| Chromosome instability
syndromes |
| Ataxia-telangiectasia (see Chap. 188) | Growth deficiency; CNS deterioration; ataxia; telangiectasia; frequent
infections; malignancies | Immunodeficiency (deficient T cell, low IgA), increased frequency
of some breaks; ↑ AFP, chromosome 11q22 | AR (208900) | 11q22/ATM peptide |
| Xeroderma pigmentosum | Extreme photosensitivity; skin atrophy; pigmentary changes;
malignancies | Defective DNA repair in UV light; UV-induced sister chromatid
exchange; several subtypes mapped to different chromosomes | AR (278700) multiple complement groups: A, C, D, E, F, G | 9q22/XPA peptide |
| Bloom syndrome (see Chaps. 188, 359) | Prenatal growth deficiency; microcephaly; malar hypoplasia;
facial telangiectasia; malignancies | Increased chromosome breaks and sister chromatid exchanges;
chromosome 15q26.1 | AR (210900) | 15q26/DNA helicose |
| Fanconi anemia | See syndromes of limb defects with hematologic abnormalities,
below | | | |
| Craniofacial syndromes |
| Goldenhar (oculoauricularvertebral dysplasia spectrum/OAV) | See syndromes associated with branchial arch derivative anomalies
(Table 177-1) | | | |
| Treacher Collins syndrome (mandibulofacial dysostosis) | See syndromes associated with branchial arch derivative anomalies
(Table 177-1) | | | |
| Velocardiofacial syndrome | See syndromes associated with cleft lip and/or palate (Table 177-1) | | | |
| Van der Woude syndrome | See syndromes associated with cleft lip and/or palate (Table 177-1) | | | |
| Nager syndrome | See syndromes associated with branchial arch derivative anomalies
(Table 177-1) | | | |
| Kabuki syndrome (Niiakawn-Kuroki) | See syndromes associated with cleft lip and/or palate
(Table 177-1) | | | |
| Stickler syndrome | See syndromes associated with cleft lip and/or palate (Table 177-1) | | | |
| Oral-facial-digital syndrome type I | See syndromes associated with cleft lip and/or palate (Table 177-1) | | | |
| Coffin-Lowry syndrome | Coarse features; mental retardation, vertebral defects; tufted distal
phalanges; scoliosis | Skeletal findings on x-ray | X-linked (303600) | Xp22/RSK2/kinase |
| Oto-palato-digital syndrome type I | Short stature; thick skull; hypertelorism; microstomia; hypodontia;
cleft palate; small trunk; short and broad distal phalanges, nails,
and metacarpals | Skeletal findings on x-ray | XR (311300) | Xq28/filamin A- |
| Alagille syndrome | Long, thin face; biliary and cardiac anomalies; Axenfeld
eye anomaly | Cardiac abnormalities on echocardiogram | AD (118450) | 20p12/JAGGEI |
| Waardenburg syndrome I | See syndromes associated with hypertelorism or frontonasal malformation
(Table 177-1) | | | |
| Syndromes characterized
by overgrowth |
| Prader-Willi syndrome (Fig. 170-5)
(see also Angelman syndrome) | Hypotonia; obesity; narrow bifrontal skull; almond-shaped eyes;
hypoplastic genitalia; small hands and feet; mental retardation;
polyphagia | Deletion of paternal chromosome 15q11 or maternal uniparental
disomy 15q11; methylation studies | Sporadic (few inherited chromosomally) (176270) | 15q11-13/- |
| Sotos syndrome | Large for gestational age; macrocephaly; prominent forehead; down-slanting
eyes; hypertelorism; mental retardation | Advanced bone age | AD (117550) | 5q35/nuclear receptor binding proteins |
| Weaver syndrome | Large for gestational age; macrosomia; camptodactyly; distinctive
face | Advanced bone age | Sporadic (277590) | — |
| Beckwith-Wiedemann syndrome | Macrosomia; macroglossia; omphalocele; ear fissures; facial
hemangioma; mental retardation | Polycythemia, hypoglycemia, duplication of paternal chromosome
11p on DNA studies | Sporadic, AD (130650) | 11p15/cyclin-dependent kinase inhibitor |
| Bardet-Biedl syndrome | Obesity, retinitis pigmentosa, syndactyly; polydactyly; hypoplastic
genitalia; mental retardation; diabetes mellitus; renal disease | Serum glucose, urinalysis, renal findings | AR (209900, 605231) | Multiple (12) loci/BBS peptide |
| Proteus syndrome | Large hands or feet; hemihypertrophy; nevi; subcutaneous tumors;
accelerated growth | Pelvic lipomas on abdominal ultrasound | Sporadic (176920) | — |
| Bannayan-Riley-Ruvalcaba syndrome (the PTEN-related syndromes) | Lipomas; vascular dysplasias | Autism | AD (153480) | 10q23/phosphate on tensin homolog |
| Limb deficiency
syndromes |
| Femoral hypoplasia—distinctive face syndrome | Short nose; hypoplastic alae nasi; long philtrum; Robin cleft micrognathia;
hypoplastic femurs and fibulae | Skeletal findings: vertebral defects short/absent femurs | Sporadic, occurs in infants of diabetic mothers (134780) | — |
| Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome | Split hand/foot malformation; ectodermal dysplasia;
cleft lip/palate | Renal defects on ultrasound | AD (604292) | 3q27/p63 |
| Hypoglossia-hypodactylia syndrome | Small to absent tongue; short to absent digits | — | Sporadic (10330) | — |
| Möbius syndrome | Cranial nerve defects; hypoplastic tongue or digits, limb deficiency,
Poland anomaly | — | Sporadic (157900) | — |
| Holt-Oram syndrome | Variable upper limb deficiency; triphalangeal thumb, congenital
heart defect, especially atrial septal defect | Cardiac abnormalities on ECG, echocardiogram | AD (142900) | 12q24/box 5 |
| Syndromes of limb
defects with hematologic abnormalities |
| Fanconi anemia syndrome | Pancytopenia; hypoplastic thumb and radius; hyperpigmentation;
abnormal facies | Bone marrow hypoplasia; increased chromosome breakage; skeletal
x-ray | AR (227650) Multiple complement groups, multiple loci (12) | 16p/A-FANC peptides |
| Diamond-Blackfan syndrome (Aase syndrome) | Triphalangeal thumb; radial hypoplasia; hypoplastic anemia;
congenital heart defect | Bone marrow | AD (105650) | 19q13/ribosomal protein S19 |
| Thrombocytopenia-absent radius (TAR) syndrome | Thrombocytopenia; absent radii; normal thumbs | Platelet count; bone marrow | AR (274000) | 1q12 |
| Arthrogryposes (multiple
congenital contractures) |
| Amyoplasia | Multiple contractures with shoulders in internal rotation, elbows
in extension, wrists in plantar flexion, feet in equinovarus; facial
hemangiomas | — | Sporadic (108110) | — |
| Freeman-Sheldon syndrome (whistling face syndrome) | Distal arthrogryposis; restricted mouth movement; ptosis
and facial hypoplasia, scoliosis | — | AD (193700) | 17p13/myosin heavy chain 3 |
| Congenital contractural arachnodactyly (Beal syndrome) | Arthrogryposis; arachnodactyly; kyphoscoliosis; abnormal
helix of ear | — | AD (121050) | 5q23/fibrillin-2 |
| Pena-Shokier “syndrome” (fetal akinesia
sequence) | Generalized arthrogryposis; hypertelorism; malformed ears;
micrognathia; pulmonary hypoplasia; usually lethal | — | AR (208150) | 3 loci/ERCC peptides |
| Cerebro-oculo-facio-skeletal syndrome | Finger, knee, elbow contractures; microcephaly; blepharophimosis,
serious CNS abnormalities, microphthalmia | — | AR (208150) | — |
| Multiple pterygium syndromes | Multiple joint webs; arthrogryposis; several types with variety of
additional anomalies, some lethal | Skeletal finding on x-ray in cervical fusion | AR, AD (253290) | 2q33/acetylocholine receptors |
| Popliteal web syndrome | Popliteal webs, lip pits; cleft lip/palate; genital
hypoplasia; nail dysplasia | — | AD (119500) | 1q/32/interferon regulation factor 6 |
| Distal arthrogryposis Type IA | Camptodactyly, foot deformities | — | AD (108120) | 9p13/topomyosin 2 |
| Syndromes with severe
neurologic abnormalities |
| Meckel-Gruber syndrome | Encephalocele; polycystic kidney, polydactyly; lethal | — | AR (249000) | 17q22/MK SI peptide and 8q21 meckelin |
| Miller-Dieker syndrome | Lissencephaly; microcephaly; micrognathia; anteverted nares | CT scan; MR imaging; deletion chromosome 17p13 by FISH | del 17p (146510) | 17p/LISI |
| Hall-Pallister syndrome | Hypothalamic hamartoblastoma; polydactyly; imperforate anus | CT scan; MRI; cranial ultrasonography; chromosome 3/7
translocation | Sporadic, AD (146510) | 7p/GLI3 |
| Angelman syndrome (see also Prader-Willi syndrome and Fig. 170-5) | Microcephaly; prognathism; ataxia; seizures; paroxysmal laughter;
mental retardation | Deletion of maternal chromosome 15q11 or paternal uniparental
disomy | Sporadic (few inherited) (105830) | 15q11-13/ubiquitin-protein ligase |
| Warburg (HARD ± E) syndrome | Hydrocephalus; agyria; retinal dysplasia; encephalocele | CT scan; MR imaging, ophthalmology muscle evaluation | AR (236670) | 2 loci 9q34 and 14q 24/protein O-mannosyltransferase |
| Metabolic syndromes
with congenital anomalies (see Section 11) |
| Congenital hypothyroidism | Large fontanelle; macroglossia, umbilical hernia | Hyperbilirubinemia; delayed bone age; decreased plasma T4; increased
plasma TSH | Sporadic, inherited forms uncommon | — |
| Menkes syndrome | Progressive neurologic deficit; sparse and broken hair; pili torti;
skeletal changes | Decreased serum cooper and ceruloplasmin; skeletal x-ray | X (309400) | Xq13/ATPase copper transport protein |
| Zellweger syndrome | Hypotonia; flat occiput; extranuchal skin; epicanthal folds; camptodactyly;
hepatomegaly; cerebral defects; retinal lesions; renal cortical cysts | Peroxisome defect; increased very long chain fatty acids;
stippled bones; increased phytanic and pipecolic acids | AR (214100) | Locus heterogeneity/11 loci and genes |
| Glutaric academia type II | Hepatomegaly, facial dysmorphism, renal cysts, GU anomalies,
acrid color | Nonketonic hypoglycemia; metabolic acidosis; hyperammonemia; organic
aciduria | AR (231680) | 15q23/electron transfer flavoprotein |
| Neonatal adrenoleukodystrophy | Seizures, demyelination, adrenal hypoplasia, retinitis pigmentosa,
deafness, hepatomegaly | Peroxisome defect; increased phytanic, pipecolic, and very
long chain fatty acids | AR (600414) | 12p13/peroxisome receptor 1 |
| Rhizomelic chondrodysplasia punctata | Short limbs, nasal hypoplasia, cataracts, ichthyosis | Peroxisome defect, increased phytanic, pipecolic acid; decreased
plasmalogens; stippled bones; vertebral body clefts | AR (215100) | PEX7 |
| Smith-Lemli-Opitz syndrome | Short stature; microcephaly; ptosis; epicanthal folds; anteverted
nares; broad alveolar ridges; syndactyly toes 2-3; cryptorchidism;
hypospadias; mental retardation | Cholesterol metabolism: elevated 7 dehydrocholesterol deficiency
of delta-7 reductase | AR (270400) | 11q12/delta 7 reductase |
| Associations |
| VATER | Vertebral defects, anal atresia, tracheoesophageal fistula, radial
dysplasia, renal dysplasia, congenital heart defect | Vertebral defects on x-rays; renal abnormalities on ultrasound | Sporadic (192359) | — |
| Other important
syndromes |
| MURCS | Müllerian duct aplasia, renal aplasia, cervicothoracic somite
dysplasia | Cervical vertebral defects on x-ray | Sporadic (none) | — |
| Robinow syndrome | Mild shortness of stature; macrocephaly; hypertelorism; short
and anteverted nose; short forearms and digits; hemivertebrae; hypoplastic genitalia | Skeletal findings on x-ray | AD, AR (180700, 268310) | — |
| Aarskog syndrome | Mild shortness of stature; hypertelorism, ptosis; anteverted
nares; short fingers with webbing; clinodactyly; inguinal hernia; shawl
scrotum | — | XD (305600) | Xp11/FGDI protein |
| CHARGE | Coloboma, congenital heart defect, choanal atresia, growth and
mental retardation; genitourinary anomalies (genital hypoplasia);
characteristic ear anomaly | Deafness | AD (214800) | 8q12/chromodia helicase |
| Trichorhinophalangeal syndrome I (TRPI) | Bulbous nose; hypoplastic nares; long philtrum; large ears; hypotrichosis;
short metacarpals and metatarsals; cone-shaped epiphyses | Skeletal survey | AD (190350) | 8q24/zinc finger transcription factor |
| Langer-Giedion syndrome (TRPII) | Bulbous nose; thickened alae nasi with upward “tenting” long philtrum;
hypodontia; cone-shaped epiphyses; exostoses; mental retardation | Skeletal survey, deletion 8q24 | Sporadic; familial translocation (150230) | 8q24/- |
| Opitz syndrome (BBB syndrome) (Opitz-Frias) | Hypertelorism, telecanthus; high and broad nasal bridge;
cleft lip/palate; hypospadias; laryngo-tracheo-esophageal cleft | — | XD/AD (3000000) | Xp/MIDI |
| Noonan syndrome | Short stature; congenital heart defect; pectus excavatum, webbed
neck; hypertelorism; lymphedema; bleeding diathesis; possible mental
retardation | Cardiac evaluation; bleeding studies | AD (163950) | 12q…/…SHP2 (2 other genes) |
| Williams syndrome | Growth delay; mental retardation; stellate iris; hypoplastic nails;
epicanthal folds; periorbital fullness; anteverted nares; supravalvular
aortic stenosis | Microdeletion of chromosome 7q11 | Sporadic (194050) deletion 7q | 7q11/elastin |
| Rubinstein-Taybi syndrome | Short stature; mental retardation; antimongoloid slant of
eyes; beaked nose; hypoplastic maxilla; broad thumbs and toes; congenital
heart defect | Microdeletion of chromosome 16p13.3 | Sporadic (180849) | 16p13/CREB binding protein |
| McCune-Albright syndrome | Multiple bony fibrous dysplasia; café-au-lait spots;
sexual precocity | Skeletal x-ray; G protein mutation mosaicism | Sporadic | 20q13/G protein |
| Costello syndrome | Severe postnatal growth deficiency, relative macrocephaly,
characteristic face, loose skin, risk of neoplasm | — | Sporadic (218040) | 11p15/HRAS peptide |
| Cardiofacial cutaneous syndrome | Cardiac defects, characteristic facies, ichthyosiform dermatosis,
growth deficiency | — | Sporadic AD (115150) | 3 loci and genes |
| Short stature syndromes |
| De Lange syndrome | Prenatal growth retardation; microcephaly; hirsutism; synophrys;
anteverted nares; downturned mouth; limb reduction defects; congenital heart
defects; mental retardation | — | Sporadic/AD (122470) | 5q13/delangin |
| Dubowitz syndrome | Prenatal growth delay; telecanthus; ptosis; blepharophimosis;
short palpebral fissures; eczema, hypotrichosis; behavioral problems | — | AR (223370) | — |
| Russell-Silver syndrome | Prenatal growth retardation; asymmetric, triangular facies;
café-au-lait spots; hypoglycemia | Renal findings on ultrasound | Usually sporadic (180860) | Methylation disorder 11p/3q23 and 14q2 |
| Seckel syndrome | Pre- and postnatal growth retardation; microcephaly; characteristic
nose; mental retardation | — | AR (210600) | — |
| Hallermann-Streiff syndrome | Proportionately small, hypoplastic mandible; microphthalmia;
cataracts, hypoplastic nose; neonatal teeth; hypotrichosis | — | Sporadic (234100) | — |