Genetics Flashcards
Why do mitochondrial diseases have a large degree of phenotypic variability
Heteroplasmy, which means that within one cell may have different ratios of normal and mutated mitochondrial DNA
Camptodactyly (flexion of proximal interphalangeal joint), thick lips, deep set eyes, prominent cupped ears, mild to severe mental deficiency, pelvic or hip dysplasia, uteral-renal anomalies
Trisomy 8 (rare, majority are mosaic since complete is lethal in utero)
Midline abnormalities, cardiac (vsd>pda), cutis aplasia, narrow hyper convex fingernails, cleft lip, small eyes, microcephaly or holoprosencephaly, persistence of fetal hemoglobin, increased neutrophils with nuclear projections
Trisomy 13 (1 in 5-10,000 live births)
Cardiac in 95-99% of patients (VSD, pda>bicuspid aortic valve, pulm stenosis, tof), clenching hands with overlapping digits, rocker bottom feet, small mouth, short sternum
Trisomy 18 (1 in 6000), females > males (3:1)
Endocardial cushion defects, hypothyroidism, hyperflexibility of joints, 5th finger with hypoplastic middle phalanx and clinidactyly, up slanting palpebral fissures, brushfield spots, pelvic dysplasia, transient myeloproliferitive disorder
Trisomy 21 (1 in 800)
Cardiac (30%) (VSD, pda, tof), transverse palmar crease, downslantint palpebral fissures, hypertelorism, mental deficiency, microcephaly, failure to thrive
Cri-du-chat (deletion 5p syndrome); partial deletion of short arm of the 5th chromosome (deleted portion is paternal origin in 80% of de novo), majority are de novo
Thumb hypoplasia, colobomas, increased risk of retinoblastoma, microcephaly, high nasal bridge, hypertelorism, epicanthal fold, microcephaly, IUGR, focal lumbar agenesis
Deletion 13q syndrome
High forehead, broad or beaked nose, hypertelorism, low set simple eat with lreauricular dimple, supraordbital ridge continuous with nasal bridge, microcephaly, severe cognitive deficits, seizures
Deletion 4p syndrome (wolf-hirschhorn syndrome) 87% de novo mutations
22q11.2 microdeletion syndrome
CATCH-22 (cardiac, abnormal facies, thymus hypoplasia, cleft palate, hypoglycemia)
Secondary to a defect in the 4th brachial arch and derivatives of the 3rd and 4th pharyngeal pouches
Most common chromosomal deletion in humans
Broad thumbs and first toes, downslanting palpebral fissures, hypoplastic maxilla, narrow palette, prominent and or beaked nose, microcephaly, cryptorchidism, postnatal growth deficiency, increased risk of tumors
Rubinstein-Taybi syndrome
16q13.3 deletion, which encodes the cAMP-regulated enhancer-binding protein
WAGR syndrome
11p13 deletion
Wilms tumor (50%), aniridia, GU abnormalities (cryptorchidism, hypospadias), retardation
Supravalvar aortic stenosis, peripheral pulmonic stenosis, hypoplastic nails, prominent lips, hoarse voice, blue eyes, stellar iris pattern, short palpebral fissures, epicanthal folds, long philtrum, mental deficiency, hypercalcemia (usually transient)
Williams syndrome
7q11.23 deletion leading to deletion of an elastin gene
Cardiac (50%): pda, VSD, asd; polydactyly, syndactyly (feet), lateral displacement of inner canthis, corneal opacity, brachycephaly
Carpenter syndrome, Autosomal recessive
Cardiac (60%): single atrium or asd; short distal extremities, polydactyly (fingers more than toes), nail hypoplasia, delayed tooth eruption, narrow thorax, typically normal intelligence but 50% mortality during infancy due to cardio respiratory difficulties
Ellis-van crevald syndrome, autosomal recessive, chondroectodermal dysplasia
Hyperpigmentation, radial hypoplasia, thumb hypoplasia, renal and GU abnormalities, pancytopenia, increased risk of AML
Fanconi pancytopenia syndrome, autosomal recessive, increased number of chromosomal breaks (requires a breakage study to assess)
Genetics of Meckel-Grubwr syndrome
Autosomal recessive, locus mapped to 17q21-24
Polydactlyly, occipital encephalocele, cystic dysplastic kidneys, bile duct proliferation, hepatic cysts, microphathalmia, cleft palate, micrognathia, cryptorchidism
Meckel-Gruber Syndrome
Encephalocele, hypertelorism, widely set nostrils, anterior cranium bifidum occultum
Frontonasal dysplasia
Encephalocele, eye abnormalities (microphthalmia, cataracts), CNS anomalies (ventriculomegaly, midline abnormalities, lissencephaly)
Walker-Warburg Syndrome
Genetics and cause of Smith-Lemli-Opitz syndrome
Autosomal recessive, defect in cholesterol synthesis, lead to low cholesterol levels and elevated precursor (7-dehydrocholesterol) levels
Second and 3rd toe syndactlyly, ptosis, cataracts, low set or slanted ears, anteverted nostrils, hypogenitalia, hypospadias, microcephaly, moderate to severe mental deficiency
Smith-lemli-opitz
Thrombocytopenia, granulocytosis, eosinophilia, anemia, absent bilateral radii, thumbs always present, ulnar abnormalities, hip dysplasia, cardiac (30%): tof, asd
TAR (thrombocytopenia-radial aplasia) syndrome
CDH, agensis or corpus callosum, dandy walker malformation, olfactory nerve abnormalities, optic hypoplasia, severe intellectual disability, coarse facial features, digital and nail hypoplasia
Fryns syndrome
Most common inherited cause of mental deficiency
Fragile X syndrome
Genetics of fragile X
X-linked dominant with 80% penetrance in males and 30% penetrance in females
Long facies, prominent forehead, large ears, large testies post puberty, mental deficiency, autism, hyper extensible fingers or joints, mild connective tissue dysplasia
Fragile x syndrome
Genetics of menkes syndrome
X-linked recessive, gene located at xq13
Risk in patients 45x/46xy
Increased risk of residual gonadal tissue that can lead to granadoblastoma so the recommendation is for exploratory laparotomy during childhood to remove this tissue
Cause of charge syndrome
Mutation in chromodomain helicase dna-binding gene 7 (chd7) on chromosome 8q12 that leads to altered chromatin; autosomal dominant but majority are de novo
Symptoms of charge syndrome
Coloboma, heart defects, atresia of the choanae, restricted growth, genital hypoplasia, and ear anomalies
(Major criteria: ear, cranial nerve abnormalities, coloboma, choanal atresia)
Genetics and cause of Schwachman-Diamond syndrome
Autosomal recessive, 90% are associated with mutation in SDS gene on chromosome 7q11, which plays an important role in the maturation of the 60 S ribosomal sub unit and ribosomal assembly
Bone marrow failure (neutropenia most common, anemia, thrombocytopenia), pancreatic dysfunction, recurrent infections, skeletal abnormalities
Schwachman Diamond syndrome
3rd and 4th finger syndactyly, add/vsd, brain abnormalities, large placenta with hydatiform changes, IUGR
Triploidy
Micronesia, synophrys, thin down-turning upper lip, long and curly eyelashes, mental deficiency, initial hypertonicity, microbrachycephaly, hirsuitism, low posterior hairline, cutis marmorata
Cornelia de Lange syndrome
Expressionless facies, micrognathia, talipes equinovarus
Mobius sequence
Cause if goldenhaar syndrome
Due to 1st and 2nd brachial arch abnormalities
Vsd, short neck, low posterior hairline, limited movement of head, deafness, abnormal cervical vertebrae, can be associated with Sprengel deformity (failure of scapula to descend to normal location leading to elevation and medial rotation of inferior portion of scapula)
Klippel-Feil sequence
Asymmetric limb hypertrophy, vascular lesions
Klippel-Trenaunay-Weber
Unilateral hypoplasia or absence of pectoralis muscle, various renal anomalies, rib anomalies, may have hemivertibrae
Poland sequence
Small triangular facies, downturning corners of mouth, short stature, congenital asymmetry of skeleton, hypoglycemia, 5th finger clinidactyly, excess sweating of head and upper trunk in infancy, cafe au lair spots, large and late closing fontanels
Russell silver syndrome
Vacterl
Vertebral anomalies, anorectal malformation, cardiac (vsd > tof, coarct), TE fistula, renal anomaly, limb anomaly
Imperforate anus, dysplastic ears, thumb anomalies
Townes-Brock’s syndrome
Inheritance of Beckwith-Wiedemann
50% are due to loss of methylation on the maternal chromosome 11, 20% are due to paternal uniparental disomy, 5% are due to gain of methylation on maternal chromosome 11
Port wine stains, and underlying spinal angiomas
Cobb syndrome, also known as cutaneomeningoapinalangiomatosis
Management of a sebaceous Nevis, and why
Excision in childhood, because of risk of progression to malignancy and later life
Location of Bohn nodules versus Ebstein pearls
Bohn nodules are located on the maxillary alveolar ridge, while Ebstein pearls are located on the hard palette
Genetics of Leigh syndrome
Mitochondrial
Cafe au lait macules, axillary freckling, maxillary freckling, macrocephaly, and learning disabilities
Legius syndrome, autosomal dominant mutation in spred1 gene
Symptoms of Aicardi syndrome
Agenesis of the corpus callosum with polymicrogyria, ocular abnormalities, hemivertibrae, and seizure
Chorioretinal lacunae are pathognomonic for:
Aicardi syndrome
Noonan’s syndrome is associated with what developmental problem
Language impairments
Inheritance pattern of Noonan syndrome
Autosomal dominant with complete penetrance but variable expression
A family history of fatal disease in male infants with severe diarrhea and dermatitis suggests
IPEX (immune dysrgulation, polyendocrinopathy, enteropathy, x-linked syndrome)
Upper eyelid coloboma associated with:
Goldenhaar syndrome
Lower eyelid coloboma associated with:
Treacher Collins
Is coloboma more common in upper or lower eyelid?
Upper
TAPVR or persistent left SVC, downslanting palpebral fissures, anal atresia, coloboma of iris, renal agenesis
Cat-eye syndrome, extra part of chromosome 22 (either in quadruplicate or triplicate)
Inheritance pattern and histopathology in congenital ichthyosiform erythroderma
Autosomal recessive
Increased stratum corneum AND increased granular layer
Secondary features of x-linked ichthyosis
Cryptorchidism in 1/4 of males, increased incidence of corneal opacities, female carriers with this deficiency often have low estradiol excretion and difficult labor
