Etiology and Pathogenesis

Trisomy 18 (Edwards syndrome) is most commonly caused by meiotic nondisjunction, and the risk is related to maternal age. However, Edwards syndrome can also result from an unbalanced translocation. If the parents of an affected infant have a normal karyotype (i.e., neither is a balanced translocation carriers), the recurrence risk for trisomy 18 in a subsequent pregnancy is no greater than the age-related risk.

Clinical Presentation

Trisomy 18 is one of the more common malformation syndromes, with an incidence of 0.3 in 100 newborn infants. On prenatal ultrasound, increased nuchal translucency may be seen early in gestation. At birth, reduced birth weight, a small placenta, and fetal distress may be noted along with multiple other clinical features (Table 118-1).

Table 118-1 Frequent Clinical Features in Trisomies 18 and 13

Etiology and Pathogenesis

Most cases of Patau syndrome are caused by trisomy 13, which also demonstrates an increased incidence with advancing maternal age. Similarly, chromosomal studies should be performed to rule out an unbalanced translocation because recurrence is higher in a parent with a balanced translocation.

Clinical Presentation

Trisomy 13 occurs with an incidence of approximately 1 in 5000 births. Early prenatal detection is possible with a combined screening protocol that includes maternal age, nuchal translucency, and maternal serum markers. The mean birth weight is reduced, and multiple dysmorphic features may be observed (see Table 118-1).

Prognosis

The median survival of a newborn with Patau syndrome is less than 1 week, and only 3% live to 6 months of age. Survivors have profound mental retardation, seizure disorders, behavioral problems, and feeding difficulties.

Etiology and Pathogenesis

Turner’s syndrome is diagnosed in a female by the absence of a second normal sex chromosome caused by the complete or partial deletion of an X or Y chromosome. The loss is not associated with advanced maternal age and may happen during spermatogenesis, oogenesis, or postzygotic nondisjunction. The resulting karyotype is 45,X in approximately half of patients with Turner syndrome, but isochromosomes with duplication of the long arm of the X chromosome, ring and marker chromosomes, and mosaicism are frequently observed.

Turner syndrome occurs in 1 in 2500 to 1 in 3000 female live births and is caused by the absence of a second normal sex chromosome. The incidence of 45,X is actually higher in pregnancy losses.

Clinical Presentation

Females with Turner syndrome may present prenatally with features of lymphedema/hydrops and/or a congenital heart defect, in puberty due to short stature or in adulthood with premature ovarian failure (Figure 118-1). Multiple organ systems may be involved, but no single feature is pathognomonic or universally present.

Figure 118-1 Turner syndrome.

Several physical features are found as a consequence of lymphatic abnormalities that include webbed neck, puffy hands and feet, dysplastic finger- and toenails, protuberant ears, and a broad chest.

Up to 45% of patients have a cardiac anomaly identified by echocardiography, most often a bicuspid aortic valve or aortic coarctation, but other cardiac anomalies such as partial anomalous pulmonary venous connection can also occur. Renal anomalies are equally frequent (40%), including renal agenesis and horseshoe kidney. Hypothyroidism may develop in 5% to 10% of girls in mid to late childhood and affects up to one-third of adult women.

Growth delay begins in childhood, but short stature may not be noticed until 5 to 10 years of age or in puberty with a blunted growth spurt. Growth hormone treatment may lead to improvement, but adult height is usually reduced.

Gonadal dysgenesis is a hallmark of Turner syndrome and typically leads to ovarian failure. Puberty occurs spontaneously in 10% of patients, and hormonal replacement therapy is necessary to achieve development of secondary sexual characteristics as well as to avoid osteoporosis and other postmenopausal complications. Nonetheless, spontaneous pregnancy has been observed in about 2% to 4% of women with Turner syndrome.

Most girls with Turner syndrome have normal developmental milestones and intelligence. About 10% of individuals experience specific learning disabilities, mental retardation, motor deficits, or difficulties with attention, maturity, and social skills. Correlation has been observed between the intellectual phenotype and the karyotype, and girls with a marker or ring chromosome have a higher prevalence of mental retardation.

Prognosis

Cardiovascular disease confers the highest risk for mortality in females with Turner syndrome. Developmental difficulties and immature behavior may lead to an older age for women to attain independence. Pregnancy can be successful using donor egg programs.

Etiology and Pathogenesis

Klinefelter syndrome is caused by a 47,XXY or 46,XY/47,XXY karyotype with mosaic men exhibiting a milder phenotype. Nondisjunction of the sex chromosomes is equally derived from either parent with only a small association with maternal age.

With an incidence of 1 in 500 to 1 in 1000 male infant births, Klinefelter syndrome is the most common sex chromosome aneuploidy.

Clinical Presentation

Newborns with 47,XXY do not have any significant dysmorphic features. In fact, 10% of boys are identified incidentally during chorionic villus sampling or amniocentesis for advanced maternal age. In rare cases, chromosomal studies are initiated in the newborn period for cryptorchidism, hypospadias, or a small phallus. About 25% of affected individuals are diagnosed in childhood, adolescence, and adulthood. A large fraction of 47,XXY men are thought to remain undiagnosed.

In childhood, language delay, learning differences, or behavioral problems may bring a boy to medical attention. Physical symptoms start to develop in adolescence with increased height, narrower than average shoulders, broader than average hips, and scoliosis or kyphosis.

Although the age and onset of puberty is unchanged in boys with Klinefelter syndrome, testicular growth is arrested, leading to oligospermia or azoospermia and low testosterone levels. A small fraction of men present with gynecomastia, eunuchoid habitus, and decreased hair (Figure 118-2). Muscle strength may be decreased. Testosterone replacement therapy aims at increasing muscle mass, libido, energy, and improving mood through support of androgen-dependent processes. Fertility is rarely preserved except in mosaic men.

Figure 118-2 Klinefelter syndrome.

Development is normal in most infants, although hypotonia and delayed acquisition of language milestones can occur. The mean IQ in individuals with Klinefelter syndrome falls into the normal range, but wide variability has been observed, and verbal IQ is consistently lower, often benefitting from speech and language therapy. Temperamental differences may manifest as shyness, lower activity, and insecurity.

Etiology and Pathogenesis

Monosomy for the distal short arm of chromosome 1 occurs in approximately 1 in 10,000 live births, but the incidence is likely to be higher with improved diagnostic tests. Most deletions are de novo caused by a terminal or interstitial deletion, a complex rearrangement, or a derivative chromosome.

Clinical Presentation

Distinctive facial features include microbrachycephaly, frontal bossing, large anterior fontanelle, marked midface hypoplasia, deep-set eyes, straight eyebrows, long philtrum, and abnormally shaped ears. Mental retardation with poor or absent speech, hypotonia, short feet, brachycamptodactyly, and brain abnormalities (dilatation of the large ventricles, atrophy, and hypoplasia) are present in more than 75% of patients. In addition, many have congenital heart defects, seizures, and ophthalmologic abnormalities. Sensorineural deafness, hypothyroidism, behavioral problems, and cardiomyopathy have also been associated with a 1p36 deletion.

Prognosis

Approximately 90% of patients have severe to profound mental retardation, with only 25% being able to walk unassisted and absent language in 75%.

Etiology and Pathogenesis

Wolf-Hirschhorn syndrome (WHS) is caused by partial monosomy for the short arm of chromosome 4 (4p-) and occurs with an estimated incidence of 1 in 50,000 live births. The deletion arises de novo in 75% of patients, with ring chromosome 4 and unbalanced translocations making up much of the remainder. The diagnosis can be made by conventional karyotype for deletions larger than 5 Mb (megabases) or by using a specific FISH (fluorescence in situ hybridization) probe or high-resolution array for smaller deletions.

Clinical Presentation

Wolf-Hirschhorn syndrome and Pitt-Rogers-Dank syndrome are clinical manifestations of a phenotypical spectrum caused by monosomy 4p. Individuals with WHS demonstrate typical facial features characterized as a “Greek warrior helmet” appearance. These include microcephaly, frontal bossing with a high frontal hairline and prominent glabella, a broad nasal bridge and beaked nose, hypertelorism, epicanthal folds, highly arched eyebrows, downturned mouth with short upper lip and short philtrum, micrognathia, and low-set, large ears often with pits or tags. Low birth weight with subsequent failure to thrive and growth restriction is common. More than 75% of patients have severe mental retardation, hypotonia, seizures, structural brain abnormalities, and feeding difficulties. Craniofacial asymmetry, ptosis, abnormal dentition, antibody deficiency, and skeletal and skin abnormalities can be found in 50% to 75%. Closure defects of the face, including cleft lip or palate, iris coloboma, cardial septal defects, and genitourinary tract abnormalities (e.g., cryptorchidism, renal agenesis or malformation), are less common, but any organ system can be involved, and a thorough clinical evaluation, including imaging studies, is recommended.

Prognosis

All patients experience global developmental delay, with 65% demonstrating severe cognitive impairment, 25% with a moderate degree, and 10% with a mild degree. Only 45% walk independently or with support. Expressive language is frequently limited to guttural or disyllabic sounds and only occasionally modulated in a communicative way, with 6% able to pronounce simple sentences. About 93% have been reported to develop generalized tonic-clonic seizures within the first 3 years of life. Heart defects are usually not complex, but antibody deficiencies may lead to recurrent respiratory tract infections and otitis media.

Etiology and Pathogenesis

Partial deletion of the short arm of chromosome 5 results in cri du chat syndrome (CdCS) and is estimated to occur in 1 : 15,000 to 1 : 50,000 newborns. Most are paternally derived de novo deletions, either terminal or interstitial, of variable size. In 10% to 15% of cases, the phenotype is attributable to familial or de novo translocations. Genotype–phenotype correlation studies have mapped characteristic symptoms to specific critical regions and genes on 5p.

Clinical Presentation

The name of the syndrome refers to the characteristic high-pitched catlike cry of the affected newborn, which is caused by laryngeal abnormalities. Other clinical findings are low birth weight, microcephaly, round face, large nasal bridge, hypertelorism, epicanthal folds, downslanting palpebral fissures, downturned corners of the mouth, low-set ears, and micrognathia. Facial features change with age, and the catlike cry disappears within the first year of life. Other organ systems are rarely involved, but stunted growth, mostly affecting head circumference and weight, is common.

Prognosis

Many infants do not survive early childhood. Patients with CdCS have severe psychomotor retardation, although they can attain milestones such as walking, talking in short sentences, and feeding themselves late in childhood. With intensive early intervention, the resulting social and psychomotor development reaches the level of a 5- to 6-year old unaffected child.

Etiology and Pathogenesis

Williams syndrome (WS) is a sporadic contiguous gene deletion disorder caused by an interstitial deletion of the long arm of chromosome 7 encompassing the Williams-Beuren syndrome critical region (WBSCR). Among the genes in the WBSCR is elastin, which is deleted in 90% of WS patients. Hemizygosity for elastin is associated with cardiovascular disease, also termed elastin arteriopathy. Occasionally, autosomal dominant transmission from a parent to a child is observed. Penetrance is 100%, but phenotypic expression is variable. The incidence of WS is estimated to be 1 in 20,000 to 1 in 50,000 newborns.

Clinical Presentation

Features include congenital heart disease (supravalvular stenosis and peripheral pulmonary stenosis), failure to thrive secondary to feeding difficulties, and hypotonia. Distinctive facial characteristics consist of a broad brow, bitemporal narrowing, periorbital fullness, a stellate or lacy iris pattern, strabismus, short nose, full nasal tip, malar hypoplasia, long philtrum, full lips, wide mouth, malocclusion, small jaw, and prominent earlobes. The face typically becomes more coarse with age. Connective tissue abnormalities lead, among other symptoms, to a hoarse voice, hyperextensible joints, and hernias. Most individuals have some degree of mental retardation, which can range from severe to mild with notable strengths in verbal short-term memory and language and weakness in visual–motor integration. Patients with WS have a unique personality and are typically overfriendly, empathic, and gregarious, which has also been termed the “cocktail party” personality. Hypercalcemia occurs in about 15% of patients and early puberty in 50%. Linear growth is stunted, and the mean adult height is below the third percentile. Adults are at risk for severe cardiovascular disease secondary to elastin arteriopathy, sudden death, hypertension, progressive sensorineural hearing loss, hypothyroidism, and diabetes mellitus. Annual surveillance is recommended.

Etiology and Pathogenesis

Miller-Dieker syndrome (MDS) is caused by variable deletions of the distal end of the short arm of chromosome 17 (17p13.3), including the gene LIS1, which plays a significant role in neuronal development. Smaller submicroscopic deletions or other sequence variations of LIS1 cause isolated lissencephaly sequence (ILS). Most cases of MDS occur sporadically, with the remaining 20% caused by a parental balanced translocation that increases the recurrence risk for subsequent pregnancies. The diagnosis can be made using FISH, high-resolution array, sequence analysis, or multiplex ligation-dependent probe amplification (MLPA) analysis of LIS1.

Clinical Presentation

Lissencephaly is defined as a cortical malformation secondary to deficient neural migration, resulting in a “smooth brain” with absent gyri (agyria) or abnormally wide gyri (pachygyria). On magnetic resonance imaging, the severity can be graded with grade 1 being the most severe (lissencephaly) to the mildest form, grade 6 (subcortical band heterotopia). MDS is distinguished from ILS through characteristic facial features consisting of high and prominent forehead, bitemporal narrowing, short nose with upturned nares, protuberant upper lip with downturned vermillion border, and small jaw. Intrauterine, poor swallowing may lead to polyhydramnios. Postnatally, severe growth restriction and microcephaly develop, and seizures occur in 90% within the first 6 months of life. Some children have an omphalocele or congenital heart defects. Hypotonia and feeding difficulties are common.

The developmental prognosis is poor for all affected children. Even with good seizure control, most children only reach the developmental milestones of a 3- to 5-month-old child. Life span is shortened, with most children with MDS dying within the first 2 years of life. Complications arise from respiratory tract infections caused by poor airway control.

Etiology and Pathogenesis

Interstitial deletions on the short arm of chromosome 17 involving 17p11.2, including the RAI1 gene, are causative for Smith-Magenis syndrome (SMS) and arise on both paternal and maternal chromosomes. Most deletions are de novo and cytogenetically visible. Most smaller deletions can be identified by commercially available FISH probes. The birth incidence is estimated to be 1 in 25,000 newborns.

Clinical Presentation

The distinctive facial features in individuals with SMS progress with age and include brachycephaly, midface hypoplasia with a broad nasal bridge, prognathism, a tented upper lip, deep-set, close-spaced eyes, and dental anomalies. More than 75% have short, broad hands and laryngeal anomalies, including polyps, nodules, edema, partial vocal cord paralysis, velopharyngeal insufficiency, or structural vocal fold abnormalities. The latter findings lead to a hoarse voice and may contribute to the significant delays in speech development. Facial features in older patients become more coarse with heavy eyebrows and persistent midface hypoplasia.

Infants have mild to moderate hypotonia and feeding difficulties that result in failure to thrive. They are developmentally delayed with speech, and fine and gross motor skills are affected. Older individuals exhibit a wide variability in cognitive and adaptive functioning, usually with mild to moderate mental retardation.

Other common features occurring in 50% to 75% of individuals are ocular abnormalities (iris anomalies, microcornea), sleep disturbances (difficulty falling and staying asleep, REM sleep abnormalities), constipation, and hypertriglyceridemia or hypercholesterolemia.

The neurobehavioral phenotype is distinctive in people with SMS and usually becomes recognizable after 18 months of age. More than two-thirds of individuals with SMS demonstrate self-injurious behavior; nail pulling (onychotillomania) and insertion of foreign objects into body orifices (polyembolokoilamania) are especially distinctive of SMS. Self-injurious behaviors, stereotypic behaviors (self-hugging, hand-licking, and page flipping), and maladaptive behaviors (frequent outbursts or temper tantrums, attention seeking, impulsivity, distractibility, disobedience, aggression, toileting difficulties) become more severe with age or significant life cycle events (e.g., school, onset of puberty).

Prognosis

If no major organ system is involved, life expectancy in patients with SMS is expected to be comparable to other patients with mental retardation, although thorough longitudinal studies have not been performed. Behavioral problems persist but seem to improve slightly in adulthood.

Etiology and Pathogenesis

Multiple different clinical syndromes are caused by a microdeletion on the long arm of chromosome 22, including DiGeorge’s syndrome, velocardiofacial syndrome, and conotruncal anomaly syndrome. The deletion involving 22q11.2 arises de novo in about 93% of patients but can be inherited in an autosomal dominant pattern from an affected parent with 100% penetrance. The diagnosis is made by FISH analysis or high-resolution array. The incidence of 22q11.2 deletion syndrome (del22q11.2) ranges from 1 in 4000 to 1 in 6000 live births but may be underestimated secondary to marked phenotypic variability. Inter- and intrafamilial clinical variability has been observed in patients with the same deletion, and genotype–phenotype correlation is difficult.

Clinical Presentation

The suspicion for del22q11.2 in a newborn is often raised by the presence of one or more of a constellation of physical findings that include congenital heart disease, especially conotruncal malformations, hypocalcemia, immune deficiency, and characteristic facial features. Frequently observed dysmorphisms include overfolded or squared-off ear helices, small and protuberant ears with preauricular pits or tags, a prominent nasal root and bulbous nasal tip, hooded eyelids, ocular hypertelorism, cleft lip and palate, asymmetric crying facies, and craniosynostosis (Figure 118-3). Infants often have feeding difficulties secondary to severe dysphagia and palatal abnormalities. In older patients, learning difficulties, growth hormone deficiency, autoimmune disease, and psychiatric illness may become apparent. Other organ systems can be involved, and a renal ultrasound to evaluate for renal abnormalities and chest radiography to assess for vertebral malformations should be performed.

Figure 118-3 22q11.2 deletion syndrome.

The majority of children with del22q11.2 experience significant developmental delay and attain motor and language milestones later than their peers. The prevalence of autism or disorders of the autistic spectrum is approximately 20%. In older individuals, full-scale IQ scores are lower than the normal population, although they have a significantly higher verbal IQ than performance IQ, evidence of stronger verbal than visual memory skills and stronger reading than math skills.

Prognosis

The mortality of patients with del22q11.2 is largely determined by the severity of the congenital heart defect. The impairment of T-cell–mediated immune function rarely requires treatment and improves over time. In adults, the incidence of psychiatric disorders, including schizophrenia, bipolar disorder, anxiety, and depression, is increased.

Future Directions

The advent of high-resolution genome array analysis has further enhanced our ability to identify microdeletion syndromes in patients with dysmorphic features, multiorgan involvement, and developmental delay. As these continue to be refined, we will surely identify and characterize many additional disorders with much smaller chromosomal deletions or duplications.