Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) has a prevalence of around 1 : 10,000 and is characterized by prenatal and postnatal growth retardation, hirsutism, and upper limb reduction defects. Craniofacial abnormalities include synophrys, arched eyebrows, long eyelashes, a small, upturned nose, small, widely spaced teeth, and microcephaly (Figure 120-1). Patients have moderate to severe mental retardation (MR), and many show autistic and self-destructive behaviors. Upper limb abnormalities range from severe deficiencies to merely proximally placed thumbs or fifth digit clinodactyly. Patients classically have growth failure as well as feeding difficulties, which include regurgitation, projectile vomiting, and swallowing difficulties. Hearing loss and speech delay are common. CdLS has dominant inheritance usually caused by de novo mutations in NIPBL (50%), SMC1A (5%), and SMC3 (<1%).

Figure 120-1 Profile of the face in a patient with Cornelia de Lange syndrome.

Rubenstein-Tabyi Syndrome

Rubenstein-Tabyi syndrome (RTS) has a prevalence of around 1 : 100,000 and is characterized by postnatal short stature, moderate to severe MR with speech difficulty, downslanted palpebral fissures, hypoplastic maxilla with narrow palate, prominent or beaked nose with columella extending below the nares, highly arched palate, grimacing smile, talon cusps, broad great thumbs and toes with radial angulation, and hirsutism. Patients have normal prenatal growth, and obesity occurs in childhood or adolescence. Developmental milestones are significantly delayed, with reading limited to the first grade level. Many patients have gastroesophageal reflux, constipation, recurrent ear infections, and dental problems secondary to tooth overcrowding in the small jaw. Most cases are caused by dominant sporadic mutations in the CREB binding protein (CBP) gene in 60% of cases and the functionally related EP300 gene in about 3% of cases.

Russell-Silver Syndrome

Russell-Silver syndrome (RSS) has a prevalence of about 1 : 100,000 and includes intrauterine growth retardation, postnatal growth deficiency, delayed bone age, normal head circumference, limb-length asymmetry, and fifth digit clinodactyly (Figure 120-2). A typical face in RSS is small and triangular with a broad and prominent forehead, downturned corners of the mouth, and micrognathia. Café-au-lait spots are sometimes present, and patients can sweat extensively. Nearly 40% of cases have been shown to have abnormal imprinting of chromosome 11p15.5, and 10% of cases demonstrate uniparental disomy (UPD) for chromosome 7. Growth hormone may benefit patients for whom growth plateaus early.

Figure 120-2 Hemihypertrophy: limb length discrepancy.

Noonan Syndrome

Noonan syndrome (NS) has been suggested to occur with a prevalence of around 1 : 2000 and demonstrates a combination of short statue, congenital heart disease, and variable developmental delay. In the neonate, the typical face has a tall forehead, hypertelorism with downslanting palpebral fissures, epicanthal folds, ptosis, vivid blue or blue-green irises, low-set posteriorly rotated ears with thickened helices, a depressed nasal root, a deeply grooved philtrum, a protruding upper lip, and retrognathia. In adolescence, the facial shape suggests an inverted triangle with a pointed chin, and the neck lengthens to accentuate the webbed appearance. Other features may include a low posterior hairline, a broad chest with superior pectus excavatum and inferior pectus carinatum, and pulmonic stenosis. Postnatal short stature is seen in half of the patients, and skeletal abnormalities, including cubitus valgus and scoliosis, may be seen. Cardiomyopathy or congenital heart disease (CHD) is present in 50% to 80% of patients with the most common anomaly being pulmonary valve stenosis. About one-third of affected individuals have a coagulation or platelet pathway defect. Skin café-au-lait spots and lentigines are prevalent. Mild MR is present in about 30% of patients. Molecular testing has demonstrated dominant mutations in the Ras signaling pathway that include PTPN11 (50%), SOS1 (13%), RAF1 (3%–17%) and KRAS (5%).

Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria syndrome (HGPS) occurs in between 4 and 8 million births and is a composite of features that develop in childhood that are reminiscent of accelerated aging (Figure 120-3). These include alopecia, diminished subcutaneous fat, stiffness of joints, bone changes, and an abnormal tightness of the skin over the abdomen and upper thighs that emerge during the second to third year of life. Facial features include a pinched nose, thin lips, protruding ears, and a thin, high-pitched voice. Skeletal manifestations include distal phalangeal osteolysis, delayed fontanelle closure, a pear-shaped thorax, micrognathia, short dystrophic clavicles, a “horse-riding” stance, thin limbs, and tightened joint ligaments. Cognitive development is normal. Patients typically develop severe atherosclerosis requiring electrocardiography, echocardiography, and carotid duplex scans every 6 months. Yearly lipid profiles and medical treatment for cardiovascular disease and elevated lipids are recommended. Hip dislocations and contractures are common and should be managed conservatively with physical and occupational therapy. Classical HGPS is caused by de novo dominant splice site mutations in the LMNA gene for which genetic testing is available.

Figure 120-3 Progeria.

Fragile X Syndrome

Fragile X syndrome (FXS) is seen in patients with a FMR1 full mutation and is characterized by moderate MR in males and mild MR in females. Males are macrocephalic, with long faces, prominent foreheads and chins, protruding ears, and large testes after puberty (Figure 120-4). Developmental milestones are delayed, and behavioral features such as tactile defensiveness, poor eye contact, perseverative speech, difficulty with impulse control, and distractibility become more prominent with age. More than 99% of patients with FXS have a loss-of-function mutation in the FMR1 gene at Xq27.3 that results from more than 200 repeats of a CGG tri-nucleotide (normal 0-40 repeats) and subsequent aberrant methylation of the gene. Individuals with 59 to 200 trinucleotide repeats are considered to have an FMR1 premutation and can have late-onset, progressive cerebellar ataxia and intention tremor in males and premature ovarian failure in females but with normal appearance and intellect. FXS demonstrates a phenomenon known as anticipation, in which the trinucleotide repeat becomes larger and the phenotype more pronounced with passage from one generation to the next. Molecular epidemiology has suggested 16 to 25 in 100,000 males affected and about half of that prevalence for females.

Figure 120-4 Fragile X syndrome.

Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome (BWS) is a growth disorder characterized by macrosomia, macroglossia, visceromegaly, omphalocele, neonatal hypoglycemia, ear creases or pits, and a risk for embryonic tumors that includes hepatoblastoma and Wilms’ tumors (Figure 120-5). Partial overgrowth, or hemihyperplasia, may occur in tissues, organs, or body segments (see Figure 120-2). Nearly 60% of people with BWS have methylation abnormalities or mutations in the imprinted 11p15 region. Mutations in the CDKN1C gene, a growth-regulating gene in this region, are seen in 40% of familial cases and 5% to 10% of nonfamilial cases of BWS. Methylation abnormalities in KCNQ1OT1 are present in 50% to 60% of the cases and in H19 in 2% to 7% of the cases. Because of the risk of tumors, abdominal ultrasonography is recommended every 3 months until age 8 years, and serum α-fetoprotein concentration is monitored during the first 3 years.

Figure 120-5 Macroglossia in a patient with Beckwith-Wiedemann syndrome.

Prader-Willi Syndrome and Angelman Syndrome

Prader-Willi syndrome (PWS) is characterized by hypotonia and difficulty feeding early in infancy followed by hyperphagia, beginning from 12 months to 6 years, that leads to central obesity. The face has a narrow bifrontal diameter, almond-shaped eyes, and a downturned mouth (Figure 120-6). Motor and language development is delayed because of cognitive impairment. Hypogonadism with incomplete pubertal development and infertility occurs. Behavioral outbursts (temper tantrums, obsessive-compulsiveness, stubbornness, and manipulation), sleep disturbances, short stature, hypopigmentation, small hands and feet, skin picking, and articulation difficulties are also seen. Treatment with growth hormone is recommended for those with PWS, and patients may thrive in settings where behavior and food intake are closely monitored.

Figure 120-6 Prader-Willi syndrome.

Diagnosis is made by DNA methylation studies for imprinting on chromosome 15q11. Lack of paternal imprinting leads to PWS, but lack of maternal imprinting leads to a distinctly different disorder called Angelman’s syndrome (AS), which demonstrates severe developmental delay, gait ataxia, inappropriately happy demeanor (frequent laughing, smiling, excitability), microcephaly, and seizures.

Deletion of one imprinted parental copy of this region causes 70% of PWS and AS. Mutations in the methylation control region and parental translocations can also cause either syndrome. Risk to siblings is up to 50% for mutations of the imprinting control center but only 1% for UPD. Although PWS is the result of dysregulation of multiple genes, AS can also be caused by mutations in the maternally expressed UBE3A.