Zitelli and more Review: Genetic Syndromes

1. Zitelli (and more!) Review:Genetic Syndromes February 2, 2009 Thanks to Katherine King for many of these slides!

2. But first…

4. 4-year-old child Five features: eyes, nose, mouth, hair, and legs Calculating the age equivalent: ¼ year for each of the five features, added to a base age of 3 years Drawing has an age equivalent of 4¼

5. Drawing by the same child at age 5 Inclusion of ears and arms, as well as improvements in proportion Drawing has an age equivalent of 4¾ years

22. Chromosomal Disorders:Aneuploidy

24. Midline defect Clenched hand with overlapping fingers Postaxial polydactyly Equinovarus deformity Punched-out scalp lesions of aplasia cutis congenita

25. Trisomy 13 (Patau) Microphthalmia, coloboma, loose skin, rocker bottom feet, missing rib Syndactyly or polydactyly Cardiac dextroposition, ASD, PDA, VSD Incidence 1:12000 5% survive first 6 months Death usually by heart failure or infection

26. Trisomy 13

28. Prominent occiput and low-set, posteriorly rotated malformed auricles Clenched hand showing typical pattern of overlapping fingers Rocker-bottom feet

29. Trisomy 18 (Edward) Incidence 1:4000 live births Males : females 1:3 5-10% survive first year Death usually due to heart failure or pneumonia

30. Trisomy 18 Meckel’s diverticulum, horseshoe kidneys Hypertonicity clenched fists and crossed legs, prominent occiput, 5th fingernail hypoplasia, dorsiflexed short hallux Short sternum, mental retardation

32. Characteristic facial features: Upward-slanting palpebral fissures Epicanthal folds Flat nasal bridge Brushfield spots

33. Bridged palmar crease: two transverse palmar creases are connected by a diagonal line Wide space between first and second toes Short fifth finger

34. Small ears Flat occiput

35. Trisomy 21 Incidence 1:600-800 Incidence increases with maternal age

36. Trisomy 21: Physical Findings Hypotonia Small head Epicanthal folds Flat nasal bridge Upward slanting palpebral fissures Brushfield spots Small mouth and ears Extra skin at the nape of neck Single transverse palmar crease 5th finger clinodactylyl Sandal toe gap

37. Trisomy 21: Associated defects Congenital heart defects Mental retardation Leukemia Hearing loss, otitis media Hirschsprung disease, duodenal atresia Cataracts Thyroid disease Hip dislocation Atlantoaxial instability/dislocation

39. Webbed neck with low hairline Shield chest with widespread nipples, abnormal ears, and micrognathia Prominent lymphedema of hands and feet

40. Turner: XO Incidence 1:10000 females Most conceptions result in miscarriage Low fertility rate and high chance of chromosomal abnormalities in offspring Estrogen replacement therapy

41. Turner: XO Webbed neck, edema of hands/feet Coarctation of the aorta Triangular facies, short stature Short stature, shield chest, wide-spaced nipples Streak ovaries, absence of secondary sex characteristics

43. Relatively narrow shoulders Increased carrying angle of arms Female distribution of pubic hair and normal penis but with small scrotum due to small testicular size Small testes and penis Gynecomastia

44. Klinefelter: XXY Incidence 1:1000 Prepubertal boys have normal phenotype Diagnosis often made after puberty Treatment: testosterone replacement

45. Klinefelter: XXY Microorchidism Sterility/azoospermia Gynecomastia Normal-borderline IQ Diminished facial hair Lack of libido Tall, eunuchoid body

46. Chromosomal disorders:deletions, etc…

47. Cat-eye syndrome: extra chromosome from Chr. 22 Iris coloboma Downslanting palpebral fissures, malformed pinna Anal atresia

48. Wolf Hirschhorn(Del 4p) Microcephaly, growth deficiency Hypotonia, seizures, developmental delay micrognathia, cleft palate/lip hypospadias ASD

49. Wolf Hirschhorn (Del 4p) Detectable by FISH “Greek warrior helmet” appearance of nose and eyes

50. Cri du Chat (Del 5p) Slow growth Cat-like cry Hypotonia, DD, low IQ Microcephaly Single palmar crease Hypertelorism

51. Cri du Chat (Del 5p)

52. Multigene sequence disorders

53. DiGeorge (Del 22q11) Cardiac Abnormal facies Thymic Hypoplasia Cleft palate Hypocalcemia T cell malfunction leads to fungal and viral infectionsT cell malfunction leads to fungal and viral infections

54. DiGeorge (Del 22q11) Mild microcephaly Cleft palate Speech delay Long tapering fingers Emotional lability

55. Williams (7q11.23) Contiguous gene disorder involving elastin and other genes FISH testing available Ca restriction may be necessary

56. Williams (7q11.23) Short stature Supravalvular aortic stenosis (SVAS) Elfin-facies Hypercalcemia Developmental delay Friendly personality (“cocktail personality”)

57. Miller-Dieker (17p13) Lissencephaly (smooth brain) Severe cognitive, developmental delay and seizures Due to multiple mutations in multigenic sequence of 17p13. Due to multiple mutations in multigenic sequence of 17p13.

58. Single gene disorders

60. Anteverted nostrils Low-set ears Small chin Clenched hand Ambiguous genitalia (pts may also have hypospadias or cryptorchidism)

61. Smith-Lemli-Opitz (11q12) Incidence 1:20,000 Abnormality in cholesterol biosynthesis due to single gene mutation: sterol delta-7 reductase gene Autosomal recessive Cholesterol supplementation may be helpful

62. Smith-Lemli-Opitz (11q12) Failure to thrive Low IQ Microcephaly, ptosis, anteverted nostrils, micrognathia Simian crease, syndactyly Genital abnormalities (hypospadias, micropenis, bifid scrotum) Renal anomalies, UPJ obstruction

64. Arachnodactyly (both fingers and toes) Clubbing due to associated cardiopulmonary problems Flattening of the arch of his foot Severe pectus carinatum Significant kyphosis and joint contractures Long arms

65. Marfan (15q21) Mutations in fibrillin gene Disproportionate growth Joint hyperextensibility Lens dislocation Dilation of the aortic root Genetic testing is difficult

67. Marked hyperextensibility of the skin Widened atrophic scars have thin papery texture Hyperextensibility of the joints of the elbow and fingers

68. Ehlers Danlos 2q31 Defect in Type 3 collagen Autosomal dominant Hyperelasticity Hyperflexible, hypermobile joints

69. Mutation in neurofibromin gene Abnormal peripheral nerve growth Incidence of 1:4000 Autosomal dominant

70. Neurofibromatosis I (17q11) Six or more café au lait spots >5mm in diameter 2 or more neurofibromas Axillary or inguinal freckling 2 or more Lisch nodules (benign iris hamartoma) Optic pathway tumor Bowing of bone structure First degree relative with NF1

71. Tuberous Sclerosis

72. Tuberous Sclerosis Autosomal dominant TSC1 gene (chr. 9) or TSC2 gene (Chr. 16) are tumor suppressors Seizures/MR/adenoma sebaceum Seizures in early infancy correlate with later MR Renal lesions (cysts, angiomyolipomas) CV: rhabdomyomas Retinal hamartomas

73. Achondroplasia 4p16.3 Mutation in the fibroblast growth factor receptor-3 gene (FGFR3) Autosomal dominant Short-limb dwarfism

74. Achondroplasia Frontal bossing, midface hypoplasia Cranio-cervical junction problems (sometimes leading to cord compression or hydrocephalus) Lumbar lordosis Normal intelligence

75. Rubenstein-Taybi (16p13) Deletion in the transcriptional regulator CREB binding protein Developmental delay, feeding problems Growth failure Microcephaly, broad thumbs Prominent nose, small chin 25% detectable by FISH Autosomal dominant with variable penetrance Often with mental retardationAutosomal dominant with variable penetrance Often with mental retardation

76. Holt Oram (12q2) Autosomal dominant Mutation in TBX1 gene Marked variability in expression Upper limb and shoulder defects: absent thumb, triphalangeal, or bifid Syndactyly phocomelia ASD alone, or VSD Probably caused by mutations in the TBX gene –unknown functionProbably caused by mutations in the TBX gene –unknown function

78. Long, wide, and protruding ears Elongated face Flattened nasal bridge Macro-orchidism

79. Fragile X Syndrome Mutation of FMR1 gene on chromosome X (trinucleotide repeat expansion) 1:4000 males Most present with MR Trinucleotide expansion is unstable, making in the inheritance unpredictable.Trinucleotide expansion is unstable, making in the inheritance unpredictable.

80. Fragile X Syndrome Language and motor delays, hypotonia Prominent ears, long face Hyperextensible joints Flat feet High arched palate Macroorchidism Hyperactivity, autistic features

81. Uniparental disomy

82. Maxillary hypoplasia Large mouth Prognathism

83. Angelman Seizures Jerky, ataxic movements Abnormal facies Chromosome 15 deletion with maternal imprinting

84. Marked obesity Excess fat over the trunk, buttocks, and proximal extremities Small hands (and feet) Hypoplastic penis and scrotum

85. Prader-Willi Low tone Large appetite—obesity Hypogonadism Developmental delay/MR Chromosome 15 deletion, paternal imprinting

86. Genetics still poorly defined

87. Noonan (12q24) Autosomal dominant Short stature Congenital heart disease Webbed neck Downslanting palpebral fissures Low set ears Mild developmental delay One form of Noonan syndrome, that which maps to 12q24.1, is due to mutations in PTPN11 (176876), a gene encoding the nonreceptor protein tyrosine phosphatase SHP2, which contains 2 Src homology-2 (SH2) domains One form of Noonan syndrome, that which maps to 12q24.1, is due to mutations in PTPN11 (176876), a gene encoding the nonreceptor protein tyrosine phosphatase SHP2, which contains 2 Src homology-2 (SH2) domains

88. Noonan (12q24)

90. Finely arched heavy eyebrows Long eyelashes Small upturned nose Long smooth philtrum Cupid's-bow mouth Small hands Hypoplastic proximally placed thumb Short fifth finger with mild clinodactyly

91. Cornelia De Lange (5p13) Sporadically occurring Severe growth retardation, limb anomalies Congenital heart disease Synophrys Thin, downturned lips Usually sporadic, autosomal dominant Homologous gene in Fruitflies is known: Nipped B facilitiates enhancer-promoter communication upstream of the notch developmental pathwayUsually sporadic, autosomal dominant Homologous gene in Fruitflies is known: Nipped B facilitiates enhancer-promoter communication upstream of the notch developmental pathway

93. Goldenhar (14q32) Vertebroauriculofacial syndrome Hemifacial microsomia Ear anomalies, deafness Epibulbar dermoid (fatty tumor of eye) Vertebral anomalies (Chiari I) MR or Normal intelligence Most cases are sporadic, unclear whether this is autosomal dominant with variable penetrance or autosomal recessiveMost cases are sporadic, unclear whether this is autosomal dominant with variable penetrance or autosomal recessive

94. Kabuki Hypertelorism, long palpebral fissures, large pinnae Developmental delay Hearing loss Possibly due to 8p deletion

95. Pierre Robin Sequence Glossoptosis, micrognathia, cleft palate 1:8500 live births Airway and feeding problems Unknown cause Surgical treatment Glossoptosis: a tongue which tens to ball up at the back of the mouth and fall back towards the throat Glossoptosis: a tongue which tens to ball up at the back of the mouth and fall back towards the throat

96. Short palpebral fissures and ptosis Low-set, dysplastic ears Small chin Choanal atresia necessitated tracheotomy Prominent forehead Hypertelorism Narrow palpebral fissures Hypoplasia of the right naris Cupid's-bow mouth

97. CHARGE Incidence 1:10,000 Coloboma Heart choanal Atresia Retardation Genital hypoplasia Ear abnormalities, deafness

98. Facial features are not dysmorphic Preaxial polydactyly of the thumb (which was associated with radial dysplasia)

99. VACTERL Vertebral defects imperforate Anus Cardiac malformations (VSD) TracheoEsophageal fistula Renal anomalies Limb (radial ray) anomalies

100. Short palpebral fissure length Mild ptosis Long simple philtrum

101. MELAS Pt presented with mild cognitive delay, short stature, neutropenia, and Wolff-Parkinson-White syndrome at age 4. By age 6 he had muscle weakness and visual and hearing impairment as a result of a series of strokes.