Trisomy 21 (down syndrome).

Trisomy 21 occurs in approximately one in every 740 live births,¹⁴ and its incidence is distributed equally between the sexes.¹⁰ The pathophysiological features of Down syndrome are caused by an overexpression of genes on human chromosome 21. Ninety-five percent of individuals have an extra copy in all of their body’s cells. The remaining 5% have the mosaic and translocation forms.¹⁵ In the United States the incidence of Down syndrome increases with advanced maternal age.¹⁰ Detection of Down syndrome is possible with various prenatal tests, and the diagnosis is confirmed by the presence of characteristic physical features present in the infant at birth.¹⁶ Down syndrome is the most common chromosomal cause of moderate to severe intellectual disability.¹⁵ The typical phenotypical features observable from birth are hypotonia, epicanthic folds, flat nasal bridge, upward slanting palpebral fissures, small mouth, excessive skin at the nape of the neck, and a single transverse palmar crease (Figure 13-1).

Information compiled by the Centers for Disease Control and Prevention for years 1968 through 1997 indicates that the median survival age of individuals with Down syndrome is 49 years, compared with 1 year in 1968. Improvements in the median survival age were less in races other than white, although the reasons for this remain unclear.¹⁴ Half of all children with Down syndrome have congenital heart defects.¹⁶ Congenital heart problems, respiratory infection, and leukemia are the most common factors associated with morbidity and mortality in childhood,¹⁷ whereas a possible increased tendency for premature cellular aging and Alzheimer disease may account for higher mortality rates later in life.¹⁸

Impairments of visual and sensory systems are also common in individuals with Down syndrome. As many as 77% of children with Down syndrome have a refractive error (myopia, hyperopia), astigmatism, or problems in accommodation.¹⁹ Hearing losses that interfere with language development are reportedly present in 80% of children with Down syndrome. In most cases the hearing loss is conductive; in up to 20% of cases the loss is sensorineural or mixed.^16,20 Obstructive sleep apnea has been reported to exist frequently in young children^21,22 and adults with Down syndrome.²³ Craniofacial impairments such as a shortened palate and midface hypoplasia, along with oral hypotonia, tongue thrusting, and poor lip closure, frequently result in feeding difficulties at birth.²⁴ Bell and colleagues studied the prevalence of obesity in adults with Down syndrome and reported it in 70% of male subjects and 95% of female subjects.²⁵ Children with Down syndrome also appear to have a higher risk of being overweight or obese,^26–28 which may be, in part, a result of the retarded growth and endocrine and metabolic disorders associated with trisomy 21.²⁸ In a small population study of children with Down syndrome, Dyken and co-workers²⁹ reported that there was a high prevalence of obstructive sleep apnea associated with a higher body mass index.

Children with Down syndrome may have musculoskeletal anomalies such as metatarsus primus varus, pes planus, thoracolumbar scoliosis, and patellar instability and have an increased risk for atlantoaxial dislocation,30–32 which has been observed through radiography in up to 10% to 30% of individuals with this syndrome^30,31 with and without neurological compromise.³³ There is some controversy in the medical community as to the necessity and efficacy of radiographic screening for the instability.^31,32 Proponents of radiographic screening argue that neurological symptoms of atlantoaxial instability may often go undetected in this population because symptoms are often masked by the wide-based gait and motor dysfunction already associated with the disorder. If the child is unable to verbalize complaints or the child is uncooperative with physical and neurological examinations, symptoms may be missed. There is particular concern about cervical instability if these children undergo surgical procedures requiring general anesthesia³² and participate in recreational sports such as the Special Olympics.³¹ Symptomatic instability can result in spinal cord compression leading to myelopathy with leg weakness, decreased walking ability,³³ spasticity, or incontinence. Although reportedly rare, there have been cases where atlantoaxial dislocation has resulted in quadriplegia.³⁰

Several researchers have explored the neuropathology associated with Down syndrome. Changes in brain shape, size, weight, and function occur during prenatal and infant development of babies with Down syndrome, with important differences apparent by 6 months of age.³⁴ The relatively small size of the cerebellum and brain stem was reported by Crome and Stern in the 1970s.³⁵ Marin-Padilla³⁶ studied the neuronal organization of the motor cortex of a 19-month-old child with Down syndrome and found various structural abnormalities in the dendritic spines of the pyramidal neurons of the motor cortex. He suggested that these structural differences may underlie the motor incoordination and intellectual disability characteristic of individuals with Down syndrome. Loesch-Mdzewska³⁷ also found neurological abnormalities of the corticospinal system (in addition to reduced brain weight) in his neuropathological study of 123 individuals with Down syndrome aged 3 to 62 years. Crome³⁸ reported lesser brain weight in comparison with normal persons. Finally, Benda³⁹ noted a lack of myelinization of the nerve fibers in the precentral area, frontal lobe, and cerebellum of infants with Down syndrome. As McGraw⁴⁰ has pointed out, the amount of myelin in the brain reflects the stage of developmental maturation. The delayed myelinization characteristic of neonates and infants with Down syndrome is thought to be a contributing factor to the generalized hypotonicity and persistence of primitive reflexes characteristic of this syndrome.⁴¹

Trisomy 18.

Trisomy 18, or Edwards syndrome, is the second most common of the trisomic syndromes to occur in term deliveries, although it is far less prevalent than Down syndrome. It occurs in one in 5000 newborns, and approximately 80% of affected infants are female.⁴² As with Down syndrome, advanced maternal age is positively correlated with trisomy 18. Most cases of Edwards syndrome occur as random events during the formation of reproductive cells; fewer cases occur as errors in cell division during early fetal development; and inherited, translocation forms rarely occur.⁴² Only 10% of infants born with trisomy 18 survive past the first year of life; female and non-Caucasian children survive longest.⁴³ The survival of girls averages 7 months; the survival of boys averages 2 months.⁴³ Individuals surviving past infancy most often have the mosaic form, and there is high variance in phenotype (Figure 13-2).⁴⁴

Individuals with trisomy 18 generally have far more serious organic malformations than seen in those with Down syndrome.⁴⁵ Typical malformations affect the cardiovascular, gastrointestinal, urogenital, and skeletal systems. Infants with trisomy 18 have low birth weight and small stature, with a long narrow skull, low-set ears, flexion deformities of the fingers, and rocker-bottom feet. Muscle tone is initially hypotonic, but it becomes hypertonic in children with longer than typical life span.⁴⁵ The period of hypertonicity in the early years may change to low tone and joint hyperextensibility by preschool and school age. Microcephaly, abnormal gyri, cerebellar anomalies, myelomeningocele, hydrocephaly, and corpus callosum defects have been reported in individuals with trisomy 18.⁴⁶

Common skeletal malformations that may warrant attention from the developmental physical or occupational therapist include scoliosis,⁴⁶ limited hip abduction, flexion contractures of the fingers, rocker-bottom feet, and talipes equinovarus.⁴⁵ Infants with trisomy 18 may also have feeding difficulties as a result of a poor suck.⁴⁷ Profound intellectual disability is another clinical factor that will affect the developmental therapy programs for children with trisomy 18.^46,47

Trisomy 13.

Trisomy 13, also commonly called Patau syndrome, is the least common of the three major autosomal trisomies, with an incidence of one in 10,000 to 20,000 live births.^8,42 As in the other trisomic syndromes, advanced maternal age is correlated with the incidence of trisomy 13.⁴⁸ Fewer than 10% of individuals with trisomy 13 survive past the first year of life^42,43; girls and non-Caucasian infants appear to survive longer.^42,43 Individuals surviving past infancy most often have the mosaic form, and there is high variance in phenotype.⁴³ As with Edwards syndrome, most cases of Patau syndrome occur as random events during the formation of eggs and sperm, such as nondisjunction errors during cell division.⁴⁸

Trisomy 13 is characterized by microcephaly, deafness, anophthalmia or microphthalmia, coloboma, and cleft lip and palate.⁴⁸ As in trisomy 18, infants with trisomy 13 frequently have serious cardiovascular and urogenital malformations and typically have severe to profound intellectual disability.⁴⁹ Skeletal deformities and anomalies include flexion contractures of the fingers and polydactyly of the hands and feet.¹⁰ Rocker-bottom feet also have been reported, although less frequently than in individuals with trisomy 18. Reported central nervous system (CNS) malformations include arhinencephalia, cerebellar anomalies, defects of the corpus callosum, and hydrocephaly.⁵⁰

Turner syndrome.

Turner syndrome affects females with monosomy of the X chromosome. The syndrome, also known as gonadal dysgenesis, occurs in one in 2500 live female births.^51,52 Turner syndrome is the most common chromosomal anomaly among spontaneous abortions.^53,54 Most infants who survive to term have the mosaic form of this syndrome, with a mix of cell karyotypes, 45,X and 46,XX. The SHOX gene, found on both the X and Y chromosomes, codes for proteins essential to skeletal development. Deficiency of the SHOX gene in females accounts for most of the characteristic abnormalities of this disorder.^52,55 Three characteristic impairments of the syndrome are sexual infantilism, a congenital webbed neck, and cubitus valgus.⁵⁶ Other clinical characteristics noted at birth include dorsal edema of hands and feet, hypertelorism, epicanthal folds, ptosis of the upper eyelids, elongated ears, and shortening of all the hand bones.^51,57 Growth retardation is particularly noticeable after the age of 5 or 6 years, and sexual infantilism, characterized by primary amenorrhea, lack of breast development, and scanty pubic and axillary hair, is apparent during the pubertal years. Ovarian development is severely deficient, as is estrogen production.^10,58 Congenital heart disease is present in 20% to 30% of individuals with Turner syndrome,⁵⁷ with a fewer number of cardiovascular malformations in individuals with the mosaic form⁵⁹; 33% to 60% of individuals with Turner syndrome have kidney malformations.⁵¹ Hypertension is common even in the absence of cardiac or renal malformations.^57,60

There are numerous incidences of skeletal anomalies, some of which may be significant enough to require the attention of a pediatric therapist. Included among these are hip dislocation, pes planus and pes equinovarus, dislocated patella,⁵¹ deformity of the medial tibial condyles,⁴⁶ idiopathic scoliosis,⁵⁷ and deformities resulting from osteoporosis.^10,57

Sensory impairments include decrease in gustatory and olfactory sensitivity^61,62 and deficits in spatial perception and orientation,⁶¹ and up to 90% of adult females have moderate sensorineural hearing loss. Recurrent ear infections are common and may result in future conductive hearing loss.⁶⁰ Although the average intellect of individuals with Turner syndrome is within normal limits, the incidence of intellectual disability is higher than in the general population.⁴⁵ Noonan syndrome, once thought to be a variant of Turner syndrome, has several common clinical characteristics; however, advancements in genetics research have shown that the syndromes have different genetic causes.^63,64

Klinefelter syndrome.

Klinefelter syndrome is an example of aneuploidy with an excessive number of chromosomes that occurs in males. The most common type, 47,XXY, is usually not clinically apparent until puberty, when the testes fail to enlarge and gynecomastia occurs.⁶⁵ Nearly 90% of males with Klinefelter syndrome possess a karyotype of 47,XXY, and the other 10% of patients are variants.⁶⁶ The incidence of Klinefelter syndrome (XXY) is about one in 500 to 1000 males, and an estimated half of 47,XXY conceptions are spontaneously aborted.⁸ The extra X chromosome(s) can be derived from either the mother or the father, with nearly equal occurrence.⁶⁷ Advanced maternal age is widely accepted as a causal factor.^8,66 FISH analysis of spermatozoa from fathers of boys with Klinefelter syndrome suggests that advanced paternal age increases the frequency of aneuploid offspring.^68–70

Most individuals with karyotype XXY have normal intelligence, a somewhat passive personality, and a reduced libido. Eighty-five percent of individuals having the nonmosaic karyotype are sterile. Individuals with the karyotypes 48,XXXY and 49,XXXXY tend to display a more severe clinical picture. Individuals with 48,XXXY usually have severe intellectual disability, with multiple congenital anomalies, including microcephaly, hypertelorism, strabismus, and cleft palate.^10,65 Skeletal anomalies include radioulnar synostosis, genu valgum, malformed cervical vertebrae, and pes planus.¹⁰ A 2010 systematic review of literature⁷¹ on neurocognitive outcomes of persons with Klinefelter syndrome concluded that problems of delayed walking in children and persistent deficits in fine and gross motor development, and problems in motor planning.^71,72 Giedd and co-workers published the results of a case-control study examining brain magnetic resonance imaging (MRI) scans of 42 males with Klinefelter syndrome and reported cortical thinning in the motor strip associated with impaired control of the upper trunk, shoulders, and muscles involved in speech production.⁷³

Cri-du-chat syndrome.

Cri-du-chat syndrome, also referred to as cat-cry syndrome, and 5p minus syndrome results from a partial deletion of the short arm of chromosome 5. Example nomenclature for a female with this syndrome is (46,XX,del[5p]). The incidence of the syndrome is estimated to be one case per 20,000 to 50,000 live births.^10,74 Although approximately 70% of individuals with cri-du-chat syndrome are female, there is an unexplained higher prevalence of older males with this disorder.⁷⁵ Advanced parental age is not a causal factor. A study completed in 1978 indicated that life expectancy was 1 year for 90% of infants born with this disorder,⁷⁶ but now life expectancy is nearly normal with routine medical care.⁷⁷

Primary identifying characteristics at birth include a definitive high-pitched catlike cry, microcephaly, evidence of intrauterine growth retardation, and subsequent low birth weight.^10,76,78 Abnormal laryngeal development accounts for the characteristic cry, which is present in most individuals and disappears in the first few years of life.⁷⁶ Other features of individuals with this syndrome include hypertelorism, strabismus, “moon face,” and low-set ears.^10,76,78 Associated musculoskeletal deformities include scoliosis, hip dislocations, clubfeet, and hyperextensibility of fingers and toes. Muscular hypotonicity is associated with this syndrome, although cases with hypertonicity have also been noted.⁷⁹ Severe respiratory and feeding problems have also been reported.⁷⁷ Postnatal growth retardation has been documented, with the median near the 5th percentile of the normal growth curve.⁸⁰

Although intellectual disability and physical deformities are more severe with larger deletions,⁷⁴ there is evidence that with early developmental intervention these children can develop language, functional ambulation, and self-care skills.^81,82

Prader-willi syndrome and angelman syndrome.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are discussed together because they result from a structural or functional loss of the PWS and AS region of chromosome 15 (15q11-13), which can occur by one of several genetic mechanisms.^83,84 PWS has an incidence of one in 15,000 to 30,000⁸³ and AS has an incidence of one in 12,000 to 20,000.^83,84 These two syndromes illustrate the effect of genomic imprinting, which is the differential activation of genes of the same chromosome and location, depending on the sex of the parent of origin (Figure 13-3).⁸

PWS results from a failure of expression of paternally inherited genes in the PWS region of chromosome 15.⁸³ Conversely, AS results when the maternal contribution in the 15q11.2-q13 region is lost.⁸⁴ OCA2 is a gene located within the PWS and AS region of chromosome 15 that codes for the protein involved in melanin production. With loss of one copy of this gene, individuals with PWS or AS will have light hair and fair skin. In the rare case that both copies of the gene are lost, these individuals may have a condition called oculocutaneous albinism, type 2, which causes severe vision problems.⁸⁴

Characteristics of PWS in infancy include hypotonia, poor feeding, lethargy, and hypogonadism.^85,86 Developmental milestones in the first 2 years of life are not acquired until approximately twice the normal age.^87,88 Between 1 and 4 years of age, hyperphagia is apparent and if uncontrolled will lead to morbid obesity and its associated health complications.^86,87,89 Most individuals with PWS have mild to moderate intellectual disability, although some individuals have IQ scores within normal limits.⁹⁰ Maladaptive behaviors such as temper tantrums, aggression, self-abuse, and emotional lability have been reported.⁹¹ As a result of extreme obesity, many individuals with PWS have impaired breathing that can produce sleepiness, cyanosis, cor pulmonale, and heart failure.⁹¹ Scoliosis is common but does not appear to be related to obesity.⁹²