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PBR: Genetics > Genetic Conditions Organized by Presenting Symptoms > Flashcards

Genetic Conditions Organized by Presenting Symptoms Flashcards

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1
Q

Chromosomal instability syndromes most commonly have what pattern of inheritance?

A

Autosomal recessive

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2
Q

What are chromosomal instability syndromes?

A

A group of disorders that are largely autosomal recessive and have an increased frequency of chromosomal breaks.

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3
Q

List four chromosomal instability syndromes.

A

Ataxia-telangiectasia, Bloom syndrome, Fanconi syndrome, and xeroderma pigmentosum.

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4
Q

What is the most common craniofacial malformation?

A

Cleft lip and/or cleft palate

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5
Q

Which ethnic group has the highest rates of cleft lip/palate? The lowest rates?

A

Native Americans have the highest rates of cleft lip/palate, while African Americans have the lowest rates.

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6
Q

What is the definition of a sequence as it relates to congenital anomalies?

A

A sequence refers to a pattern of anomalies that result from a single identifiable event in development. It does not necessarily have an underlying genetic abnormality.

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7
Q

What is the primary embryologic defect in patients with Pierre Robin sequence?

A

Mandibular hypoplasia.

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8
Q

Describe the sequence progression and resultant physical abnormalities associated with Pierre Robin sequence.

A

Mandibular hypoplasia > tongue displacement > interrupted closure of the lateral palatine ridges > U-shaped cleft palate. On exam, this presents as micrognathia, retrognathia, glossoptosis (displacement of the tongue into the airway), respiratory distress, and feeding problems. Respiratory distress can lead to pHTN.

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9
Q

What is the amniotic band sequence?

A

Absence or malformation of a body part due to amniotic band adherance during fetal development. This can present as disruptive clefts of the face and palate, constriction rings of the limbs and/or digits, and amputations.

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10
Q

What is the relationship between hemifacial microsomia and Goldenhar syndrome?

A

Goldenhar and hemifacial microsomia are considered to be the same disorder, but the term “Goldenhar syndrome” is used only if epibulbar dermoids are present.

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11
Q

What is hemifacial microsomia?

A

It is the association of external ear anomalies (microtia, anotia, canal atresia, and/or preauricular tags) with maxillary and/or mandibular hypoplasia.

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12
Q

List 3 congenital anomalies which can occur in conjunction with hemifacial microsomia.

A

Cervical vertebral anomalies, cardiac defects, and renal anomalies.

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13
Q

Describe the findings typical of a patient with Goldenhar syndrome.

A

Hemifacial microsomia (external ear abnormalities + maxillary and/or mandibular hypoplasia), epibulbar lipodermoids (lateral-inferior fibrous-fatty masses on the globe), vertebral defects, cardiac anomalies, and renal anomalies.

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14
Q

What syndrome is characterized by branchial cleft fistulas or cysts, preauricular pits, cochlear and stapes malformations, mixed sensory and conductive hearing loss, and renal dysplasia/aplasia?

A

Branchio-Oto-Renal syndrome.

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15
Q

What is the inheritance pattern for Branchio-Oto-Renal syndrome?

A

Autosomal dominant

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16
Q

Describe the features typical of patients with Treacher-Collins syndrome.

A

Micrognathia, zygomatic arch clefts, various forms of ear malformations, down-sloping palpebral fissures, and colobomata of the lower eyelids. Conductive hearing loss is often present as well.

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17
Q

What is the inheritance pattern in Treacher-Collins syndrome?

A

Autosomal dominant

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18
Q

Define craniosynostosis.

A

The early, pathologic fusion of calvarial sutures.

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19
Q

What is the most common suture involved in single-suture craniosynostosis?

A

The saggital suture.

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20
Q

What is the male:female ratio for isolated saggital craniosynostosis?

A

5:1 male:female ratio

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21
Q

List, in descending order of frequency, the four types of single-suture craniosynostoses.

A

Saggital > coronal > metopic > lambdoid

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22
Q

What type of head growth is seen with early fusion of the saggital sutures?

A

Saggital craniosynostosis results in excessive anterior/posterior growth with a resulting long, narrow head shape with frontal and occipital prominence. This is known as scaphocephaly or dolichocephaly. ***Pic?

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23
Q

What type of head growth is seen with early fusion of the coronal or sphenofrontal sutures?

A

Coronal craniosynostosis results in unilateral flattening of the forehead, elevation of the ipsilateral orbit and eyebrow, and a prominent ear on the affected side, known as frontal plagiocephaly. ***Pic?

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24
Q

Which forms of craniosynostosis are more common in females?

A

Coronal and sphenofrontal craniosynostosis

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25
What type of head growth is seen with early fusion of the metopic sutures?
Metopic craniosynostosis results in a keel-shaped forehead and hypotelorism, known as trigonocephaly. ***Pic?
26
What is the appearance of an infant with early fusion of the coronal, sphenofrontal, and frontoethmoidal sutures? What is the name for this head shape?
This combination of synostoses results in a cone-shaped head, known as turricephaly. ***Pic?
27
What is positional plagiocephaly?
The postnatal flattening of the skull that is caused by the infant's preference of sleeping/resting position.
28
Where would you expect to see flattening of the skull in infants with plagiocephaly due to torticollis?
These infants typically have flattening of the occipitoparietal area.
29
What form of craniosynostosis can have a similar clinical appearance as that of plagiocephaly?
Lambdoid craniosynostosis
30
How would one differentiate between positional plagiocephaly and lambdoid craniosynostosis on exam?
The ipsitateral ear is displaced anteriorly in positional plagiocephaly vs posterior/inferior for lambdoid synostosis; ipsilateral frontal prominence is present in plagiocephaly but not synostosis; contralateral occipitoparietal prominence is present in lambdoid synostosis but not plagiocephaly; lambdoid ridge and submastoid prominences are seen in synostosis but not plagiocephaly; positional plagiocephaly stops progressing after 7 months because children aren't lying on their heads as often, while lambdoid synostosis continues to progress after 7 months.
31
What is the most common type of skeletal dysplasia?
Achondroplasia
32
Describe the findings in achondroplasia.
Disproportionately short stature with rhizomelic shortening (short lengths of the most proximal ("root") segments of the upper arms and legs compared to the distal segments), lumbar lordosis, trident hands, macrocephaly, and characteristic facial findings (flat nasal bridge, prominent forehead, and midface hypoplasia). ***Image 22-11
33
What is the inheritance pattern in achondroplasia, and what gene is responsible?
It is an autosomal dominant disorder in which most individuals have a de novo mutation of FGFR3 (fibroblast growth factor receptor 3) on chromosome 4p16.3.
34
What risk factor is associated with increased risk for a child being born with achondroplasia?
Increased paternal age
35
What skull structural abnormality can occur in infants with achondroplasia?
Foramen magnum stenosis and/or craniocervical junction abnormalities can occur in infancy and cause compression of the upper cord - resulting in apnea, quadriparesis, growth delay, and hydrocephalus.
36
List 5 x-ray findings characteristic of individuals with achondroplasia.
Squared-off iliac wings, flat and irregular acetabulum roofs, thick femoral necks, "ice-cream scoop" shaped femoral heads, and rhizomelic shortening.
37
What are the thanatophoric dysplasias?
There are two types (1 and 2), which are both caused by FGFR3 mutations. Most cases are lethal, but those who survive to infancy present with macrocephaly with very short limbs.
38
What physical exam findings can help to differentiate between Thanatophoric Dysplasia Type 1 and Type 2?
Individuals with Type 1 have bowed femurs, while those with Type 2 have straight femurs. Type 2 infants also have a "cloverleaf" skull caused by premature closure of the sagittal, coronal, and lambdoid sutures.
39
List 3 characteristic x-ray findings associated with Thanatophoric Dysplasia.
Platyspondyly (flatness of the body of the vertebrae), flared metaphyses of the long bones, and short iliac bones. Individuals with Type 1 have bowed femurs as well.
40
What is the most commonly affected bone in Caffey disease?
The mandible is involved in >95% of cases and is the most commonly affected bone.
41
What is Caffey disease (infantile cortical hyperostosis)?
It is characterized by extreme irritability, fever, anorexia, and soft tissue swelling caused by subperiosteal cortical thickening of underlying bone. Soft tissue swelling is painful and indurated but without suppuration and only minimally warm and red. Typically, changes in the bones begin prior to 6 months of age and resolve by 24 months of age.
42
What is the inheritance pattern for Caffey disease (infantile cortical hyperostosis)?
Autosomal dominant, with incomplete penetrance.
43
What bones are most commonly affected in individuals with Caffey disease (infantile cortical hyperostosis)?
Mandible (most common), clavicles, ribs, long bones, and scapulae.
44
What are the typical radiologic and laboratory findings in patients with Caffey disease (infantile cortical hyperostosis)?
Leukocytosis, elevated ESR, and elevated alkaline phosphatase + layers of cortical diaphyseal periosteal new bone formation and cortical thickening on X-ray.
45
What alternate diagnosis must be considered in patients presenting with Caffey disease (infantile cortical hyperostosis)? What finding is helpful in differentiating between the two diagnoses?
Non accidental trauma should be on the differential for any child with periosteal elevation on imaging studies. The mandibular involvement in Caffey disease is most helpful in differentiating between the two.
46
What is osteogenesis imperfecta?
A disorder characterized by osseous fragility, short stature, and skeletal findings that vary based on the type.
47
What is the underlying pathophysiology of the four most common types of osteogenesis imperfecta?
Abnormal structure of Type 1 collagen
48
How would one differentiate between non accidental trauma and osteogenesis imperfecta?
No form of osteogenesis imperfecta causes retinal hemorrhage or subdural hematoma, which helps to distinguish it from injuries due to abuse.
49
Describe a child with osteogenesis imperfecta Type 1.
Multiple fractures (most occur before puberty, but rarely at birth), blue sclerae, delayed fontanelle closure, hyperextensible joints, hearing loss, decreased stature, and dentinogenesis imperfecta (a disorder of tooth development with discolored, weak teeth).
50
Which form of osteogenesis imperfecta is the mildest and most common?
Osteogenesis imperfecta Type 1
51
Which type of osteogenesis imperfecta is the most severe and usually results in death in infancy?
Osteogenesis imperfecta Type 2
52
Which type of osteogenesis imperfecta has the highest risk of neurologic complications? What neurologic findings are most common?
Osteogenesis imperfecta Type 3; hydrocephalus and basilar skull invagination are typical.
53
How does Osteogenesis Imperfecta Type 3 usually present?
In the newborn period, with numerous fractures.
54
What is the hallmark clinical finding in patients with Osteogenesis Imperfecta Type 4?
Tibial bowing
55
What are the classic scleral findings in osteogenesis imperfecta Type 4?
The sclerae are typically white or near-white.
56
Compare/contrast the scleral findings in Osteogenesis Imperfecta Types 1, 3, and 4.
Type 1 = dark blue sclerae for life. Type 3 = dark blue sclerae at birth, which lighten with age. Type 4 = white or near-white sclerae.
57
What causes most deaths in Marfan syndrome?
Most deaths are due to cardiovascular complications, namely aortic root dilatation and rupture.
58
Describe the (7) classic findings in a patient with Marfan syndrome.
Tall stature, high-arched palate, upward lens dislocation, joint hypermobility, pectus carinatum or excavatum, spontaneous pneumothorax, and mitral valve prolapse.
59
Which gene is responsible for Marfan syndrome?
A mutation in the FBN1 gene (which encodes the protein fibrillin-1) results in Marfan syndrome.
60
Which disorder has many features similar to Marfan syndrome?
Homocystinuria
61
How might one differentiate between Marfan syndrome and homocystinuria?
In Marfan syndrome, there is no intellectual disability and the lens dislocates upward (superior intelligence, superior lens). In homocystinuria, patients have decreased intelligence and the lens dislocates downward (inferior intelligence, inferior lens).
62
What routine screening should be performed in patients with Marfan syndrome?
These patients should have annual or semi-annual echocardiograms to monitor aortic root diameter.
63
What steps should be taken to minimize the risk of aortic root dilation in patients with Marfan syndrome?
Antihypertensives are used to treat and prevent aortic root dilatation. Patients should avoid weightlifting and strenuous exercise, but regular aerobic exercise is still important for heart health.
64
Describe the typical findings in classic Ehlers-Danlos syndrome.
Hyperextensible skin, hypermobile joints, easy bruising, and dystrophic scarring.
65
What cardiac abnormalities are most common in individuals with Ehlers-Danlos?
Mitral valve prolapse and proximal aortic dilatation.
66
What are the (8) classic skin findings in patients with Ehlers Danlos?
"Doughy" skin; extra skin over the hands, feet, and stomach; stretchy, rubber-band-like skin; fragile skin, which splits with minor trauma, especially over shins, knees, elbows, and chin; scarring is abnormal and typically appears thin and shiny; increased bruising with normal coagulation factors (except capillary fragility testing); wrinkled palms and soles; and pseudotumors at the heels, elbows, and knees from abnormal scarring.
67
What are the (2) classic skin findings in neurofibromatosis Type 1?
Café-au-lait spots and benign cutaneous neurofibromas.
68
What are the 7 diagnostic criteria used to make a diagnosis of Neurofibromatosis Type 1? How many criteria must be present for a diagnosis to be made?
Patients must have at least 2 of the following criteria for diagnosis: ≥6 café-au-lait spots of ≥5 mm in greatest diameter in prepubertal children and ≥15 mm in postpubertal children; ≥2 neurofibromas of any type or ≥1 plexiform neurofibroma; freckling of the axillary or inguinal areas; optic glioma; ≥2 Lisch nodules (iris hamartomas); sphenoid dysplasia or thinning of the long bone cortex, with or without pseudarthrosis; and 1st degree relative with NF1.
69
In what 3 syndromes would you expect to see patients with Café-au-lait spots?
Neurofibromatosis Type 1, McCune-Albright, and Russell-Silver syndromes.
70
What are neurofibromas?
They are benign, peripheral nerve sheath tumors that are a collection of Schwann-like cells, fibroblasts, and extracellular matrix.
71
What is one serious complication of plexiform neurofibromas?
They have a 10% risk of malignant transformation into malignant peripheral nerve sheath tumors.
72
What are the classic findings on MRI brain in children with Neurofibromatosis Type 1? What is the clinical significance?
Focal areas of T2 weighted signal intensity (FASI) are believed to represent areas of abnormal myelination. They are most often located in the basal ganglia, along the optic tracts, and in the brainstem, thalamus, and/or cerebellum. There is no associated mass effect, malignant potential, or contrast enhancement. FASI gradually disappear over time and are generally absent by 30 years of age.
73
How frequently is neurofibromatosis Type 1 due to a new mutation?
50% of cases are due to sporadic/de novo autosomal dominant mutations
74
What genetic abnormality is responsible for Neurofibromatosis Type 1?
The NF1 gene encodes the protein neurofibromin and maps to chromosome 17.
75
Describe how neurofibromatosis Type 2 differs from Type 1.
NF1 and NF2 are very distinct disorders, with no common genetic factors and hardly any clinical overlap. NF2 is characterized by bilateral vestibular schwannomas and has many other CNS abnormalities, while NF1 may have mild delays and learning disorders but is characterized by a number of benign oculocutaneous findings.
76
What abnormalities to vestibular schwannomas cause in neurofibromatosis Type 2?
The vestibular schwannomas cause sensorineural hearing loss, tinnitus, imbalance, and facial weakness.
77
What are some of the first clinical signs commonly seen in children with neurofibromatosis type 2?
Lens opacities or cataracts occur as one of the first signs of disease and can be used for screening in children.
78
List 5 CNS tumors one might expect to find in a patient with neurofibromatosis type 2.
Bilateral vestibular schwannomas, intracranial meningiomas, spinal schwannomas, cranial nerve schwannomas (CN5 is most common), and ependymomas.
79
What are the diagnostic criteria for neurofibromatosis type 2?
The presence of either bilateral acoustic neuromas alone or a 1st degree relative with NF2 and either unilateral acoustic neuroma, 2 of the other common CNS tumors, or lenticular opacity.
80
What study should be performed in relatives of patients with neurofibromatosis type 2?
MRI brain should be performed to detect vestibular schwannomas small enough to be surgically removed, this preserving hearing.
81
What is the mode of inheritance for neurofibromatosis type 2?
Autosomal dominant
82
What is the mode of inheritance for tuberous sclerosis?
Autosomal dominant
83
Describe the skin findings in tuberous sclerosis.
Hypopigmented macules (ash-leaf spots) are present in ~90% of cases. Shagreen patches may be present as well (oval shaped nevoid plaques appearing on the trunk or lower back which may be smooth or crinkled and skin-colored or slightly hyperpigmented).
84
What cardiac tumors are common in infants with tuberous sclerosis?
Cardiac rhabdomyomas. Nearly 50% of infants have multiple cardiac rhabdomyomas, but these regress over time.
85
What neurologic complication can be seen in some patients with tuberous sclerosis?
Infantile spasms
86
If an infant is diagnosed with infantile spasms, what genetic disorder should you evaluate for?
About 50% of patients with infantile spasms will also have tuberous sclerosis.
87
Which genes are implicated in the development of tuberous sclerosis?
Tuberous sclerosis is caused by mutations in TSC1 (on chromosome 9) or TSC2 (on chromosome 16).
88
What medication is used to treat infantile spasms in patients with tuberous sclerosis?
Vigabatrin
89
What (4) types of cancer are more common in patients with BRCA1 mutations?
Breast cancer, ovarian cancer, colorectal cancer and prostate cancer.
90
What (5) types of cancer are more common in patients with BRCA2 mutations?
Breast cancer, ovarian cancer, melanoma, pancreatic cancer, and prostate cancer.
91
Which autosomal dominant genetic disorder confers a 100% risk for the development of colon cancer?
Familial adenomatous polyposis
92
What is von Hippel-Lindau syndrome?
A highly penetrant autosomal dominant multisystem cancer disorder that presents with various benign and malignant tumors of the eyes, CNS, kidneys, pancreas, adrenal glands, and reproductive glands.
93
What genetic abnormality is responsible for the development of von Hippel-Lindau syndrome?
von Hippel-Lindau syndrome is caused by a mutation in the VHL tumor suppressor gene on chromosome 3.
94
What (6) tumors are commonly seen in patients with von Hippel-Lindau syndrome?
Hemangioblastomas, pheochromocytomas, endolymphatic sac tumors, renal cell carcinomas, and cystadenomas and neuroendocrine tumors of the pancreas.
95
What is the classic presentation of a patient with von Hippel-Lindau syndrome?
Diagnosing a cerebellar hemangioma in adolescence or a retinal angioma by 10 years of age.
96
What is the leading cause of mortality in patients with von Hippel-Lindau syndrome?
Renal cell carcinoma presents in the patients' 40s and is the leading cause of mortality in VHL.
97
What is Cowden Syndrome?
It is a PTEN hamartoma tumor syndrome that includes a high risk of benign and malignant hamartomas of the thyroid, breast, and endometrium. Affected patients typically have macrocephaly, as well as facial papules and trichilemmomas.
98
What is Bannayan-Riley-Ruvalcaba syndrome?
It is a PTEN hamartoma tumor syndrome which is usually diagnosed around 5 years of age and is characterized by patients with macrocephaly, pigmented macules of the glans penis, lipomas, and non-malignant intestinal hamartomatous polyposis (which can cause obstruction).

PBR: Genetics (6 decks)

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