A 2 week old infant male was delivered to a 30 year old G2P1 mother at 41 weeks gestation. Mother reportedly had an uncomplicated prenatal course with good prenatal care. Newborn length, weight, and head circumference were at the 3rd percentile. The newborn period was complicated by feeding difficulties. A genetics consultation was requested due to unusual facial features including bitemporal narrowing, periorbital fullness, short nose, full lips, wide mouth, and small jaw. An echocardiogram detected peripheral pulmonic stenosis. The geneticist requested a chromosomal microarray analysis, which reveals a 1.8 Mb (megabase) deletion of chromosome 7q11.23 consistent with Williams syndrome.
You see a 16 year old male at the pediatric outpatient clinic. He has motor and speech delay including a history of walking at 20 months and first words at about 2 years old. On physical exam you observe he has macrocephaly, a long face, prominent forehead, and large ears. Auscultation reveals a systolic murmur. You note poor eye contact and perseverative speech during the appointment. He has a diagnosis of autism through the Department of Education. You order DNA testing for fragile X syndrome that returns positive with greater than 1000 CGG repeats in the FMR1 (fragile X mental retardation 1) gene.
This chapter reviews some common syndromes that present in infancy or childhood. The infant described in Case 1 has Williams syndrome. The boy described in Case 2 has fragile X syndrome. Other syndromes reviewed here include Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Prader-Willi syndrome, Angelman syndrome, Sotos syndrome, Noonan syndrome, CHARGE syndrome, Rett syndrome, and achondroplasia.
Williams syndrome is a microdeletion syndrome including the elastin gene (ELN) and surrounding genes on chromosome 7. Deletions are mostly de novo (new mutations). When inherited, Williams syndrome follows an autosomal dominant pattern of inheritance. The deletion involved can be detected by fluorescence in situ hybridization (FISH). However, this condition is currently often detected by chromosomal microarray analysis, which simultaneously tests for many microdeletions and microduplications. Features of Williams syndrome can include cardiovascular disease (arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), and connective tissue, growth and endocrine abnormalities. Patients typically have mild intellectual disability with a specific cognitive profile (strengths in language, but weakness in visuospatial cognition), unique personality characteristics (overfriendliness, excessive empathy, anxiety), and distinctive facies (broad brow, bitemporal narrowing, periorbital fullness, a stellate/lacy iris pattern, full lips, wide mouth). Management focuses on supportive treatment and surveillance for complications including special education needs, psychological, psychiatric, behavioral, cardiac, endocrine, and renal evaluations, and follow-up care as needed.
Fragile X syndrome is considered one of the most common inherited forms of intellectual disability. This condition is inherited in an X-linked dominant manner. Recent studies estimate a prevalence of 16 to 25 in 100,000 males and the prevalence of females affected is thought to be about one half of this. About 99% of cases of fragile X syndrome are caused by trinucleotide (CGG) repeat expansion and associated methylation that disrupt the FMR1 (fragile X mental retardation 1) gene expression and result in loss of gene function. The number of trinucleotide (CGG) repeats in exon 1 of the FMR1 gene determines whether the individual will have features of the condition and his/her chance of having affected offspring. Specifically, individuals with 5 to 44 repeats (normal allele size) are not affected and not at risk to have affected offspring. Women with 45 to 54 repeats (intermediate allele size) have a small chance to pass a premutation allele size expansion to their offspring. Women with 55 to 200 repeats (premutation allele size) are at risk for expansion during transmission of the allele; therefore these women are at risk to have offspring with fragile X syndrome. In addition, older adults with a premutation may develop fragile X-associated tremor/ataxia syndrome (FXTAS) and women who are premutation carriers may develop FMR1-related primary ovarian insufficiency (POI). More than 200 repeats (full mutation allele size) are associated with the fragile X syndrome. Males with a full mutation typically have moderate to severe intellectual disability. Other features, which become more apparent with age, include minor craniofacial anomalies (long face, prominent forehead, large ears), macro-orchidism, behavior concerns (hyperactivity, hand flapping, hand biting, temper tantrums, and occasionally autism) and cardiac findings (mitral valve prolapse, aortic root dilatation). About half of females with a full mutation have intellectual disability and about half have normal intellect. Whether a female with a full mutation has intellectual disability or not is thought to be related to the brain activity level of the X chromosome with the full mutation, compared to the brain activity level of the X chromosome with the normal FMR1 allele. Affected females have the associated physical and behavioral features at a lower frequency and with milder involvement than males. Polymerase chain reaction (PCR) plus Southern blot analysis are currently the recommended techniques for molecular testing for Fragile X syndrome. PCR sensitively measures the number of repeats in the normal to lower premutation range and Southern blot analysis can detect normal, premutation and full mutation size alleles.
Beckwith-Wiedemann syndrome is an overgrowth disorder due to abnormal regulation of gene transcription in the imprinted domain of chromosome 11p15.5. Imprinted domains have different chemical modifications depending on whether the domain is of maternal or paternal origin, which leads to specific differences in gene expression. In about 85% of patients, this condition is de novo. In about 15% of cases, it is familial and inherited in an autosomal dominant manner. Key characteristics include macrosomia, macroglossia, hemihyperplasia (hemihypertrophy), visceromegaly, omphalocele, ear creases and pits, certain renal abnormalities, and increased risk of embryonal tumors (e.g. Wilms tumor, hepatoblastoma). Treatment and management depend on specific symptoms. Macroglossia rarely is severe enough to cause airway obstruction and feeding issues but may require surgical reduction. Hemihyperplasia may require orthopedic management. Overall, the risk of embryonal tumor is approximately 7.5%, and a tumor surveillance protocol is recommended. This includes quarterly abdominal ultrasounds and serum alpha fetoprotein measurements through early to mid childhood. Molecular testing can confirm the diagnosis of Beckwith-Wiedemann syndrome and the different underlying genetic mechanisms are associated with this condition. Among individuals with this condition, specific molecular tests detect the loss of methylation (a type of imprint) at Imprinting Center 2 at 11p15 in about 50% of cases, paternal uniparental disomy of 11p15 in about 20% of cases, and a gain of methylation at Imprinting Center 1 at 11p15 in about 5% of cases. Uniparental disomy (UPD) refers to the inheritance of both copies of a chromosome from one parent, instead of the typical one copy of each chromosome from each parent. In addition, mutations in the gene CDKN1C (cyclin-dependent kinase inhibitor 1C), which is located at 11p15, are found in about 40% of familial cases and 5% to 10% of de novo cases. For about 20% of patients, the cause of Beckwith-Wiedemann syndrome is unknown.
Russell-Silver syndrome is characterized by asymmetric intrauterine growth retardation (IUGR), postnatal growth deficiency with normal head circumference, body asymmetry, characteristic facial features, and fifth finger clinodactyly (curved fingers). Common health concerns involve growth, skeletal abnormalities, hypoglycemia, and gastrointestinal disorders. There are at least two genetic types of Russell-Silver Syndrome, one involving the imprinted domain at chromosomal locus 11p15.5 and one involving chromosome 7. Regarding the imprinted domain at 11p15.5, 30% to 50% of patients have hypomethylation of Imprinting Center 1 at this locus. Other imprinting anomalies and duplications involving this domain have been reported in patients. The genetic mechanism in 7% to 10% of patients is maternal uniparental disomy of chromosome 7. Mosaic and segmental maternal uniparental disomy of chromosome 7, and chromosome 7 deletions and duplications have also been detected in patients with Russell-Silver Syndrome. When a couple has a child with this condition due to hypomethylation of Imprinting Center 1 or maternal uniparental disomy of chromosome 7, the recurrence risk in future pregnancies is low and the patient’s risk for affected children is also low.
Prader-Willi syndrome is due to abnormal imprinting within the Prader-Willi syndrome/Angelman syndrome region on chromosome 15. Typical features include congenital hypotonia resulting in early failure to thrive, short stature, global developmental delay, usually mild intellectual disability, genital hypoplasia, hypothalamic hypogonadism, and characteristic behavior problems (temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics). Most patients experience excessive appetite (hyperphagia) with central obesity if access to food is not controlled. Most recently, growth hormone has been used to increase lean body mass, improve muscle tone, and help reduce the risk of obesity and improve linear growth. Other interventions include nutritional, physical, occupational, and speech therapy, orchiopexy, other endocrine treatment as needed, and behavioral management. Prader-Willi syndrome is due to the absence of the expression of paternally imprinted genes in the Prader-Willi syndrome/Angelman syndrome region on chromosome 15. Causes of this include deletion of this region on the paternally derived chromosome 15, maternal uniparental disomy of chromosome 15 and, rarely, imprinting defects. A methylation analysis test can detect Prader-Willi syndrome in greater than 99% of cases by determining whether a region with the paternal imprint is present. A couple’s recurrence risk is most often less than 1% but can be up to 50% if an imprinting defect is involved (rare).
Angelman syndrome is due to the absence of expression of the maternally imprinted UBE3A (ubiquitin protein ligase E3A) gene in the Prader-Willi syndrome/Angelman syndrome region on chromosome 15. Causes include deletion of this region on the maternally derived chromosome 15 (about 68% of patients), paternal uniparental disomy of chromosome 15 (about 7% of patients), and imprinting defects (about 3% of patients), which can all be detected by methylation analysis. About 11% of patients have a UBE3A gene mutation that can be detected by UBE3A sequence analysis. A typical natural history for a patient with Angelman syndrome includes a normal newborn history and examination with developmental delay noted between 6 and 12 months of age, which is eventually classified as severe with minimal to no use of words and relatively stronger receptive language skills. Patients usually have a gait ataxia and unique behaviors including a happy demeanor often with hand-flapping. Most patients have slow head growth with microcephaly by age 2 years, and seizures that begin before age 3 years. Craniofacial features can be subtle with wide mouth, widely spaced teeth and a prominent chin. Generalized hypopigmentation may be noted in those with deletions of chromosome 15. A couple’s recurrence risk is less than 1% if the cause is a deletion or uniparental disomy and up to 50% if the cause is an imprinting defect or UBE3A mutation.
Sotos syndrome is caused by deletion or mutation in the NSD1 (nuclear receptor binding SET domain protein 1) gene. Deletion mutations, rather than smaller mutations, are more common among Japanese patients. This is thought to be due to variations in chromosome structure, such that recombination events at the associated chromosomal locus, 5q35, may be more common among Japanese patients. Sotos syndrome is de novo in over 95% of cases but can be inherited in an autosomal dominant manner. A clinical diagnosis of Sotos syndrome can be made for individuals who have cardinal facial features, overgrowth, and a learning disability. Typical facial features, which are most recognizable between ages 1 and 6 years, include a tall prominent forehead, a long narrow face, a prominent narrow jaw (head/face shape like an inverted pear), down slanting palpebral fissures, and sparse frontotemporal hair. About 90% of affected children have a height and/or head circumference two or more standard deviations above the mean. Affected adults usually have macrocephaly but may be of normal height. Most patients have intellectual disability, which is highly variable and ranges from mild to severe. Confirmation of Sotos syndrome can include NSD1 sequencing and deletion/duplication analysis. Sotos syndrome as a contiguous gene deletion syndrome can sometimes be detected by chromosomal microarray analysis.
Noonan syndrome is a single gene disorder. Molecular testing has found that patients have a single mutation in one of several genes that interact in the RasMAPK pathway (a complex pathway of cellular proteins that communicate a signal from a cell surface receptor to the nuclear DNA). About 50% of patients have a mutation in the PTPN11 (protein tyrosine phosphatase, non-receptor type 11) gene, which is the gene most frequently involved in Noonan syndrome. This condition is inherited from an affected parent (autosomal dominant) in 30% to 75% of cases. Key clinical features of Noonan syndrome include a broad or webbed neck, short stature, congenital heart defect, variable intellectual disability, sternal deformity (pectus excavatum and/or carinatum), and coagulation defects. Characteristic facies include low-set, posteriorly rotated ears, widely spaced eyes with epicanthal folds and thick eyelids. Genotype-phenotype correlations have been observed among individuals with Noonan syndrome. For example, pulmonic valvular stenosis correlates with PTPN11 mutations. Within the differential diagnosis for Noonan syndrome are conditions with overlapping clinical features that are also caused by mutations in RasMAPK pathway genes (e.g., Costello syndrome and cardiofaciocutaneous syndrome). Generally, the mutations that cause Noonan syndrome are missense mutations that are detectable by sequence analysis. Molecular diagnosis may require a multigene panel or tiered sequential gene testing.
CHARGE syndrome is a single gene disorder. About 65% to 70% of patients suspected to have this condition have a mutation in the CHD7 (chromodomain helicase DNA binding protein 7) gene detectable by sequence analysis. CHARGE syndrome is generally de novo and has an autosomal dominant pattern of inheritance. CHARGE is an acronym that stands for Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities, and Ear anomalies. Ear anomalies can include outer, middle, and inner ear abnormalities. Cranial nerve dysfunction, orofacial clefts, and tracheoesophageal fistula are also common findings. Clinical diagnostic criteria for CHARGE syndrome have been developed. Affected infants and children require airway, feeding, cardiac, ophthalmologic, and hearing evaluations, and developmental assessment and intervention.
Rett syndrome is a single gene disorder associated with mutations in the MECP2 (methyl-CpG binding protein 2) gene. Greater than 99% of cases involve a de novo mutation and this condition is inherited in an X-linked manner. MECP2 mutations are most often lethal in males. Among affected females, distinct presentations include classic Rett syndrome, variant Rett syndrome, and rarely, mild learning disability. Classic Rett syndrome occurs in about 1 in 8,500 females. Rare surviving males can have neonatal encephalopathy or severe intellectual disability. In order to meet diagnostic criteria for classic Rett syndrome, females must show a period of regression, with onset between 6 and 18 months of age, followed by stabilization, loss of purposeful hand skills, loss of spoken language, gait abnormalities, stereotypic hand movements, and other behavioral and growth abnormalities. Females with classic Rett syndrome usually live into adulthood but are at higher risk than the general population for sudden, unexplained death. The diagnostic criteria for atypical Rett syndrome include a period of regression followed by recovery or stabilization. Recommended management includes surveillance and symptomatic treatment for seizures, sleep disturbances, and agitation, constipation, scoliosis and cardiac conduction abnormalities. To confirm a diagnosis of Rett syndrome, MECP2 sequence analysis can be performed first. This detects mutations in about 80% of patients with classic Rett syndrome and about 40% of patients with atypical Rett syndrome. If the sequence analysis returns normal, MECP2 deletion/duplication analysis can be pursued. This detects mutations in about 8% of patients with classic Rett syndrome and about 3% of patients with atypical Rett syndrome. The differential diagnosis for this condition includes mutations in CDKL5 (cyclin-dependent kinase-like 5) and FOXG1 (forkhead box G1) which are associated with similar phenotypes. Angelman syndrome is also in the differential diagnosis of Rett syndrome.
Achondroplasia is the most common heritable form of disproportionate short stature, with an incidence of about 1 in 27,000 births. This condition is de novo in 80% of patients and is inherited in an autosomal dominant manner. When both parents have achondroplasia, each pregnancy has a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance to have homozygous achondroplasia, which is a lethal condition. 98% of individuals have a G to A nucleotide substitution at position 1138 of the FGFR3 (fibroblast growth factor receptor 3) gene, while a G to C substitution at the same nucleotide position is seen in about 1% of patients. Clinical features include short stature, rhizomelic (proximal limb) shortening of arm and legs, trident hand configuration (shortened fingers), lumbar lordosis, macrocephaly with frontal bossing, and depressed nasal bridge. A clinical diagnosis should be followed by a skeletal survey which shows typical features of the cranium, long bones, and spine. Molecular testing can also be performed. Patients generally have delayed motor milestones due to mild to moderate hypotonia and large head size. Imaging of the brain and spinal cord is indicated to evaluate the size and shape of the foramen magnum and to detect evidence of impingement of the cervical spine, in addition to monitoring respiratory and neurologic status. Hydrocephalus can present at any age. Intelligence and lifespan are generally near normal unless central nervous system problems occur. Recommended management includes monitoring and treatment of concerns regarding growth, obstructive sleep apnea, middle ear dysfunction, leg bowing, thoracolumbar kyphosis, lumbar lordosis, spinal stenosis, and socialization.
1. Which of the above conditions involve trinucleotide repeat expansion?
2. Which of the above conditions can show an autosomal dominant pattern of inheritance?
3. Which of the above conditions show an X-linked dominant pattern of inheritance?
4. Which of the above conditions involve imprinting?
5. Which of the above conditions are associated with somatic overgrowth?
6. Which of the above conditions involve neurologic regression?
7. Which of the above conditions can be diagnosed using chromosomal microarray analysis?
8. Which of the above conditions is associated with a webbed neck?
1. Morris CA (Updated 2006 Apr 21). Williams Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
2. Saul RA, Tarleton JC (Updated 2012 Apr 26). FMR1-Related Disorders. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org.Accessed 2013 Apr 9.
3. deVries BB, van den Ouweland AM, Mohkamsing S, et al. Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group. Am J Hum Genet. 1997;61:660–7.
4. Shuman C, Beckwith JB, Smith AC, Weksberg R (Updated 2010 Dec 14). Beckwith-Wiedemann Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
5. Li M, Squire JA, Weksberg R. Molecular genetics of Beckwith-Wiedemann syndrome. CurrOpinPediatr. 1997;9:623–9.
6. Li M, Squire JA, Weksberg R. Molecular genetics of Wiedemann-Beckwith syndrome. Am J Med Genet. 1998;79:253–9.
7. Saal HM (Updated 2011 Jun 02). Russell-Silver Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed2013 Apr 9.
8. Abu-Amero S, Wakeling EL, Preece M, Whittaker J, Stanier P, Moore GE.Epigenetic signatures of Silver-Russell syndrome. J Med Genet.2010;47:150–54.
9. Kim Y, Kim SS, Kim G, Park S, Park IS, Yoo HW. Detection of maternal uniparental disomy at the two imprinted genes on chromosome 7, GRB10 and PEG1/MEST, in a Silver-Russell syndrome patient using methylation-specific PCR assays. Clin Genet. 2005;67:267–9.
10. Driscoll DJ, Miller JL, Schwartz S, Cassidy SB (Updated 2012 Oct 11). Prader-Willi Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
11. Dagli AI, Williams CA (Updated 2011 Jun 16). Angelman Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
12. Jiang Y, Lev-Lehman E, Bressler J, Tsai TF, Beaudet AL. Genetics of Angelman syndrome. Am J Hum Genet. 1999;65:1–6.
13. Tatton-Brown K, Cole TRP, Rahman N (Updated 2012 Mar 08).Sotos Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
14. Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, Horn D, Hughes HE, Temple IK, Faravelli F, Waggoner D, Turkmen S, Cormier-Daire V, Irrthum A, Rahman N. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet. 2005b;77:193–204.
15. Miller DT, Adam MP, Aradhya S, et al: Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010 May 14;86(5):749-64.
16. Allanson JE, Roberts AE (Updated 2011 Aug 04). Noonan Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
17. Jongmans M, Otten B, Noordam K, van der Burgt I. Genetics and variation in phenotype in Noonan syndrome. Horm Res. 2004;62 Suppl 3:56–9.
18. Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70:1555–63.
19. Lalani SR, Hefner MA, Belmont JW, Davenport SLH (Updated 2012 Feb 02). CHARGE Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
20. Vissers LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36:955–7.
21. Christodoulou J, Ho G (Updated 2012 Jun 28). MECP2-Related Disorders. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
22. Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, Williamson S, Leonard H. Rett syndrome in Australia: a review of the epidemiology. J Pediatr. 2006;148:347–52.
23. Pauli RM (Updated 2012 Feb 16). Achondroplasia. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 2013 Apr 9.
24. Oberklaid F, Danks DM, Jensen F, Stace L, Rosshandler S. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. J Med Genet. 1979;16:140–6.
1. Fragile X syndrome
2. Williams syndrome, Beckwith-Wiedemann syndrome, Sotos syndrome, Noonan syndrome, CHARGE syndrome, and achondroplasia
3. Fragile X syndrome and Rett syndrome
4. Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Prader-Willi syndrome, and Angelman syndrome
5. Beckwith-Wiedemann syndrome and Sotos syndrome
6. Rett syndrome
7. Williams syndrome and some cases of Sotos syndrome. A deletion may also be detected in most cases of Prader-Willi and Angelman syndrome, which can usually be distinguished by phenotype, but requires methylation analysis for molecular confirmation.
8. Noonan syndrome