MULTIPLE CONGENITAL ANOMALIES SYNDROMES

Question 1

CHARGE SYN

Answer 1

Acronym: Coloboma, hrt defects, atresia choanal, growth retardation, genital, ear, Genetics: AD, CHD7 gene, usually de novo mutation

Question 2

BECKWITH-WIEDEMANN SYN (BWS)

Answer 2

Macrosomia (overgrowth), hemihyperplasia (uneven growth), omphalocele, macroglossia, increased risk for malignancy (Wilms tumor and hepatoblastoma), Genetic Mechanism: Usually sporadic, chr11&raquo_space;two imprinting centers; 50% loss of methylation on maternal chr11 IC2, 20% paternal UPD; 5% gain of methylation on mat chr11 IC1, mutations in maternal CDKN1C–gene signals NOT to grow (normally CDKN1C expressed on mat chr); Testing Strategy: Methylation first (methylation alterations at both IC1 and IC2 suggest UPD), then CDKN1C sequ and del/dup (CDKN1C testing identifies 40% w/ fam hx and 5% w/ no fam hx)

Question 3

RUSSELL-SILVER SYN

Answer 3

Slow growth but head growth normal, FTT, triangular face (upside down triangle–prominent forehead, narrow chin), hypoglycemia, Genetic Mechanism: chr11 and chr7: SEE SUPPLEMENTAL CARD 30-50% loss of methylation on pat chr11&raquo_space; IFG2/H19 region, 10% mat UPD chr7; Testing Strategies: Methylation studies first, then UPD

Question 4

VATER/VACTERL ASSOCIATION

Answer 4

Acronym: vertebral, anal atresia, cardiac, tracheo-esophageal fistula, renal/kidney, limbs (at least three); sporadic with no clear pattern of inheritance (about 1% risk for recurrence)

Question 5

NOONAN SYNDROME

Answer 5

Philtrum, low-set ears rotated backward, webbed neck, short stature, congenital heart defects, hematological malignancies, most w/ nml intelligence, Genes: PTPN11, SOS1, RAF1, RIT1, autsomal dominant, Prenatal: cystic hygroma, increased NT

Question 6

PROGERIA

Answer 6

Appearance of rapid aging; beaked nose, alopecia, loss of subcutaneous fat, arteriosclerosis&raquo_space; hrt attk, stroke, Genetics: LMNA, Aut dominant

Question 7

BARDET-BIEDL SYN

Answer 7

Vision loss due to deterioration of retina: Night&raquo_space; peripheral&raquo_space; tunnel and visual acuity (central)&raquo_space; legally blind by early adulthood, obesity, Genetics: BBS1 and BBS10, genes involved in structure and function of cilia

Question 8

COFFIN-LOWRY SYN

Answer 8

Intellectual disability and develop delay, SIDES (stimulus induced drop episodes), soft hands, short, tapered fingers, Genetics: RPS6KA3 (Rupert Potter Says 6 Keys Are 3), X-linked dominant, most de novo

Question 9

CORNELIA DE LANGE

Answer 9

Arched unibrow (synophrys), low set ears, small upturned nose, upper extremity anomalies (arms, hands, fingers), excessive body hair; Genetics: Cohesin complex disruption: 50% cases NIPBL (a dominant), can be X-linked dom: HDAC8 (feature includes delayed closure of fontanelle), SMC1A

Question 10

JOUBERT SYN

Answer 10

Molar tooth sign on MRI; Genetics: Involved in primary cilia, usually A recessive, rarely X-linked recessive

Question 11

FRYNS SYN

Answer 11

Congenital diaphramatic hernia&raquo_space; pulmonary hypoplasia, finger and toe abnormalities (underdeveloped); Poor prognosis (die before birth or in early infancy); A recessive but no single gene has been identified

Question 12

PALLISTER KILLIAN SYN

Answer 12

Severe hypotonia, coarse face, sparse hair, Genetics: i(12p)&raquo_space; chr12 with two p arms; mosaic» some cells have two copies of chr12 + i(12p); not inherited

Question 13

RUBENSTEIN-TAYBI SYN

Answer 13

Short stature, ID, broad thumbs and first toes, big nose, Genetics: CREBBP–Cats React Extra Bad Because Poo (regulating cell growth and division), EP300 genes, A dominant, but most de novo

Question 14

TREACHER-COLLINS SYN

Answer 14

Underdevelopment of facial bones (cheeks and chin)O, Abnormal ears, Genetics: TCOF1 (reduce production of rRNA), 60% de novo but A dominant, the rest passed from affected parent

Question 15

GOLDENHAR SYN (AKA OCULOAURICULAR DYSPLASIA)

Answer 15

Hemifacial microsomia (“abnml smallness”) + epibulbar (ocular) dermoids, microtia, Genetics: sporadic

Question 16

X-LINKED ADRENOLEUKODYSTROPHY

Answer 16

Affects the nervous system white matter»three phenotypes: Childhood cerebral form (begins as ADD, impaired adrenocortical function, abml brain MRI), Adrenomyeloneuropathy (AMN) (begins w/ stiffness and weakness in legs, impaired adrenocortical function), Addison’s disease only (no neurologic abnormality); Genetics: ABCD1 gene, X-linked, Testing Strategy: Very Long Chain Fatty Acids (elevated VLCFA), MRI, molecular testing of ABCD1

Question 17

X LINKED AGAMMAGLOBULINEMIA (XLA)

Answer 17

Very Few B cells (protection against infection), first few months healthy given mother’s anitbodies&raquo_space;recurrent infections (pneumonia, pink eye, sinusitis), Genetics: BTK gene, X-linked recessive

Question 18

FAMILIAL MEDITERRANEAN FEVER

Answer 18

Recurrent episodes painful imflammation abdomen, chest, joints, attacks proceeded by prodrome&raquo_space; can lead to amyloidosis&raquo_space; kidney failure, Genetics: MEFV gene (instructions for pyrin found in white blood cells» mutations lead to reduced activity of pyrin, A. recessive, but sometimes A. dominant, sometimes displays pseudodominance (affected parent + carrier parent)

Question 19

BLEPHAROPHIMOSIS, PTOSIS AND EPICHANTHAL INVERSUS (BPES)

Answer 19

Eyes and Os; Narrowing of the eye opening, droopy, upward fold of inner eyelid, telecanthus (wide set eyes) and premature ovarian insufficiency (POI), Genetics: FOXL2 gene, A. dominant

Question 20

AARSKOG SYN (AKA AARSKOG-SCOTT SYN)

Answer 20

Widow’s peak hairline, hand abnormalities, brachydactyly, shawl scrotum; Genetics: FGD1 gene (account for 20% of people); X-linked recessive, females can show mild symptoms like short stature, hypertelorism, widow’s peak.

Question 21

COSTELLO SYN

Answer 21

Loose skin folds (hands and feet), heart problems, short stature (reduced growth hormone levels), anal and mouth papillomas, increased risk for cancer such as rhabdomyosarcoma and neuroblastoma; Considerable overlap with Noonan, especially in infancy; Lymphatic dysplasia therefore may see increased NT, cystic hygroma, etc on prenatal ultrasound) Genetics: HRAS gene (cell growth and division), A dominant; Testing Strategy: NGS panel

Question 22

ECTRODACTYLY ECTODERMAL DYSPLASIA CLEFTING SYN (EEC)

Answer 22

Ectrodactyly (central fingers and/or toes) AKA split hand/foot malformation; Ectodermal = skin (hyperkeratosis), hair (sparse), teeth, sweat glands (hypohidrosis); Cardinal signs = malformations of hands/feet, clefting, ectoderm; Genetics: TP63 gene mutations (EEC type 3) or chromosomal 7 abnormalities (EEC type 1); Testing Strategy: NGS of TP63 (more than 90% of cases) > if neg&raquo_space; microarray; Gonadal mosaicism; A dominant

Question 23

HIRSCHPRUNG

Answer 23

Absence of nerves in parts of the intestine&raquo_space; severe constipation or complete blockage of intestine, can lead to enterocolitis and intestinal perforation; Most common type is “short-segment disease” (nerve cells missing from last segment of large intestine)–x4 more common in men than women; “long segment” disease most severe and occurs in most of the large intestine–affected men and women equally; If concern for syndrome: Waardenburg, Mowat-Wilson syn, congenital central hypoventilation syn; Genetics: Multifactorial, but mutations in RET cause A dominant disease (incomplete penetrance)

Question 24

KABUKI SYN

Answer 24

Facies, skeletal, Dermatological, ID and post natal growth deficiency: Infantile hypotonia, DD and ID + Typical facies: fetal fingertip pads, abml ears, eyes, eyebrows; Genetics: Mostly A. dominant (de novo) but can be X-linked (KMT2D and KDM6, respectively)