. Autosomal semidominant means that a mutation in one gene of the autosomal chromosome pair results in a mild version of the disease, while mutations in the gene on both chromosomes results in the full-blown disease. Ichthyosis vulgaris is caused by mutations in filaggrin and inherited in a autosomal semidominant manner. This is the genetic explanation for why the phenotype of ichthyosis vulgaris can vary significantly across individuals.

Answer 200

►A The split in dystrophic epidermolysis bullosa is found in the sublamina densa, where the collagen VII anchors the epidermis to the anchoring plaques in the dermis. The remaining options are incorrect.

Answer 201

►D Clouston syndrome is associated with a defect in Connexin 30 (GJB6 gene). Findings include palmoplantar keratoderma with transgradiens, dystrophic nails, sparse hair with absent body, eyelash, eyebrow hair after puberty. KID syndrome and Vohwinkel syndrome are associated with a defect in Connexin 26 (GJB2). Vohwinkel syndrome variant is associated with a loricrin defect. Erythrokeratoderma variabilis has mutations in Connexin 31 (GJB3) and 30.3(GJB4).

Answer 202

►D Severe combined immunodeficiency is a heterogeneous group of disorders characterized by decreased humoral and cell mediated immunity. Patients may have recurrent infections including cutaneous ones, GVHD (due to in utero cmaternal lymphocytes), sepsis, oral candidiasis, and diarrhea. Implicated genes include the IL-2 receptor (x-linked recessive form) and adenosine deaminase deficiency (autosomal recessive form).

Answer 203

►C This patient has chronic granulomatous disease characterized by dysfunctional phagocytic cells. The most common molecular defect in chronic granulomatous disease is a mutation in the gene encoding the b subunit of cytochrome b. Carriers have a significant incidence of discoid lupus erythematosus, photosensitivity, Raynaud's phenomenon, and aphthous ulcers. Carriers of ataxia telangiectasia are at risk for breast cancer.

Answer 204

►A Diffuse congenital hemangiomatosis is characterized by multiple hemangiomas with the liver being the most common extracutaneous site, followed by the lungs. Liver hemangioma may be complicated by hepatomegaly, obstructive jaundice, and portal hypertension.

Answer 205

►A Lipoid proteinosis is an autosomal recessive disorder caused by defects in the extracellular matrix protein 1 gene. It is characterized by scars and yellow papules of the face and oropharynx, yellowish papules on the eyelid margin, hoarse voice, verrucous nodules of the elbows and knees, and calcification of the temporal lobe and hippocampus with occasional seizures.

Answer 206

►C Hemochromatosis is an autosomal recessive disease resulting in increased intestinal iron absorption and iron deposition in a variety of organs. Clinical features include generalized metallic-grey hyperpigmentation, koilonychia, sparse or absent hair, hepatomegaly, cardiac failure/arrhythmias, insulin-dependent diabetes, hypogonadism and polyarthritis

Answer 207

►A Blue rubber bleb nevus syndrome is described above. There are multiple venous malformations on the extremities and trunk, often present at birth to early childhood. The number of these lesions increase with age. The lesions may have increased sweating and can be combined with lymphatic- venous malformations. Skin lesions can be a clue to gastrointestinal venous malformations which can lead to secondary bleeding and anemia. The most reasonable screening test to determine if the patient has GI hemorrhage is a stool guiac. An MRI or complete blood count can be helpful, but are not the best test to start with. A skin biopsy is not indicated. If there is GI blood loss, evaluation by a gastroenterologist is useful.

Answer 208

►A Patients that have NF1 have a 1% incidence of pheochromocytoma. Other syndromes with flushing and pheo like symptoms are von Hippel-Lindau and MEN2.

Answer 209

►C Harlequin fetus is an autosomal recessive disorder. The gene defect is ABCA12.

Answer 210

►C This description is most likely a white sponge nevus, an autosomal dominant defect in keratin 4/13. Keratin 1/10 is mutated in epidermolytic hyperkeratosis and Unna-Thost PPK, Keratin 6a/16 in pachyonychia congenita type I, and keratin 6b/17 in pachyonychia congenita type II.

Answer 211

►A Buschke Ollendorff syndrome is a rare genetic syndrome characterized by multiple connective tissue nevi and osteopoikilosis. Osteopoikilosis is dysplasia of bone leading to the presence of multiple bone islands in the skeleton. The defective gene is LEMD3. Osteopathia striata is associated with focal dermal hypoplasia. Tibial bowing is seen in rickets. Lumbar ankylosis is found in ankylosing spondylitis. Frequent fractures of long bones is seen in osteogenesis imperfecta.

Answer 212

►C Plakoglobin is an intracellular desmosomal component which binds desmogleins/desmocollins on one side and to desmoplakin on the other. Desmoplakin in turn binds to the keratin intermediate filaments, K1/10 in most cases. Mutation of desmoplakin leads to CarvajaL syndrome, which is associated with a striate palmoplantar keratoderma, woolly hair and Left sided cardiomyopathy. A simple way to remember this is the L in Carvajal cooresponds to the Left sided cardiomyopathy vs. the right sided disease in Naxos disease.

Answer 213

►A Bloom Syndrome and Rothmund-Thompson syndromes are caused by autosomal recessive mutations in DNA helicases. The common features include photodistributed poikiloderma. Patients with Bloom syndrome also demonstrate facial dysmorphism, hypo-gammaglobulinemia with recurrent respiratory and gastrointestinal tract infections, hypogonadism, leukemias and lymphomas, gastrointestinal adenocarcinomas, and oral/esophageal SCCs. Patients with Rothmund-Thompson syndrome develop premalignant acral keratoses, alopecia, nail dystrophy, cataracts, hypogonadism, and occasional solid tumors.

Answer 214

►A Fabrys disease is an X linked recessive disorder. Patients can also get cornea verticillata that look like whorled corneal deposits. They can also get spoke like lens deposits, conjunctival and retinal tortuosity, oculomotor abnormalities.

Answer 215

►A Platelets without dense bodies cause excess bleeding in Hermansky-Pudlak syndrome. Other features of this condition include oculocutaneous albinism, ceroid lysosomal storage disease resulting in pulmonary fibrosis, granulomatous colitis.

Answer 216

►A Patient with Darier's disease have alternating red and whit longitudinal bands with a V-shaped distal nicking, subungual hyperkeratosis and skin findings in the seborrheic areas.

Answer 217

►D Wiskott-Aldrich Syndrome is inherited in an X-linked recessive manner. Epidermolysis bullosa simplex and ichthyosis vulgaris are inherited in an autosomal dominant (AD) manner. Sjogren- Larsson and Netherton‘s syndrome are inherited in an autosomal recessive manner.

Answer 218

►A Buschke-Ollendorf syndrome is an autosomal dominant disorder with dermatofibrosis lenticularis disseminata (elastomas) and osteopoikilosis, or round opacities of the bones. It is caused by a defect in LEMD 3 (MAN1), which codes an inner nuclear membrane protein. Focal dermal hypoplasia can cause osteopathia striata; osteogenesis imperfecta can have bone fractures; and chondrodysplasia punctata can have stippled epiphyses.

Answer 219

►C Palmoplantar keratoderma with deafness is caused by a defect connexin 26 encoded by GJB2. A defect in SLURP-1 causes Mal de Meleda. A defect in plakophilin causes ectodermal dysplasia with skin fragility. A defect in cathepsin C lysososomal papain like cysteine proteinase causes Papillon LeFevre and Haim Munk.

Answer 220

►C The clinical manifestation of Hartnup disease is similar to that of pellagra because the resultant defect in the transport of amino acids leads to low levels of tryptophan. Since tryptophan is required to make nicotinic acid, pts with Hartnup disease manifest the same symptoms as niacindeficient patients (pellagra).

Answer 221

►A Patients with X-linked hypohidrotic ectodermal dysplasi have pegshaped/conical teeth. They have problems with perspiration and thickened nails.

Answer 222

►D Buschke-Ollendorf syndrome is an autosomal dominant syndrome associated with increased elastic fiber in the skin. Key features include dermatofibrosis lenticularis disseminata (also called juvenile elastomas) and osteopoikilosis.

Answer 223

►B Chronic granulomatous disease is characterized by a defect in the ability to kill catalase positive organisms within phagocytic leukocytes. This results from a neutrophilic defect in the cytochrome found in the NADPH oxidative pathway responsible for a respiratory burst. The nitroblue tetrazolium (NBT) reduction assay demonstrates the leukocytes ability to reduce the dye and produce a blue color change. Patients with chronic granulomatous disease are unable to reduce the dye.

Answer 224

►D Cystathione beta-synthetase is defective in homocystinuria, an autosomal recessive conditions characterized by increased homocystine and methionine levels in blood and urine. Other findings include a malar flush, DVTs/emboli, cardiovascular disease, livedo reticularis, leg ulcers, blonde hair/fair complexion, downward lens dislocation, glaucoma, mental retardation, seizures, psychiatric disorders and a marfanoid body habitus. The other enzymes are not involved in this condition.

Answer 225

►A The description above is the classic description for pachyonychia congenita (PC) type I or Jadassohn-Lewandowsky syndrome. Jackson-Lawler syndrome is PC type II, Schafer-Branauer syndrome is PC type III and pachyonychia congenita tarda is PC type IV.

Answer 226

►A Bjornstad syndrome is the most likely diagnosis. This rare syndrome (~25 cases) is autosomal recessive. Findings are of deafness and pili torti. The most common hair finding in Menkes syndrome is pili torti, but it is not associated with hearing loss. Argininosuccinic aciduria is associated with trichorrhexis nodosa and has no associated hearing loss.

Answer 227

►A The diagnostic criteria for neurofibromatosis I include meeting 2 or more of the following 7 criteria: (1) >5 café au lait macules (CALMs) that are >5mm in a prepubertal person or >15 mm in a postpubertal person, (2) >1 neurofibroma or 1 plexiform neurofibroma, (3) axillary/inguinal freckling (Crowe‘s sign), (4) optic glioma, (5) >1 Lisch nodule (iris hamartoma), (6) sphenoid dysplasia, (7) 1st degree relative with neurofibromatosis I.

Answer 228

►A Children with Cornelia de Lange are usually severly retarded with an IQ <35. In addition to the features listed above, other features include cutis marmorata, hypoplastic nipples and umbilicus, low-pitched cry in infancy and congenital heart defects. While most cases are inherited in a sporadic manner, those cases which are familial are thought to be autosomal dominant and associated with the NIPBL (nipped-beta-like) gene. Prognosis is poor with premature death often secondary to sspiration or recurrent pulmonary infection.

Answer 229

►E Incontinential pigmenti is an X-linked dominant disorder caused by a mutation in the NEMO gene located at Xq28. NEMO is an NF-KB modulator. A genetic defect in NEMO leads to defective activation of NF-KB (a transcription factor). MEN IIa is caused by a mutation in the RET proto-oncogene, piebaldism is caused by the C-kit protocogene, chediak-higashi is caused by a mutation in lysosomal tracking, and Vohwinkel‘s is caused by a defect in GJB2 which encodes connexin 26.

Answer 230

►C Congenital contractural arachnodactyly is an autosomal dominant disorder caused by mutationsin fibrillin 2. Affected patients have long limbs, arachnodactyly, scoliosis, and crumpled ears.

Answer 231

►A Waardenburg's syndrome is characterized by depigmented patches, white forelock, and deafness. Both type 1 and 3 are caused by mutations in Pax3. Type 3 is also associated with limb abnormalities. MITF and SOX10 defects are responsible for types 2 and 4 respectively. C-kit proto- oncogene mutatios are seen in piebaldism.

Answer 232

►A Prenatal diagnosis of X-linked ichthyosis is by low to absent estriol during triple screen, presence of non hydrolyzed sulfated steroids in maternal urine. Postnatal diagnosis by serum protein electrophoresis shows increased serum cholesterol sulfate levels.

Answer 233

►A Skin disorders associated with the RAS-ERK-MAPK pathway include: Cardio-facio-cutaneous syndrome, Costello, LEOPARD, NF, and Noonan. Rothmund-Thompson is a RecQ DNA helicase defect. Carney complex and Tuberous sclerosis are associated with the cAMP & AMP activated protein kinase pathway. Griscelli syndrome involves defective vesicle trafficking/transport.

Answer 234

►A Von Hippel-Lindau syndrome is characterized by all the options listed except connective tissue nevi. Other findings include pancreatic cysts/carcinoma and cutaneous capillary malformations of the head and neck and polycythemia.

Answer 235

►C Richner-Hanhart syndrome (tyrosenemia type II) is an autosomal recessive disorder caused by a deficiency in hepatic tyrosine aminotransferase. This disease is characterized by painful PPK, pseudoherpetic keratitis and blindness. Treatment is low-tyrosine/phenylalanine diet.

Answer 236

►A Adams-Oliver syndrome is defined by aplasia cutis congenita (ACC) (shown in the image), usually of the midline scalp with limb hypoplasia. Bart's syndrome also has ACC as a finding, but it is usually present on the lower extremities and associated dominant dystrophic epidermolysis bullosa. Progeria is a premature aging syndrome associated with a lamin -A mutation. Dunnigan syndrome is also known as Familial partial lipodystrophy and is associated with a mutation in the laminin A/ C. Neither are associated with findings of ACC.

Answer 237

►A The SPINK5 gene encodes for LEKTI, a serine protease inhibitor important in the regulation of proteolysis in epithelia formation and keratinocyte terminal differentiation, is mutated in Netherton‘s Syndrome. Other findings include: trichorrhexis invaginata (bamboo, ball and socket hair), atopic dermatitis, and anaphylaxis from food allergy. SLURP1 is mutated in Mal de Maleda, GJB2 in Vohwinkel‘s syndrome, LMX1B in Nail-Patella syndrome, and CYLD in Familial Cylindromiasis.

Answer 238

►D The Ehrlenmeyer flask deformity is found in the femoral midshaft as well as aseptic necrosis of the femoral head and widening of the distal femur. Endochondromas are seen in Maffucci syndrome, Osteopoikilosis in Buschke-Ollendorf syndrome, Melorheostosis (linear hyperostosis under affected skin) in linear scleroderma and supernumerary vertebrae with extra ribs in incontinentia pigmenti.

Answer 239

►D The patient likely has Howel-Evans Syndrome. These patients present with symmetric focal weight bearing PPK in the second decade to adulthood. After the third decade, esophageal carcinoma can occur. These patients should have periodic endoscopic evaluation.

Answer 240

►D Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. Mutations in IL-17 receptor A (IL-17RA, autosomal recessive) and IL-17 receptor F (IL-17F, autosomal dominant) have been reported. IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity.

Answer 241

►A High output congestive heart failure can lead to death in these children. Obstructive jaundice and portal hypertension both occur, but are less likely to cause death. The hemangiomas will undergo spontaneous regression.

Answer 242

►D Hailey-Hailey is an autosomal dominant disorder that usually affects the intertriginous areas. Clinically, there is erythema and linear fissures of the axilla and groin. On pathology, the characteristic finding is acantholytic dyskeratosis in a "dilapidated brick wall" pattern. The gene defect responsible is calcium ATPase 2C1.

Answer 243

►A Fibrofolliculomas are small, benign, yellow or flesh colored papules that are usually inherited in an autosomal dominant fashion and have a predilection for the face, neck and upper trunk. Birt Hogg- Dube syndrome is an autosomal dominant condition characterized by multiple fibrofolliculomas, trichodiscomas, acrochordons, collagenomas. This condition is important to recognize due to its association with renal cell carcinoma. In addition, lung cysts and bullous emphysema are also features of the condition with spontaneous pneumothorax being a potential complication. Muir- Torre syndrome is an autosomal dominant condition caused by a defect in hMSH2 gene. This condition is associated with sebaceous neoplasms including sebaceous carcinoma, sebaceous hyperplasia, sebaceous epithelioma, sebaceous adenoma as well as keratoacanthomas. These can be markers for underlying malignancy in this condition; notably adenocarcinoma of the colon, breast, urinary tract, lung and endometrium. Gardner syndrome is an autosomal dominant condition caused by a defect in the APC familial adenomatous polyposis gene in which patients have multiple hamartomatous polyps of the colon with a high rate of malignant transformation. Cutaneous clues to the diagnosis include multiple epidermoid cysts, fibromas, and desmoid tumors. Other manifestations include osteomas, supernumary teeth, and congential hypertrophy of the retinal pigment epithelium. Tuberous sclerosis, (TS),also known as Bourneville's syndrome is caused by defects in hamartin and tuberin, found on chromosome 9 and 16, respectively. Patients with TS are at increased risk of muliple neoplasms including retinal hamartomas, angiomyolipomas, and cardiac rhabdomyomas. Cutaneous manifestations include ash-leaf macules, shagreen patchs, cafe-au-lait macules, confetti macules, facial angiofibromas, and periungual fibromas. As the name implies, basal cell nevus syndrome is associated with multiple basal cell carcinomas. In addition palmoplantar pitting, multiple milia and epidermoid cysts are seen. It is autosomal dominantly inherited and caused by a defect in the patched gene.

Answer 244

►A Parkes-Weber syndrome has the additional feature of arteriovenous fistulas. The remaining features are not part of these syndromes.

Answer 245

►B This patient has multiple endocrine neoplasia type IIb (MEN IIb) characterized by pheochromocytoma, thyroid cancer, and rare parathyroid carcinoma as well as mucosal neuromas cutaneously. These patients have a marfanoid body habitus. This syndrome is caused by the RET proto-oncogene.

Answer 246

►A Congenital erythropoetic porphyria has dental findings of erythrodontia. Hutchinson teeth and mulberry molars are congenital syphilis. Hypodontia is a finding of X-linked hypohidrotic ectodermal dysplasia.

Answer 247

►D In Wilson's disease (Hepatolenticular Degeneration) one will find a vague greenish discoloration of the skin on the face, neck, and gentalia Hyperpigmentation), azure lunulae (sky-blue moons) of the nails, and Kayser-Fleischer rings. This is due to the body retaining excessive amounts of copper.

Answer 248

►B Wilson‘s disease (also known as hepatolenticular degeneration) is an autosomal recessive disorder result in defective biliary excretion of copper, leading to copper accumulation in the liver, brain and cornea. Clinical features include hepatomegaly, cirrhosis, ataxia, dysarthria, decreased motor coordination, pretibial hyperpigmentation, blue lunulae, and copper deposition in the cornea— Kayser-Fleisher ring, which can be diagnosed using a slit-lamp.

Answer 249

►A Sturge-Weber syndrome is a sporadic disease characterized by a capillary malformation in the trigeminal distribution. Patients may have associated cerebral atrophy, vascular malformations of the leptomeninges, and seizures. All patients with Sturge-Weber should be referred to the opthamologist for glaucoma screening.

Answer 250

►A All of the syndromes listed have X-linked dominant inheritance. CHILD syndome also has findings of stippled epiphyses. Incontinentia pigmenti is caused by defects in the NEMO gene. Findings include peg/conical teeth, eye and CNS defects and alopecia. There are no bone abnormalities. Focal Dermal Hypoplasia, otherwise known as Goltz syndrome has findings of linear atrophy following Blaschko's lines with areas of fat herniation, mucocutaneous papillomas and pits, alopecia, nail dystrophy, tooth abnormalities and osteopathia striata (striations of the long bones). Bazex syndrome is associated with follicular atrophoderma, hypohidrosis, hypotrichosis and multiple basal cell carcinomas. There are no bone abnormalities associated.

Answer 251

►C Pili trianguli et canaliculi is also known as Spun-glass hair or Uncombable Hair Syndrome. Netherton patients have trichorexis invaginata, Menkes kinky hair patients have short, brittle sparse hairs, ―tiger tail* hair is seen in trichothiodystrophy, and pili torti is seen in bjornstad syndrome.

Answer 252

►D Ataxia Telangiectasia (Louis-Bar syndrome) is an autosomal recessive disorder usually caused by mutations in the ATM gene, which is a chromosomal strand break repair enzyme. Cerebellar ataxia is the first sign, followed by telangiectases of the conjunctiva and skin. Thymic hypoplasia predisposes to increased infections. There is increased sensitivity to ionizing radiation resulting in hematologic and solid tumors. Female carriers have increased risk of breast cancer.

Answer 253

►D The pathogensis of Xeroderma Pigmentosum shows mutations i genes encoding DNA repair enzymes, leading to defective DNA excision repair upon exposure to UV radiation. Severe combined deficiency syndrome-major defect in cell-mediated and humoral immunity; most lack antibody-dependent cellular cytotoxicity and natural killer cell function. The pathogensis for Griscelli Syndrome is a mutation in gene encoding for myosin Va or RAB27 a. Sjogren -Larsson Syndrome has mutations in the FALDH gene. Bourneville's syndrome (Tuberous Sclerosis) shows a mutation in either TSC1 ancoding hamartin or TSC2 encoding tuberin.

Answer 254

►A Myotonic dystrophy with multiple pilomatricomas is described above. Activating mutations in Beta-catenin are found in this syndrome. The other listed options are desmosomal proteins and are not involved in this syndrome.

Answer 255

►A Epidermal nevus syndrome has many findings, including: sporadic inheritance, nevus unius lateris, capillary malformations, cafe au lait macules, mantal retardation and seizures, deafness, hemiparesis, hemihypertrophy of limbs, kyphoscoliosis and rare solid tumors. A biopsy is helpful to rule out epidermolytic hyperkeratosis. If positive, the patientǁs offspring are at risk for generalized epidermolytic hyperkeratosis.

Answer 256

►C Netherton syndrome is caused by a mutation in the SPINK5 gene, encoding LEKT1. This is a serine protease inhibitor which is important in downregulating inflammation. Early presentation is with failure to thrive, generalized erythema/scale, hypernatremia, and sparse hair with the characteristic finding of trichorrhexis invaginata. Pili torti and trichorrhexis nodosa also can be seen. Eyebrow hair is most commonly affected. Omenn syndrome is an autosomal recessive form of severe combined immunodeficiency (SCID) with findings of failure to thrive, erythroderma, scaling, chronic diarrhea, lymphadenopathy, and hepatosplenomegaly. Leiner syndrome can present with failure to thrive, immunodeficiency and seborrheic dermatitis. Wiskott-Aldrich syndrome is an x- linked recessive condition with mutations of the WAS gene. Presentation includes atopic dermatitis, thrombocytopenia, recurrent bacterial infection, lymphoreticular malignancy with non-Hodgkin's lymphoma being the most common, and increased IgA, D and E. With the characteristic hair changes, atopic dermatitis alone is not the most likely diagnosis.

Answer 257

►C Both Focal Dermal Hypoplasia (Goltz Syndrome) and Incontinentia Pigmenti are inherited as X linked dominant (lethal in males). And both can have lesions along the lines of Blaschko with many similarities in systemic involvement. However, Incontinentia Pigmenti is differentiated from Focal Dermal Hypoplasia by presence of blistering lesions in addition to hyperkeratosis and hyperpigmentation.

Answer 258

►D Pachyonychia congenital is an autosomal dominant condition with 20 nail dystrophy. The patient described has Type II (Jackson-Sertole) disease, which includes steatocystoma multiplex, natal teeth, multiple cysts, and micropthalmia, and is caused by mutations in keratins 6b& 17. Type I (Jadassohn-Lewandowsky) also includes focal symmetric PPK, follicular hyperkeratosis, oral leukokeratoses and is caused by mutations in keratins 6 &16. Type III includes the clinical features of type I + corneal leukokeratosis. Mutations in keratins 5&14 represents EB simplex, Laminin 5 mutation is seen in Junctional EB, and plakophilin 1 mutation is seen in ectodermal dysplasia with skin fragility.

Answer 259

►D Chediak higashi is an autosomal recessive disorder caused by a mutation in the LYST gene codes for a lysosomal tracking protein. This protein regulates microtubule mediated lysosomal fusion. A defect in this gene leads to giant lysosomal granules seen in neutrophils (leading to defecting phagocytosis and decreased chemotaxis), melanocytes (pigment dilution), and neurons. OCA1 is tyrosinase negative albinism; OCA2 is tyrosinase positive albinism with a mutation in P gene on chromosome 15.

Answer 260

►C Loss-of-function mutations in phosphatase and tensin homolog gene (PTEN) mutations cause 80% of Cowden Syndrome, a rare autosomal-dominant disorder, characterized by high risks of breast, thyroid, and other cancers. Other mechanisms of loss of function such as hypermethylation of the KILLIN gene has been identified in Cowden Syndrome. Bannayan Riley-Ruvalcaba and Proteus syndrome are associated with PTEN loss-of-function mutations. Birt-Hogg-Dube is associated with loss-of-function mutations in FLCN gene. Galli-Galli Disease is not a malignancy-associated disease and is the result of KRT5 mutations.

Answer 261

►D Dyskeratosis congenita is usually inherited in an X-recessive fashion due to mutations in the dyskerin gene, which is involved in ribosomal RNA synthesis. The less common autosomal dominant form is caused by mutations in the telomerase gene. Clinically, there is reticulated pigmentation of skin, poikiloderma, alopecia, nail atrophy, premalignant oral leukoplakia, and Fanconi-type pancytopenia that can result in early death. They also get severe oral SCC.

Answer 262

►A Uncombable hair syndrome is characterized by pili trianguli et canaliculi. On examination of the hair, it is triangular with a canal-like groove runs along the shaft. The clinical findings are that of blond, shiny, "spun glass" hair. It is an autosomal dominant syndrome with no known gene locus. The remaining syndromes do not have this hair finding present.

Answer 263

►A Patient with NF 1 have an initial presenting sign of cafe-au-lait macules. Axillary or inguinal freckling is known as Crowe's sign. This is pathogonomic for NF 1. Patients with NF 1 can have a lit lam examination that will show Lisch nodules that will confirm the diagnosis.

Answer 264

►B Chondrodysplasia punctata is a peroxisomal disorder caused by mutations in several genes that is associated with ichthyosiform erythroderma in lines of Blaschko, follicular atrophoderma, and stippled epiphyses.

Answer 265

►E Buschke-Ollendorf syndrome is an autosomal dominant disorder characterized by dermatofibrosis lenticularis disseminata (cutaneous elastomas distributed symmetrically over the buttocks, trunk and proximal extremities), and osteopoikilosis (round opacities in bones).

Answer 266

►A Hereditary Hemorrhagic Telangiectasia syndrome is described above. The first signs in over 50% of cases is epistaxis in childhood to young adulthood. Telangectiasias develop in the 30's and 40's. Other findings include gastrointestinal telangiectasia, hepatic and pulmonary arteriovenous malformations. The other syndromes listed can have cutaneous vascular lesions and should be considered on the differential for hereditary hemorrhagic telangiectasia syndrome.

Answer 267

►A Mutations in the ABCA12 gene cause harlequin ichthyosis. X-linked ichthyosis (XLI) caused by a steroid sulfatase (STS) deficiency. Keratitis-ichthyosis-deafness syndrome is caused by a mutation in the GJB2 (connexin 26) gene. Ichthyosis vulgaris is caused by a defect in profilaggrin gene and lamellar ichthyosis involves a mutation in the gene for transglutaminase 1 (TGM1).

Answer 268

►A Li-Fraumeni syndrome is a familial tumor syndrome caused by mutations in the tumor suppressor gene p53. They are at risk for a wide range of malignancies with particularly high occurrences of soft tissue sarcomas, breast cancer, brain tumors, acute leukemia, and adrenal cortical carcinoma. Soft tissue sarcomas are among the most common reported with this disease.

Answer 269

►C Familial dysplastic nevi/melanoma syndrome is linked with increased risk of pancreatic cancers and astrocytomas. There are no reported increased risks for patients with familial dysplastic nevi syndrome and the other types of cancers listed.

Answer 270

►B The RET proto-oncogene is mutated in Multiple Endocrine Neoplasia type II. Type IIb is described above. Other findings include rare parathyroid abnormalities, megacolon, thickened lips and thick, everted upper eyelids. Menin is associated with MEN type I, PTEN with Cowden disease, BHD with Birt-Hogg-Dube syndrome and STK11 with Peutz-Jeghers syndrome.

Answer 271

►C The most common type of EDS is EDS type I (gravis). Cutaneous features include hyperextensible skin, gaping wounds, cigarette-paper scars, molluscoid pseudotumors, calcified subcutaneous nodules, and bruises. Systemic features include hypermobile joints with dislocation, hernias, mitral valve prolapse, blue sclerae, Gorlinǁs sign (tongue reaches nose), and absence of the lingual frenulum.

Answer 272

►E Cornelia de Lange is also known as Brachmann-de Lange syndrome. Cutaneous manifestations include cutis marmorata, hirsutism, hypoplastic nipples and umbilicus. Patients also have small hands and feet. They have characteristic facies which include hirsutism on the forehead, trichomegaly, synophrys, anteverted nostrils, long philtrum, and low-set ears.

Answer 273

►A Patients with Hay-wells syndrome has a mutations in P63. They have wiry, sparse hair, ankyloblepharon, PPK, partial anhidrosis, cleft lip, palate, absent, and dystrophic nails.

Answer 274

►A Sjogren-Larsson syndrome is an autosomal recessive disorder caused by mutations in the fatty aldehyde oxidoreductase/alcohol dehydrogenase gene. This disorder is characterized by ichthyosis, spastic ditetraplegia, mental retardation, epilepsy, glistening dot retinal pigmentation, and dental enamel dysplasia.

Answer 275

►B Painful crises and whorled corneal opacities are found in Fabry disease which is caused by a defect in alpha-galactosidase A. The remaining conditions do not have these findings.

Answer 276

►C Maffucci syndrome is a sporadic condition caused by defects in the parathyroid hormone/ parathyroid hormone related protein type 1 receptor. There are venous malformations of distal extremities, and benign enchondromas that can degenerate into chondrosarcomas.

Answer 277

►E Cysteine and Methionine levels are decreased in hair and nails of patients with trichothiodystrophy. Other sulfur containing amino acids include: Gluthathione, Taurine, and Homocysteine. Testing hairs for decreased sulfur content is an indirect method of determining this. The other listed amino acids are present in normal levels in the hair and nails of trichothiodystrophy patients.

Answer 278

►A Hallopeau Siemens dystrophic EB is characterized by pseudosyndactyly, mitten deformities of the hands and feet. Non Hallopeau Siemens is much less severe. Not present in junctional epidermolysis bullosa or epidermolyisis bullosa simplex.

Answer 279

►A Keratins are expressed in pairs of acidic and basic keratins and are tissue- and differentiation- specific. Keratins 1 and 9 are expressed in the suprabasal palmoplantar epidermis, keratins 1 and 10 in suprabasal nonpalmoplantar epidermis, keratins 2e and 10 in the granular layer, keratins 4 and 13 in mucosal epithelium, keratins 5 and 14 in the basal layer, and keratins 8 and 18 in simple epithelium.

Answer 280

►E Ehlers-Danlos Syndrome type with congenital adrenal hyperplasia is caused by mutations in tenascin-X.

Answer 281

►A CHIME syndrome has all the findings of colobomas of the eye, heart defects, ichthyosiform dermatosis, mental retardation and ear defects.

Answer 282

►A Acrodermatitis enteropathica is due to a defect in zinc absorption and will respond to zinc supplementation. Iron, Vitamin B1/12 supplementation will not result in improvement in this condition. Findings include periorificial, scalp, and acral dermatitis, scaling, vesicles/bullae, erosions, alopecia, diarrhea and stomatitis.

Answer 283

►E Ulerythema ophryogenes is a rare disorder that affects children and young adults. It is characterized by keratosis pilaris atrophicans and loss of lateral third of eyebrow.

Answer 284

►B Ehlers-Danlos Syndrome type 4 (Vascular) is caused by mutations in collagen 3 in some cases. There is a tendency to develop arterial and visceral rupture resulting in early death.

Answer 285

►C Enamel pits are the characteristic dental findings in tuberous sclerosis. Peg teeth are found in incontinentia pigmenti and anhidrotic ectodermal dysplasia. Anodontia is found in hypomelanosis of ito and incontinentia pigmenti. Odontogenic cysts are seen in Gorlin syndrome, and retention of primary teeth is characteristic of Job syndrome.

Answer 286

►B Proteus is due to an AKT1 mutation. The remaining syndromes are due to PTEN mutations. The PTEN gene produces a phosphatase the regulates the cell-cycle and apoptosis, therefore acting as a tumor suppressor gene. Tissues affected by this mutation are those with increased proliferation such as epidermis, the oral and gastrointestinal mucosa, and the thyroid and breast epithelium. All of the syndromes listed have mutations in PTEN.

Answer 287

►E The above described patient has homocystinuria, an autosomal recessive disorder caused by a deficiency in cystathionine beta-synthase, leading to an accumulation of homocysteine. Clinical features include: malar flush, DVTs, livedo reticularis, leg ulcers, downward lens displacement, myopia, glaucoma, sparse fine hair, mental retardation, and musculoskeletal anomalies.

Answer 288

►B CHILD syndrome is an X-linked dominant syndrome which is lethal in males. It is caused by a peroxisomal biogenesis disorder. It is characterized by unilateral ichthyosiform erythroderma, limb/visceral hypoplasia, and stippled epiphyses. Stippled epiphyses can also be seen in chondrodysplasia punctata. Polyostotic fibrous dysplasia is found in McCune-Albright syndrome, calcification of falx cerebri in Gorlin's syndrome, osteopoikilosis in seen in BuschkeOllendorf syndrome.

Answer 289

►D Classic Vohwinkel syndrome is caused by mutations in connexin 26, a gap junction protein. Ichthyotic Vohwinkel syndrome is caused by mutations in loricrin and has ichthyosis but not deafness.

Answer 290

►A This patient has Sjorgen-Larsson syndrome, which is autosomal recessive disorder caused by a deficiency of FALDH. These patients have the clinical triad of congenital ichthyosis, tetraplegia, and mental retardation. The ichthyosis is notable in that there is accentuation of the flexures and lower abdomen.

Answer 291

►A Patients that have Howel-Evans syndrome are subject to squamous cell carcinoma of the esophagus and also PPK on the hands. It is inherited in an autosomal dominant fashion.

Answer 292

►C The patient described may have Cowden's syndrome, an autosomal dominant condition caused by a defect in the PTEN tumor suppressor gene. Patients with Cowden's disease are at increased risk for thyroid and breast carcinoma. In addition, they characteristically have multiple hamartomatous polyps of the gastrointestinal tract that are typically benign. Cutaneous features of Cowden's syndrome which may serve as clues to the diagnosis include multiple oral papillomas with a "cobblestone" appearance on the lips, gingival, and buccal mucosa, acral keratotic papules on the dorsal hands and wrists, palmoplantar punctate keratoses and multiple facial tricholemmomas. Patients with this condition need careful malignancy surveillance.

Answer 293

►C The mutation in X-linked icthyosis is found in the gene for aryl sulfatase C, a steroid sulfatase. The genetic defect in Fabry disease occurs in alpha-galactosidase A (which hydrolyzes glycolipids and glycoproteins), the defect in lamellar icthyosis codes for transglutaminase 1 and the defect in chediak higashi occurs in a lysosomal transport protein.

Answer 294

►A Patients with Naxos syndrome has a mutation in plakoglobin which is autosomal recessive. It is associated with woolly hair and cardiomyopathy.

Answer 295

►A The major diagnostic criteria are: 6 or more cafe au lait macules >5mm in prepubertal individuals and >15mm in post pubertal individuals, 2 or more neurofibromas of any type or one plexiform neurofibroma, axillary or inguinal freckling, 2 or more lisch nodules, sphenoid wing dysplasia or thinning of long bone cortex with or without pseudoarthosis, first degree relative with NF1.

Answer 296

►A A patient was progeria has a mutation in the LMNA gene which encodes lamin A and C. It is distinguished from adult progeria by early onset.

Answer 297

►A Type 3 Ehlers-Danlos syndrome, or benign hypermobile Ehlers-Danlos syndrome, is a relatively mild form of EDS with recurrent joint dislocations. The syndrome is a result of defective collagen 3. Defective collagen 5 is seen in EDS types 1 and 2 (gravis and mitis, respectively). Lysyl oxidase deficiency is seen in Type 5 (x-linked). Collagen 2 mutations can lead to Type 7 (arthrochalasis multiplex congenita). The PLOD gene is involved in type 6 (ocular-scoliotic).

Answer 298

►C Dyskeratosis congenita, also called Zinsser-Engman-Cole syndrome, is an X-linked recessive genodermatosis caused by a mutation in DKC1. DKC1 encodes for dyskerin, which helps to maintain telomeres through the pseudouridylation of rRNA. Features of this condition include reticulate gray-brown hyperpigmentation, dystrophic nails, alopecia and Fanconiǁs type pancytopenia. Patients may have premalignant leukoplakia which should be followed closely.

Answer 299

►D Homocystinuria is an autosomal recessive disease caused by a deficiency of cystathionine synthetase. Manifestations of this condition may include mental retardation, marfanoid habitus, malar flush, ectopic lentis, embolic phenomena and leg ulcers.

Answer 300

►D Papillon-Lefevre is a palmoplantar keratoderma caused by a mutation in chromosome 11q14, leading to a defect in Cathepsin C, a lysosomal enzyme. Clinical manifestations of papillon lefevre include sharply demarcated palmoplantar keratoderma with extension to dorsal surface (transgrediens), spare hair, periodontitis, and pyoderma.

Answer 301

►B Pseudoxanthoma elasticum is genodermatosis characterized by redundant skin, angioid streaks, yellow papules on the mucous membranes and bleeding from gastric artery. On histology, readily apparent denerative changes of the elastic fibers are prominent, even without special stains.

Answer 302

►B Gorlin syndrome (Basal Cell Nevus Syndrome)is an autosomal dominant disorder due to a defect in the PTCH gene whose function normally inhibits ―SMOOTHENEDǁ signaling. Odontogenic cysts and palmoplantar pits are characteristic features, in addition to multiple bas al cell carcinomas. Other features include: frontal bossing, kyphoscoliosis, calcification of falx cerebri, hypertelorism, ovarian fibromas and rarely mental retardation.

Answer 303

►C SPRED-1 acts as a suppressor of the Ras/MAPK pathway, the same pathway involved in neurofibromatosis-1. Likewise, defects in SPRED1 are the cause of neurofibromatosis type 1 like syndrome, also known as Legius Syndrome. Legius Syndrome has the following characteristics: cafe au lait spots, axillary and inguinal freckling, learning disability, and macrocephaly; likewise patients can actually meet criteria for the clinical diagnosis of NF-1. Although Legius Syndrome has many overlapping features with NF1, neurofibromas, lisch nodules, and CNS tumors have not been reported. (Brems H, et al. Nat Gen 2007.)

Answer 304

►B The gene responsible for APECED is the AIRE gene, an autoimmune regulator. Th e XAP101 encodes dyskerin, a defect in which causes dyskeratosis congenita. A defect in CGI-58 causes Chanarin-Dorfman or neutral lipid storage disease with ichthyosis. Defect in the ALOX genes cause congenital ichthyosiform erythroderma. A defect in the PAHX gene causes Refsum syndrome.

Answer 305

►A Turner’s syndrome results from nondysjunction during gametogeneiss leading to the XO genotype. Clinical features include short stature, redundant neck folds/webbed neck, multiple pigmented nevi, low set hairline, triangular facies, low-set ears, ptosis, wide-set nipples, shortened 4th and 5th metacarpals, hypoplasia of lymphatics, coarctation of the aorta, and horseshoe kidneys.

Answer 306

►C McCune-Albright syndrome is due to a sporadic somatic mutation in Gs subunit of adenylate cyclase. The "coast of Maine" cafe au lait macule is a characteristic finding. Other findings in clude polyostotic fibrous dysplasia and precocious puberty. Tuberous sclerosis, Neurofibromatosis type I, Watson syndrome (pulmonic stenosis and CALM's) and Russell-Silver syndrome (CALMs, short stature, precocious puberty, cryptorchidism and musculoskeletal/craniofacial defects) all have CALMs as a feature, but not the jagged type seen in McCune-Albright syndrome.

Answer 307

►A Rothmund-Thomson syndrome is an autosomal recessive disorder. They have a sparse scalp, eyebrow, and eyelash hairs. Poikiloderma is seen in sun-exposed areas, dystrophic nail and juvenile cataract.

Answer 308

►A The ATM gene is a member of the phosphatidylinositol-3 family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair according to OMIM. Defects in endoglin (TGF beta3 binding protein) is deficient in Osler-Weber-Rendu syndrome. The VEGF receptor 3 is defective in hereditary lymphedema. The NEMO gene is defective in Incontinentia Pigmenti. Its product, NF-kB essential modulator (NEMO) is a key activator in the NF-kB pathway. KIP2 is involved in AD Beckwith-Wiedemann syndrome and is an inhibitor of G1 cyclin/Cdk complexes.

Answer 309

►A Patients with Darier‘s disease should not be treated with lithium due to its worsening or in some cases unmasking the disease. The mechanism for this is not known. Lithium treatment does not worsen the other listed conditions.

Answer 310

►A Bilateral vestibular schwannomas are related to type II neurofibromatosis. The remaining options are diagnostic criteria for NF-1. Greater than 5 CALMS is the same as 6 or more CALMS as listed in the diagnostic criteria.

Answer 311

►C This patient has Lhermitte-Duclos disease, which is a hamartomatous overgrowth of cerebellar ganglion cells. Approximately half of patients have Cowden syndrome. Breast cancer is the correct answer, which affects 25-35% of female patients. Patients can also develop thyroid and genitourinary carcinoma (endometrial, urethral, renal cell, and transitional cell carcinoma of the renal pelvis). Malignant degeneration of hamartomatous colon polyps is rare.

Answer 312

►B Gorlin's syndrome (Basal cell naevus syndrome) is not associated with multiple lipomas. The PTEN associated syndromes (Cowden's, Bannayan-Riley-Ruvalcaba and Proteus syndromes) are all associated with multiple lipomas as well as Gardner's, neurofibromatosis and MEN.

Answer 313

►D Orofaciodigital sydrome 1 is an X-linked dominantly inherited disorder caused by a defect in the CXORF5 gene. The rest of the above conditions are inherited in an x-linked recessive pattern.

Answer 314

►C Ichthyosis with confetti, a severe, sporadic skin disease in humans, is caused by mutations in the gene encoding keratin 10 (KRT10); all result in frameshifts into the same alternative reading frame, producing an arginine-rich C-terminal peptide that redirects keratin 10 from the cytokeratin filament network to the nucleolus.

Answer 315

►A Bjornstad syndrome has a characteristic sensorineural deafness that is bilateral and also flattened twisted hairs called pili torti that causes the hair to look lusterless. It can be autosomal dominant and cases of autosomal recessive conditions have been reported

Answer 316

►A Patients with homocystinuria have elevated serum homocysteine and methionine levels due to a deficiency of cystathionine beta synthase.

Answer 317

►C Anhidrotic ectodermal dysplasia is an x-linked recessive disorder which presents with the triad of hypohydrosis (or anhidrosis) with hyperpyrexia, anodontia (other dental findings include peg teeth, molars with hooked cusps) and sparse hair. Patients tend to overheat.

Answer 318

►B Cowden syndrome (multiple hamartoma syndrome) is an autosomal dominant disorder caused by mutations in PTEN, a phosphatase that dephosphorylates tyrosine, serine, and threonine. Clinically, there are numerous facial trichilemmomas, oral papillomas, acral keratotic papules, sclerotic fibromas, breast fibroadenomas and adenocarcinomas, thyroid adenomas and adenocarcinomas, and hamartomatous polyps of the gastrointestinal tract.

Answer 319

►B Muir-Torre syndrome is an autosomal dominant disorder due to a DNA mismatch repair gene (MSH2). Patients present with sebaceous tumors, with adenomas being the most common (sebaceous carcinomas next common) and associated visceral malignancies such as colon cancer (most common).

Answer 320

►B Chronic granulomatous disease is diagnosed by the nitroblue tetrazolium reduction assay. The abnormal white blood cells cannot reduce dye due to the inability to produce the respiratory burst. This is needed to kill catalase positive organisms after phagoc ytosis. Fumarate hydratase is defective in familial multiple cutaneous leiomyomatosis, sphingomyelinase in Niemann-Pick disease and glucocerebrosidase in Gaucher disease.

Answer 321

►A SLURP1 (Secreted LY6/UPAR-related protein 1) is defective in Mal de Meleda. Keratin 1/9 are defective in Unna-Vorner/Thost palmoplantar keratoderma, an AD diffuse symmetric nontransgradiens PPK. TOC gene is defective in Howel-Evans syndrome, an AD PPK associated with focal, pressure-related, non-transgradiens PPK and esophageal cancer/oral leukoplakia. Loricrin mutations are seen in Vohwinkel syndrome variant and symmetric progressive erythrokeratodermia. Cathepsin C defects are seen in Haim- Munk syndrome (PPK+periodontitis+acroosteolysis+onychogryphosis) and Papillon-Lefevre syndrome (sharply demarcated transgradiens, stocking-glove PPK+periodontitis+dural calcifications and choroids attachments).

Answer 322

►A Beare-Stevenson cutis gyrata syndrome has been linked to mutations in fibroblast growth factor receptor 2. This syndrome is characterized by: craniosynostosis, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, prominent umbilical stump, furrowed palms and soles. Apert syndrome is also linked to this mutation. BSCL2 is linked to Berardinelli-Seip congenital lipodystrophy, LMNA to Familial partial lipodystrophy and ATP7A to Menkes kinky hair syndrome.

Answer 323

►D Monilethrix is an autosomal dominant condition which, by definition, presents with beaded hair. Clinically, patients present with short, sparse lusterless hair. Keratosis pilaris is the most common associated feature.

Answer 324

►D Menkes kinky hair syndrome is an x-linked recessive disorder caused by a mutation at Xq12 leading to defective intestinal copper transport.

Answer 325

►A Muir-Torre syndrome is an autosomal dominant disease caused by mutations in MSH2 and MLH1, DNA mismatch repair genes. Clinically, patients have multiple sebaceous tumors (adenomas are most common), keratoacanthomas, and are at risk for adenocarcinoma of the colon.

Answer 326

►E Nevoid basal cell carcinomas syndrome (Gorlin syndrome) is an autosomal dominant condition caused by mutations in the patched gene, which is involved in the hedgehog signaling pathway. Patients develop innumerable BCCs, palmoplantar pits, painful odontogenic jaw keratocysts, frontal bossing, bifid ribs, and calcification of the falx cerebri. Medulloblastomas and ovarian fibromas and fibrosarcomas are associated with this condition.

Answer 327

►A Cowden's disease is an autosomal dominant disorder is a mutation in the PTEN gene. It is associated with breast cancer, follicular thyroid, and colon hamartoma.

Answer 328

►B The findings described are consistent with Wiskott-Aldrich syndrome. The characteristic triad can be simplified to the 3 P's - Pruritus (atopic dermatitis), Purpura (thrombocytopenia leading to purpura and other bleeding) and pyogenic infections. The remaining options are related to Wiskott- Aldrich in that they all have immunodeficiency as a feature, but not the same spectrum of disease.

Answer 329

►A Pseudoherpetic keratitis and a painful PPK describes a patient with Richner-Hanhart syndrome (tyrosenemia type II). Treatment is with a diet low in tyrosine and phenylalanine. A diet low in glycine, cytosine, biotin or zinc would not be helpful in this syndrome.

Answer 330

►A Lysyl oxidase deficiency is related to type V or X-linked Ehlers-Danlos syndrome (EDS). Type IX, also has x-linked recessive inheritance with mild symptoms of EDS with occipital exostoses and hernias. Lysyl hydroxylase deficiency is seen in type VI EDS, linked with severe kyphoscoliosis, retinal detachment and other eye abnormalities. Collagen V deficiencies are seen in type I (Gravis) and type II (Mitis) EDS, associated with skin elasticity, gaping wounds, hypermobile joints, Gorlins sign, blue sclera and mitral valve prolapse.

Answer 331

►A Lamellar ichthyosis is an autosomal recessive condition. If each parent is a heterozygous carrier, there is a 25% chance that the child will be affected, 50% chance that the child will be a heterozygous carrier and a 25% chance that the child will not be a carrier or affected with lamellar ichthyosis.

Answer 332

►E Epithelioid blue nevi have been reported with and without association with cardiac myxomas as a component of the Carney complex (NAME/LAMB syndrome). Carney complex is an autosomal dominant disorder caused by mutations in PRKAR1A. Patients have cutaneous and atrial myxomas, blue nevi, ephelides, adrenocortical disease, and testicular tumors.

Answer 333

►A Patient with Muir-Torre Syndrome have a high incidence of colon cancer. It is an autosomal dominant disorder caused by the mutation in either MSH2 or MLH1 gene. The other malignancy can be seen with this syndrome but colon is the most common.

Answer 334

►A Regarding the genetics of melanoma, BRAF mutations are more common than NRAS mutations on non sun-damaged skin. C-kit is associated with mucosal melanoma. Acral melanoma are associated with c-kit more commonly than with BRAF.

Answer 335

►A Neurofibromatosis I occur due to a microdeletion at 17q11.2 involving the NF1 gene, which encodes for neurofibromin. It is an autosomal dominant disorder characterized by numerous benign tumors (neurofibromas) of the peripheral nervous system, cafe au lait macules, freckling in the area of the armpit (crowǁs sign), two or more growths on the iris of the eye (known as Lisch nodules or iris hamartomas), tumor on the optic nerve (optic glioma), abnormal development of the spine (scoliosis), the temple (sphenoid) bone of the skull, or the tibia (one of the long bones of the shin) and a first degree relative (parent, sibling, or child) with NF1. The other proteins in the list are associated with other syndromes: In neurofibromatosis type 2, a NF2 gene mutation has been identified which encodes for a protein called Merlin, in tuberous sclerosis two genetic mutations have been identified on two separate chromosomes namely tuberin and hamartin, and a Folliculin mutation is seen in Birt Hogg Dube syndrome.

Answer 336

►E First sign is ataxia. Telangiectasias occur later in puberty. Carriers show an increased risk of breast cancer.

Answer 337

►B Patients with Hermansky-Pudlak syndrome are tyrosinase positive albinos. In addition to their pigmentary dilution and increased risks for cutaneous malignancies, patients lack platelet granules leading to impaired platelet aggregation (and therefore a bleeding diathesis). There is also a lysosomal membrane defect which leads to the accumulation of ceroid lipofuscion in macrophages within the lung (leading to pulmonary fibrosis), gastrointestinal tract (leading to granulomatous colitis), and heart (cardiomyopathy).

Answer 338

►A Anhidrotic ectodermal dysplasia is a X-linked recessive disease caused by mutations in ectodysplasin, a member of the tumor necrosis family. Patients may have dry skin with pigmentation periorbitally, hypohidrosis, sparse hair, hypo-anodontia, nail dystrophy, and frontal bossing, and saddle nose deformity. In addition to abnormalities of other ectodermally derived structures, the breast and nipple-areolar complex may be absent or hypoplastic.

Answer 339

►A LAD-1 manifests as a B2-integrin deficiency and often times presents as at birth with a delayed umbilical cord separation.

Answer 340

►B Lipoid proteinosis is an autosomal recessive condition characterized by yellow papules on the face and oropharynx, eyelid string of pearls, hoarse voice, verrucous nodules of elbows and knees, and bean-shaped temporal and hippocampal calcification with occasional seizures. Histologically, there are PAS+ deposits in the affected tissue.

Answer 341

►D All of the syndromes listed are XD. Other XD syndromes are: Incontinentia pigmenti and Bazex syndrome.

Answer 342

►A Nevoid basal cell syndrome is an inherited condition with a defect in the PTCH gene. The dental findings are odontogenic keratocysts.

Answer 343

►A Cowden syndrome is a autosomal dominant syndome with tricholemmomas, oral mucosal papules, acral keratotic papules, thyroid goiter, GI polyps, and fibrocystic breast disease. Malignant associations include breast, thyroid follicular carcinoma, and colon adenocarcinoma-malignant transformation of the polyps. They are also at increased risk for renal cell carcinoma and endometiral carcinoma

Answer 344

►A A patient that has clinical signs of xeroderma pigmentosum with mental retardation, dwarfism and gonadal hypoplasia is known as De-Santis-Cachione syndrome. Those that have xeroderma pigmentosum have skin cancer at a young age and is from mutations in DNA excision repair enzymes involved in UV induced thymidine dimers.

Answer 345

►D Bonnet Bechaune Blanc syndome, also know as Wyburn-Mason syndrome, is characterized by a facial vascular malformation and ipsilateral intracranial and retinal AVMs. Encephalotrigeminal angiomatosis is another name for Sturge-Weber. Von Lohuizen's disease is another name for cutis marmorata telangiectatica congenita.

Answer 346

►C Tricholemmomas are seen in Bannayan-Riley-Ruvacalba syndrome. This is an autosomal dominant condition with macrocephaly, lipomas, hemangiomas, skeletal abnormalities, lymphangioma circupscriptum, angiokeratomas, penile lentigines, acanthosis nigricans, and achrocrodons. There is an increased incidence of breast, thyroid, and GI cancers. Tricholemmomas are also associated in Cowden's syndrome.

Answer 347

►A Multiple endocrine neoplasia (MEN) syndrome type Iib, also called multiple mucosal neuroma syndrome is an autosomal dominant condition due to a defect in the RET protooncogene on chromosome 10q11.2. This rare condition is associated with mucosal neuromas on the tongue and lips, medullary thyroid carcinoma, pheochromocytoma, and gastrointestinal ganglioneuromatosis. In addition, patients can also present with a marfanoid habitus and facial dysmorphism. Mucosal neuromas can be a dermatologic clue to the underlying diagnosis as these lesions appear during early childhood and present as pink, pedunculated nodules. As the major cause of mortality in these patients is medullary thyroid cancer, which nearly all patients will have by early adulthood, aggressive screening, with serial calcitonin level, and prophylactic thyroidectomy are warranted.

Answer 348

►A The erythematous keratotic plaques of KID Syndome occur on face, extremities > trunk. KID Syndrome is characterized by keratitis, icthyosis, and deafness. It is inherited in an autosomal

Answer 349

►D Cobb syndrome is a sporadic disease characterized by cutaneous vascular malformations associated with malformations of the spinal cord.

Answer 350

►D Basal cell nevus syndrome is an autosomal dominant disease caused by mutations in the PTCH1 gene. Clinically, patients may have numerous basal cell carcinomas, palmoplantar pits, jaw cysts, frontal bossing, bifid ribs, calcification of falx cerebri, medulloblastoma, ovarian fibromas and fibrosarcomas.

Answer 351

►E Cronkhite-Canada is associated with gastrointestinal polyposis, nail atrophy, alopecia, generalized pigmentation of skin and melanotic macules on the fingers. It is inherited in a sporadic manner.

Answer 352

►E All of the answers are correct. Laminin 5 is a protein integral in the adhesion of the dermis to the epidermis. Also involved in junctional epidermolysis bullosa is bullous pemphigoid antigen 2, collagen 17 and BP180, which are synonymous for the same structure.

Answer 353

►C Riley-Day syndrome is also known as Familial Dysautonomia. It is an autosomal recessive disorder with the gene defect on the long arm of chromosome 9. Patients have unmyelinated sensory and sympathetic neurons and autonomic dysfunction, leading to hyperhidrosis, decreased corneal sensation and tear flow, hypersalivation, gastroesophageal reflux, decreased deep tendon reflexes, and lack of pain sensation. They also exhibit abnormal histamine skin test.

Answer 354

►C Tay Syndrome is also known as trichothiodystrophy, or (P)IBIDS: (photosensitivity), icthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature. Hair shaft has a characteristic ―tiger tail appearance under polarized light and the low cystine content in hair and nails is thought to be responsible for the phenotype seen.

Answer 355

►C McCune-Albright syndrome is a sporadic condition caused by somatic mutations in the Gs subunit of adenylate cyclase. Key clinical features include ―coast of Maine cafe au lait macules, polyostotic fibrous dysplasia, and precocious puberty.

Answer 356

►A The ferritin is the best screening test for hemochromatosis, an autosomal recessive disease of increased intestinal iron absorption. The other tests are not the best method for screening.

Answer 357

►A The patient has cutis marmorata with low set hair line, trichomegaly, synophrys, hirsutism, and heart defect. The associated gene is NIPBL and SMC1L1.

Answer 358

►C Job syndrome or Hyper IgE syndrome is characterized by these findings. In addition, there is a peripheral eosinophilia, eczematous dermatitis, frequent bronchitis and pneumonia, otitis media and sinusitis. The other listed conditions are associated with immunodeficiency. Wiskott-Aldrich can have eczematous dermatitis and all of these syndromes will have abnormal infections. They do not have markedly increased levels of IgE like Job syndrome.

Answer 359

►A Her mother is a heterozygote for the condition and her father is homozygous as a non -carrier. Gardner syndrome is passed in an autosomal dominant fashion. She has a 50% chance of also being a heterozygote from her mother and a 50% chance of being completely unaffected.

Answer 360

►A The child described most likely has lipoid proteinosis, a rare inherited disease of connective tissues that is inherited in an autosomal recessive manner. The implicated defective protein is extracellular matrix protein-1. Collagen III and Tenascin-X defects are seen in Ehlers-Danlos syndrome. Elastin defects are seen in cutis laxa. Fibrillin-1 defects are seen in Marfan disease.

Answer 361

►E Female carriers of chronic granulomatous disease have an increase incidence of discoid lupus, infections and apthous stomatitis.

Answer 362

►A While pili torti is not exclusively found in Menkes kinky hair syndrome, this is the most common hair abnormality found. Trichorrhexis nodosa can be also seen. Trichorrhexis invaginata is commonly found in Netherton syndrome. Pili triangulati et canaliculati is the finding seen in Uncombable hair syndrome.

Answer 363

►A Sturge-weber syndrome has defects in facial capillary malformation with underlying soft tissue and skeletal hypertorphy, ipsilateral arteriovenous malformation (AV), cerebral calcification, hemiparesis, hemianopia, and contralateral seizures.

Answer 364

►C Brooke-Spiegler syndrome is an uncommon disease with a predisposition to develop cutaneous adnexal neoplasms such as cylindromas, trichoepitheliomas, spiradenomas, trichoblastomas, basal- cell carcinomas, follicular cysts, organoid nevi, and malignant transformation of preexisting tumors in the affected individuals.

Answer 365

►C Approximately 15-20% of patients with Maffucci's syndrome and Oillier's will develop chondrosarcoma. They are due to a defect in a isocitrate dehydrogenase 1 or 2.

Answer 366

►A Patients with Refusum syndrome have a deficiency in phytanic acid oxidase deficiency. The ocular abnormalities seen are pigmentary retinopathy, cataracts, nystagmus, and night blindness

Answer 367

►A The patient has pseudoxanthoma elasticum which is due to a mutation in an adenosine triphosphate binding transporter protein. The eye abnormality seen is angioid streaks on the retina, hemorrhages and loss of vision. They also have claudicaton and gastrointestinal hemorrhage.

Answer 368

►A Wiskott-Aldrich syndrome is an x-liked recessive disorder localized to Xp11.3. The gene involved codes for WAS, and the protein product has been implicated in lymphocyte and megakaryocyte signal transduction.

Answer 369

►A Klippel-Trenaunay Weber syndrome is characterized by a triad of port -wine stain, varicose veins, and bony and soft tissue hypertrophy involving an extremity. Filariasis is an acquired infection that leads to obstruction and scarring of the lymphatics. Neurofibromatosis is associated with neurofibromas, cafe-au-lait macules and Lisch nodules, but not with lymphedema and vascular malformations. Proteus syndrome is associated with vascular abnormalities, lipomas and asymmetric limb hyperplasia, and plantar connective tissue nevi, but usually not lymphedema. Lymphedema of the dorsal hands and feet can be seen in Turner syndrome, but typically not this extensive.

Answer 370

►B Hoyeraal-Hreidarsson syndrome is has all of the features of dyskeratosis congenita plus posterior fossa malformations. Bloom syndrome and Cockayne syndrome both have poikiloderma as features, but do not include posterior fossa malformations as part of the syndrome. WiskottAldrich syndrome does not include any of these findings.

Answer 371

►A These findings are most characteristic of Von Hippel-Lindau syndrome. VHL is a tumor suppressor gene which is mutated in this syndrome. Other findings include: renal and pancreatic cysts/ carcinoma, pheochromocytoma, and cerebellar/other CNS hemangioblastomas. Endoglin is defective in Osler-Weber-Rendu, PTH/PTHrP type I receptor in Maffucci syndrome, VEGF receptor-3 in Nonne-Milroy disease (hereditary lymphedema) and MFH1 in lymphedema and ptosis syndrome.

Answer 372

►D Sphenoid wing dysplasia is seen in neurofibromatosis type I. Patients with Tay syndrome have short stature, patients with tuberous sclerosis have phalangeal cysts and periosteal thickening, patients with Mafucci syndrome have enchondromas and short stature, and patients with NF-2 do not have any characteristic musculoskeletal findings.

Answer 373

►A Buschke-Ollendorf syndrome is caused by a loss-of-function mutation in LEMD3.

Answer 374

►E A mutation in Lamin A causes Progeria (Hutchinson-Gilford syndrome). Other findings include nail atrophy and muscle/bone wasting. Presentation is in the first or second year of life. An increased urine hyaluronic acid can be helpful in diagnosis.

Answer 375

►E Ataxia telangiectasia is associated with mutations in ATM gene. Leukocyte adhesion deficiency is associated with mutations in the common chain of CD18 which is a beta-2 integrin family member, FUCT1, or KINDLIN3. Chronic granulomatous disease is due to mutations in the NADPH oxidase. SCID is a heterogenous group of genetic disorders due to mutations in Jak-3, IL-7Ralpha, CD45, CD3delta/CD3episilon, RAG1/RAG2, and Artemis (DCLREC1C). W HIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis) is due to a gain-offunction mutation in CXCR4 which results in the retention of neutrophils in the bone marrow. It is inherited in an autosomal-dominant fashion.

Answer 376

►C Mal de Meleda is an autosomal recessive disease characterized by transgedient malodorous PPK, hyperhidrosis, keratotic plaques at knees and elbows, subungual hyperkeratosis, and koilonychia. The gene defect is SLURP 1.

Answer 377

►A A patient has Piebaldism with a mutation in c-KIT protooncogene with a white forelock. The patient has depigmented patches on the central faces, mid-extremities, and abdomen. The patient can have Hirschsprung, deafness and heterochromia irides.

Answer 378

►D Findings of angiokeratoma corporis diffusum are found in all three listed conditions. They cannot by distinguished by skin exam.

Answer 379

►A Berardinelli-Seip congenital lipodystrophy is described above. Familial partial lipodystrophy is characterized by a defect in LMNA and has symmetric lipoatrophy of trunk and limbs with sparing of neck, shoulders, buffalo hump area and genitalia, tuboeruptive xanthomas, acanthosis nigricans and hypertriglyceridemia. Bjornstad syndrome is characterized by pili torti and deafness.

Answer 380

►B Darier's disease is an autosomal dominant disorder characterized by greasy hyperkeratotic papules. The papules often coalesce into a warty plaque and have a tendency for secondary viral or bacterial infection. The mutation is in calcium ATPase 2A2. The classic nail finding is red and white longitudinal bands with V-shaped nicking.

Answer 381

►B Oculocutaneous albinism (OCA) type 1 (Tyrosinase negative albinism) is caused by mutations in the tyrosinase gene. OCA type 2 (tyrosinase positive albinism) is caused by mutations in the P gene. OCA type 3 is caused by mutations in the tyrosinase related protein 1 gene. C -kit mutations cause piebaldism and NEMO mutations cause incontinentia pigmenti.

Answer 382

►A Maffucci syndrome is inherited in a sporadic manner, with mutations in isocitrate dehydrogenase 1 or 2 (IDH-1, IDH-2).

Answer 383

►B Dyskeratosis congenita has premalignant oral leukoplakia in addition to cutaneous poikiloderma and nail dystrophy. Pachyonychia congenita also has leukoplakia, but it is benign in nature. Additional features of pachyonychia congenita are thickened nails with nail bed hyperkeratosis and palmoplantar keratoderma. Keratosis follicularis, also known as Darier\'s disease, is characterized by benign whitish papules on the oral mucosa, cutaneous keratotic papules in seborrheic distribution, and longitudinal erythronychia with V-nicking of the distal nail plate. Papillon-Lefevre has gingivitis, without oral leukoplakia, and acral hyperkeratosis. Anhidrotic ectodermal dysplasia does not have leukoplakia. It consists of anhidrosis or hypohidrosis, hypotrichosis, and anodontia.

Answer 384

►C C-kit staining is present in desmoplastic melanoma. It is also seen in acral melanocytic lesions. Ras is found in all melanocytic lesions. P53 mutations are found in actinic keratoses, SCCIS, and SCC.

Answer 385

►B X-linked ichthyosis patients have comma-shaped corneal opacities that are asymptomatic yet highly characteristic.

Answer 386

►A Phenylketonuria will cause a "mousy" odor in the urine. Patients with Alkaptonuria will have black urine. Maple syrup urine disease will have a sweet odor. Hunter/Hurler diseases are not associated with urinary issues.

Answer 387

►C Tuberous sclerosis is an autosomal dominant condition caused by mutations of the TSC1 (hamartin) or TSC2 (tuberin) genes. These are tumor suppressor genes. Skin findings include hypopigmented macules, connective tissue nevus, facial angiofibromas, periungual fibromas and cafe au lait macules. Dental enamel pits and gingival fibromas are oral findings that are associated with this condition. The remaining conditions do not have dental pits.

Answer 388

►B The 'maltese cross' finding in urine is characteristic of Fabry disease. Alkaptonuria will show dark urine with a pH > 7.0. There are no urinary findings in Hunter syndrome, Gaucher or Neimann-Pick disease.

Answer 389

►A The patient described has Menkes Kinky Hair syndrome, an X-linked recessive disease due to a defect in an intestinal copper transport protein. Clinical features include pili torti, short, brittle steel-woolǁ* hair, and spare eyelashes and sparse broken eyebrows. The skin is often hypopigmented with a soft, ―doughyǁ* consistency and redundancy. Musculoskeletal manifestations include metaphyseal widening with spurs in the long bones

Answer 390

►C Phenylketonuria is an autosomal recessive condition caused by a mutation in the gene coding for phenylalanine hydroxylase. Defect in this enzyme results in accumulation of phenylalanine and its metabolites. Increased phenylalanine has toxic effects on the central nervous system in addition to competitively inhibiting tyrosine in melanogenesis. Inhibition of melanogenesis results in pigmentary dilution of the hair and skin. Other features of this condition include a predisposition to eczema, sclerodermoid changes of the skin, urine that has a distinctive "mousy" odor, psychomotor delay, mental retardation, seizures and hyperreflexia. A low-phenylalanine diet instituted early on can prevent these manifestations of the disease. The morbidity of phenylketonuria has improved since the advent of routine neonatal screening for this condition.

Answer 391

►C Epidermolysis bullosa simplex is caused by mutations in keratin 5 and 14 resulting in bullae within basal cell keratinocytes.

Answer 392

►A A patient with KID syndrome has an autosomal dominant disease and mutation in connexin 26. They have keratitis, ichthyosis, deafness and alopecia.

Answer 393

►C The Dowling-Maera variant of epidermolysis bullosa simplex is associated with widespread bullae, significant mucous membrane and laryngeal/esophageal involvement, nail dystrophy, and early death.

Answer 394

►A Schopf-Schulz-Passarge syndrome is associated with hydrocystomas of the eyelids, hypotrichosis (near complete loss of hair early in life), hypodontia, nail abnormalities and multiple palmoplantar eccrine syringofibroadenomas. The other listed syndromes do not fit the description above.

Answer 395

►A Characteristic features of Russell-Silver include short stature, bony asymmetry, triangular facies, clinodactyly of fifth finger, and precocious sexual development with cryptochordism/hypospadias. Broad thumbs are seen in Rubinstein-Taybi and shortened fourth and fifth metacarpals are seen in Turner syndrome. Osteopathia striata is characteristic of focal dermal hypoplasia.

Answer 396

►D Rubinstein-Taybi syndrome has been associated with a deletion localized to the short arm of chromosome 16. Patients are severely retarded with strabismus, crytorchidism, and congenital heart defects. They have a characteristic beaked nose with nasal septum below alae accompanied by a broad nasal bridge, downslanting palpebral fissures, and broad thumbs and halluces.

Answer 397

►B Mild to moderate mental retardation occurs in up to 50% of cases. A Fanconi -type pancytopenia may occur resulting in early death. These children have alopecia, not hirsutism, along with nail dystrophy. There is an increased risk for development of premalignant oral leukoplakia, as well as many cancers.

Answer 398

►A Erythropoietic protoporphyria is a relatively common form of porphyria, characterized by photosensitivity. Over time, superficial waxy scars and milia are identified in sun-exposed areas. The defective gene is ferrochelatase. Uroporphyrinogen decarboxylase is mutated in porphyria cutanea tarda. Porphybilinogen deaminase is defective in acute intermittent porphyria. Uroporphyrinogen III synthase is defective in congenital erythropoietic porphyria. Protoporphyrinogen oxidase is mutated in variegate porphyria.