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

Clinical diagnosis is confirmed by laboratory genetic testing techniques including DNA-based methylation testing, FISH probe, and pyrosequencing assays.^86,93 Most cases of PWS are caused by random mutations in parental reproductive cells.⁸⁷ Other cases may result from translocation errors.^86,94 Parental studies are important in translocation cases because 20% of cases cited in the literature involved familial rearrangements, which may significantly increase the risk of recurrence.⁹⁵

Angelman syndrome, named after Dr. Harry Angelman, who first described children with AS in 1965, is characterized by developmental delay or intellectual disability, seizures, ataxia, progressive microcephaly, and severe speech impairments. Tongue thrusting, drooling, and sucking and swallowing disorders occur in 20% to 80% of children. Individuals often display spontaneous bouts of laughter accompanied by hand-flapping movements and a characteristic walking posture of arms overhead and flexed elbows.^8,84,96 Infants appear normal at birth, but severe developmental delay becomes apparent by 6 to 12 months of age. More unique features of the disorder do not appear until after 1 year of age. Children with AS typically have structurally normal brains on MRI and computed tomography (CT) scans, but electroencephalogram (EEG) findings are often abnormal, showing a characteristic pattern that may assist with diagnosis before other clinical symptoms emerge,^84,97 and molecular studies can also confirm the disorder before all of the clinical criteria for this diagnosis are met.⁸⁴

Most cases of AS occur as a result of mutations involving deletion or deficient function of the maternally inherited UBE3A gene. This gene codes for an enzyme, ubiquitin protein ligase, involved in the normal process of removing damaged or unnecessary proteins in healthy cells. In most of the body’s tissues except the brain, both copies (maternal and paternal) of the UBE3A gene are active. Only the maternal copy of the gene is normally active in the brain, so if this copy is absent or deficient, the normal cellular housekeeping process breaks down.⁸⁴ The risk of having another child with AS can vary from 1% to 50% depending on which of the six known genetic mechanisms is responsible for the disorder.

Acute lymphoblastic leukemia.

ALL accounts for one fourth of all childhood cancers, and it is the most common type of childhood cancer.102–104 ALL occurs when the DNA of immature lymphoblasts is altered and they reproduce in abnormal numbers, crowding out the formation of normal cells in the bone marrow.^102,105 Sixty percent of cases of ALL occur in children, with the peak incidence in the first 5 years of life. A rise in the incidence of ALL has been reported during major periods of industrialization worldwide^105,106 and is hypothesized to be associated with exposure to radiation¹⁰⁷ and other environmental teratogens^108,109 in the preconception, gestational, and postpregnancy periods.^103,106

With advancements in medical treatment protocols for pediatric patients, 5-year survival rates have improved to 80%.¹⁰⁴ Children aged 1 to 9 years at diagnosis have a better prognosis than infants, adolescents, or adults diagnosed with ALL.¹⁰³ There are numerous forms of translocation mutations associated with ALL. Some translocation forms of ALL do not respond well to combination chemotherapy treatment; an example is the translocation that occurs between chromosomes 9 and 22, known as the “Philadelphia chromosome.”^104,110 Other translocations that result in hyperdiploidy (more than 50 chromosomes), in particular within chromosomes 4, 10, and 17, may confer a more favorable outcome.¹¹¹

Frequently, diagnosis is made when a physician relates the child’s history of a persistent viral respiratory infection with other characteristic clinical signs and symptoms consistent with hematopoietic leukemia. The key symptoms of ALL are pallor, poor appetite, lethargy, easy fatigue and bruising, fever, mucosal bleeding, and bone pain.⁹⁹ A complete blood count will show a shortage of all types of blood cells, including red, white, and platelets. Diagnosis is confirmed by the presence of lymphoblasts in bone marrow. Radiographs may be necessary to determine metastases, and cerebrospinal fluid will be examined because early involvement of the CNS has important prognostic implications.¹⁰⁶ Cytogenetic studies will be performed to aid in selection of treatment protocols and prognosis.¹⁰⁴

Referral to physical and occupational therapists is made for other common problems such as muscle cramps, muscle weakness, impaired gross and fine motor performance, decreased energy expenditure, osteopenia, and osteoporosis.¹¹²

Osteogenesis imperfecta.

OI is a spectrum of diseases that results from deficits in collagen synthesis associated with single-gene defects, most commonly of COL1A1 and COL1A2, located on chromosomes 17 and 7, respectively.^10,113 OI is characterized by brittle bones resulting from impaired quality, quantity, and geometry of bone material and hyperextensible ligaments.^114,115 Deafness, resulting from otosclerosis, is found in 35% of individuals by the third decade of life.⁴⁵ New knowledge about this disease from molecular genetic studies and bone histomorphometry has expanded the classification subtypes of OI into types I through VII.^113,116 These classifications are helpful in determining prognosis and management, although there is a continuum of severity of clinical features and much overlap in the features among the different classifications.¹¹⁶ Types I, IV, V, and VI occur in the autosomal dominant pattern; whereas type VII occurs as a recessive trait, and types II and III can occur as either dominant or recessive traits.¹¹³ OI types V and VI account for only 5% of cases, and type VII has been found to date only in a Native Canadian population.¹¹⁶ This section will compare and contrast only types I through IV.

The overall incidence of OI is one in 10,000 live births in the United States, with types I and IV accounting for almost 95% of all patients with OI.¹¹³ Ninety percent of dominant forms of OI can be confirmed by DNA analysis.¹¹⁷ Type I is the least severe form, followed by types IV and III, with type II being the most severe.

Type I is characterized by blue sclera, mild to moderate bone fragility, joint hyperextensibility, and hearing loss in young adulthood.¹¹⁷ There are no significant deformities; individuals with this type may not sustain fracture until ambulatory, and incidence of fractures decreases with age.¹¹⁷ Type IV OI is characterized by more severe bone fragility and joint hyperextensibility than is type I. Bowing of long bones, scoliosis, dentinogenesis imperfecta, and short stature are common.^114,116,118

Children with type IV OI are often ambulatory but may require splinting or crutches.¹¹⁴

Children with type III OI have severe bone fragility and osteoporosis; often there are fractures in utero. Type III occurs primarily in autosomal dominant inheritance in North Americans and Europeans.¹¹⁶ The less frequent, autosomal recessive form of OI, type III is characterized by progressive skeletal deformity, scoliosis, triangular facies, large skull, normal cognitive ability, short stature, and limited ambulatory ability.^114,116,119 The long bones of the lower extremities are most susceptible to fractures, particularly between the ages of 2 to 3 years and 10 to 15 years,⁴⁵ with the frequency of fractures diminishing with age. Intramedullary rods inserted in the tibia or femur may minimize recurrent fractures.³⁶

Type II, the most severe form, is most often lethal before or shortly after birth, although there are a few cases of children living to 3 years.^116,119 Infants with type II OI have multiple fractures, often in utero, and underdeveloped lungs and thorax; therefore many die from respiratory complications after birth. Most type II cases are the result of spontaneous mutations; because only one copy of the gene is sufficient to cause the disorder, it is still commonly classified as an autosomal dominant condition. There are fewer cases of autosomal recessive inheritance.⁸

Prevention of fractures is an important goal in working with individuals with OI, but fear of handling and overprotection by caregivers may limit a child’s optimal functional independence. Caregiver education in careful handling and positioning should begin in the patient’s early infancy, and training in the use of protective orthoses and assistive devices is appropriate from the period of crawling through ambulation.^115,120,121 Aquatic therapy can be a valuable treatment strategy for children with OI.^120,121

Tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is characterized by a triad of impairments: seizures, intellectual disability, and sebaceous adenomas; however, there is wide variability in expression, with some individuals displaying skin lesions only.¹²² Infants are frequently normal in appearance at birth, but 70% of those who go on to show the complete triad of symptoms display seizures during the first year of life. Although tuberous sclerosis is inherited as an autosomal dominant trait, 86% of cases occur as spontaneous mutations, with older paternal age a contributing factor. TSC affects both sexes equally, with a frequency of one in 5800 births.¹²³ Mutations in the TSCI and TSC2 genes are known to cause tuberous sclerosis.¹⁰ The normal function of these genes is to regulate cell growth; if these genes are defective, cellular overgrowth and noncancerous tumor formation can occur.¹²³ Tumor formation in the CNS is responsible for most of the morbidity and mortality with TSC,¹²³ followed by renal disease associated with formation of benign angiomyolipomas.¹²² Diagnostic criteria for TSC have been established, and the determination can be made clinically; results of genetic testing are currently viewed as corroborative.¹²² Hypopigmented macules are often the initial finding. These lesions vary in number and are small and ovoid. Larger lesions, known as leaf spots, may have jagged edges.¹²³ Sebaceous adenomas first appear at age 4 to 5 years, with early individual brown, yellow, or red lesions of firm consistency in the nose and upper lips. These isolated lesions may later coalesce to form a characteristic butterfly pattern on the cheeks. Known also as hamartomas (tumor-like nodules of superfluous tissue), the skin lesions are present in 83% of individuals with tuberous sclerosis.⁴⁵

Delayed development is another characteristic during infancy,¹²⁴ particularly in the achievement of motor and speech milestones. Cerebral cortical tubers are present in over 80% of patients and account for cognitive disability including autism.¹²² Ultimately, 93% of individuals who are severely affected will have seizures, usually of the myoclonic type, in early life, progressing in later life to grand mal seizures. Seizure development is the result of formation of nodular lesions in the cerebral cortex and white matter.⁴⁵ Tumors are also found in the walls of the ventricles. Neurocytological examination reveals a decreased number of neurons and an increased number of glial cells and enlarged nerve cells with abnormally shaped cell bodies.¹⁰ Surgical excision of seizure-producing tumors has been successful in some cases.¹²²

Other associated impairments include retinal tumors and hemorrhages, glaucoma, and corneal opacities.¹²³ Cyst formation in the long bones and in the bones of the fingers and toes contributes to osteoporosis. Cardiac and lung tissues are also affected by TSC, and these effects are included in the major diagnostic criteria.¹²²

Neurofibromatosis.

There are two recognized forms of NFM: neurofibromatosis 1 (NFM1) and neurofibromatosis 2 (NFM2).125–127 Neurofibromas, or connective tissue tumors of the nerve fiber fasciculus, impede the development and growth of neural cell tissues^126,127 and are the hallmark feature of NFM1. Neurofibromas are noncancerous, and malignant changes are rare in children¹²⁸ but an increased risk of malignancy has been observed in adult patients with NFM1 and is a major contributor to decreased life expectancy by approximately 15 years.¹²⁹ Tumors typically increase in number with increasing age. About half of all cases of NFM are caused by sporadic mutation in parental germ cells or during fetal development.^125–127 Schwannomas are the main tumor type of NFM2 and classically appear bilaterally on the vestibular nerves.^127,130 NFM1 is also known as von Recklinghausen disease. Compared with type II, type I is more common (one per 3000 births)^10,126 and usually identified in younger children. It is associated with mutations in the NF1 gene, which produces a protein, neurofibromin, the complete function of which is not yet understood but which is suspected to be a tumor suppressor. Diagnostic criteria for NFM1 include the presence of two of the following features: six or more café-au-lait spots, two or more fibromas, freckling in the axillary or inguinal region, optic pathway glioma, two or more Lisch nodules, specific osseous lesions, and a first-degree relative with NFM1.¹²⁶ Infants usually appear normal at birth, but initial café-au-lait spots appear by age 3 years in 95% of individuals (Figure 13-4).¹³¹ Cognitive impairment is the most common neurological complication of NFM1¹³¹ and is postulated to be caused by altered expression of neurofibromin in the brain and/or hyperintense lesions in the brain seen on MRI.¹³¹ These focal areas of high signal intensity on T2-weighted MRI, known as unidentified bright objects (UBOs), are seen in 60% of children and young adults with NFM1. The lesions, commonly found in the basal ganglia, internal capsule, thalamus, cerebellum, and brain stem,^128,132 tend to disappear in adulthood and often do not cause other overt neurological symptoms.¹²⁸ Fewer than 10% of individuals are mentally retarded, but about 30% to 60% of affected children have learning disabilities that are mild and nonprogressive.^128,133 Poorer social skills and differences in personality, behavior, and quality-of-life perception have been reported in children with NFM1 compared with children without the disorder.¹²⁶

In older children and adolescents, pain, itching, and stinging can occur from cutaneous neurofibromas, and in approximately half of all patients, neurological motor deficits occur from plexiform neurofibromas when the growth puts pressure on peripheral nerves, spinal nerve roots, and the spinal cord.¹³¹ One percent to 5% of children aged 0 to 6 years develop symptoms associated with optic pathway glioma.^126,128 Neurofibromatous vasculopathy interferes with arterial and venous circulation in the brain.^126,131,134 Hydrocephalus occurs in some individuals.^126,128 Hypertension is common and may develop at any age,¹²⁶ and cardiovascular disease is a major cause of premature death.^129,131,135 Headaches are a commonly reported symptom in children, adolescents, and adults.^{126,128,136,137}

Scoliosis may develop in 10% of patients and is rapidly progressive from ages 6 to 10 years, or it may manifest in a milder form without vertebral anomalies during adolescence.¹²⁶ Other skeletal deformities include pseudarthrosis of the tibia and fibula, tibial bowing, craniofacial and vertebral dysplasia, rib fusion, and dislocation of the radius and ulna.¹²⁶ Differences in leg length¹²⁶ also have been noted and may contribute to scoliosis. NFM2 occurs less frequently than type I (one in 25,000 to 40,000 births)¹⁰ and is caused by a mutation in the gene encoding the protein neurofibromin 2, also called Merlin.¹⁰ Merlin is produced in the nervous system, particularly in Schwann cells that surround and insulate the nerve cells of the brain and spinal cord. Although type II shares characteristics with type I, it is commonly characterized by tumors of the eighth cranial nerve (usually bilateral), meningiomas of the brain, and schwannomas of the dorsal roots of the spinal cord.¹⁰ Contrary to first descriptions of NFM1 and NFM2, café-au-lait spots are seldom a singular feature of NFM2¹²⁷; rather, signs and symptoms of tinnitus, hearing loss, and balance dysfunction usually appear during adolescence or in the person’s early 20s.^125,127 Problems with visual acuity caused by strabismus and refractive errors are common in young children.¹³⁸ NFM2 may be underrecognized in children up to 10 years old because early hearing loss and tinnitus are present in only 20% of cases and otherwise only singular features of the condition are observed. Infants may have cataracts, and children may demonstrate unilateral facial paralysis, eye squinting, mononeuropathy (foot or hand drop), meningioma, spinal tumor, or cutaneous tumor. It is recommended that children of parents with NFM2 should be considered to be at 50% risk for NFM2 and screened from birth.¹³⁰

Cystic fibrosis.

CF is one of the most common autosomal recessive disorders and is more common in Caucasians, affecting one in 2000 to 4000.¹⁰ The CF gene has been mapped to chromosome 7, and its protein product, CF transmembrane regulator (CFTR).⁸ CFTR is involved in the regulation of chloride channels of the bowel and lung, which is dysfunctional in patients with CF. Although CF has markedly variable expression, the overall median survival time has improved from about 6 years of age in the 1940s to an average of 36 years of age in 2006.¹³⁹ In addition to the phenotypical features of CF, diagnosis of CF is made when two or more disease-causing mutations exist on the CTFR gene.¹³⁹ Newborn screening tests for CF are required in all states in the United States.¹⁴⁰

Fibrotic lesions of the pancreas cause pancreatic insufficiency in the majority of patients, which leads to chronic malnutrition. Ten percent to 20% of newborn infants with CF also have intestinal tract involvement with a meconium ileus. The sweat glands are commonly affected; high levels of chloride found in the sweat is the basis for the sweat chloride test used in diagnosis. The most serious impairment in CF is the obstruction of the lungs by thick mucus, which leads to chronic pulmonary obstruction, infection that destroys lung tissue, and eventual death from pulmonary disease in 90% of individuals.⁸

Improved survival rate in recent decades is a result of improved antibiotic management, aggressive chest physical therapy, and pancreatic replacement therapy. Postural drainage, percussion, vibration, and breathing exercises are key components of the management program provided by the therapist and caregivers.¹⁴¹ Modern and less labor-intensive devices such as those that provide positive expiratory pressure may not be as effective at clearing secretions as conventional chest physiotherapy,¹⁴¹ but patient and caregiver compliance with a regular program may be improved with them.¹⁴² Attention to diet is important, and every attempt should be made to maintain a routine exercise program with a goal of helping the children be more active to improve their respiratory status and to prevent secondary impairments of adolescence and adulthood such as stress incontinence in young women caused by excessive coughing,^143,144 chronic back pain, and osteopenia and osteoporosis.¹⁴⁵

Massery¹⁴³ describes the relationship among respiration, postural control, and secondary impairments that develop in individuals with CF in the musculoskeletal and neuromuscular systems. She addresses the threefold problem faced by individuals with CF: (1) lung dysfunction leading to increased respiratory demand; (2) increased workload of respiration as a deforming force on the immature musculo-skeletal frame; and (3) resultant impaired motor strategies for postural control during physical activity. Patients were once widely cautioned to avoid overexertion and fatigue with exercise, but as patients are living longer, more evidence supports the benefits of regular, even vigorous exercise for children and adults with CF. Guidelines for exercise frequency and intensity have been published by the Association of Chartered Physiotherapists in Cystic Fibrosis.¹⁴⁶

Hurler syndrome (mucopolysaccharidosis I, severe type).

Hurler syndrome is an inborn error of metabolism that results in abnormal storage of mucopolysaccharides in many different tissues of the body.⁹⁷ The incidence is estimated to be one in 100,000 live births for the severe forms¹⁰ and one in 500,000 for milder forms.¹⁴⁷ IDUA is the only gene currently known to be associated with this multisystem disorder.¹⁴⁷

Infants born with Hurler syndrome are usually normal in appearance at birth, may have inguinal or umbilical hernias,¹⁴⁷ and may have higher birth weights than their siblings. Symptoms of this progressively deteriorating disease usually appear during the latter half of the first year of life,¹⁴⁷ with the full disease picture apparent by 2 to 3 years of age.^10,147 Diagnosis is made by identification of deficiency in lysosomal enzymes.^147,148 Premature death, usually from cardiorespiratory failure, occurs within the first 10 years of life.¹⁴⁷

Characteristic physical features are caused by storage of glycosaminoglycans (GAGs)¹⁴⁷ and include a large skull with frontal bossing, heavy eyebrows, edematous eyelids, corneal clouding, a small upturned nose with a flat nasal bridge, thick lips, low-set ears, hirsutism, and gargoyle-like facial features. Growth retardation results in characteristic dwarfism.¹⁴⁷ Some individuals with the physical characteristics of Hurler syndrome have normal intelligence, but most have progressive and profound intellectual disability.^10,147

Spastic paraparesis or paraplegia and ataxia have been observed in individuals with Hurler syndrome.⁸ Commonly reported orthopedic deformities include flexion contractures of the extremities, thoracolumbar kyphosis, genu valgum, pes cavus, hip dislocation, and claw hands as a result of joint deformities.⁴⁵ Defective ossification centers of the vertebral bodies results in spinal deformity, complications of nerve entrapment, atlanto-occipital instability, and restricted cervical range of motion.¹⁴⁷ Conductive and sensorineural hearing loss is common.¹⁴⁷ Delayed motor milestones have been noted as early as 10 months of age,¹⁴⁸ with severe disabilities occurring with increasing age. Adaptive equipment often is needed, and most children with Hurler syndrome become wheelchair users in their later years.¹⁴⁸

Phenylketonuria.

PKU is the result of one of the more common inborn errors of metabolism. Mutations of the PAH gene located on chromosome 12 cause a deficiency in the production of phenylalanine hydroxylase.¹⁴⁹ Without this enzyme, there is no conversion of phenylalanine to tyrosine, resulting in an abnormally excessive accumulation of phenylalanine in the blood and other body fluids.^149,150 If untreated, this metabolic error results in mental and growth retardation, seizures, and pigment deficiency of hair and skin.¹⁵¹ PKU is most prevalent among individuals of northern European ancestry, with a frequency of one in 10,000 to 15,000 births in the United States.¹⁴⁹ It is estimated that one of every 50 individuals is heterozygous for PKU.⁸

Children born with PKU are usually normal in appearance, with microcephaly and delayed development becoming apparent toward the end of the first year. Parents usually become concerned with the child’s slow development during the preschool years.¹⁵¹ If PKU is untreated, the affected child may go on to develop hypertonicity (75%), hyperactive reflexes (66%), hyperkinesis (50%), or tremors (30%),¹⁵² in addition to intellectual disability. IQ levels generally fall between 10 and 50, although there have been reported rare cases of untreated individuals with normal intelligence.¹⁵¹

A simple blood plasma analysis, which is mandatory for newborn infants in all 50 U.S. states,¹⁴⁰ can detect the presence of elevated phenylalanine levels in nearly 100% of cases.¹⁵⁰ This test is ideally performed when the infant is at least 72 hours old. If elevated phenylalanine levels are found, the test is repeated, and further diagnostic procedures are performed. Placing the infant on a low phenylalanine diet (low protein) can prevent the intellectual disability and other neurological sequelae characteristic of this disorder.¹⁵¹ Follow-up management by an interdisciplinary team consisting of a nutritionist, psychologist, and appropriate medical personnel is advised in addition to the special diet. Individuals with poor compliance with the recommended diet have a greater risk of osteopenia in adulthood.¹⁵⁰

Spinal muscle atrophy.

SMA (5q SMA) is characterized by progressive muscle weakness because of degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei.^153,154 Diagnosis of SMA is based on molecular genetic testing for deletion of the SMN1 gene (named for “survival of motor neuron 1”), location 5q13. Another gene, SMA2, can modify the course of SMA. Individuals with multiple copies of SMA2 can have less severe symptoms or symptoms that appear later in life as the number of copies of the SMN2 gene increases.¹⁵⁵ The overall disease incidence of SMA is five in 100,000 live births.¹⁵⁵

The clinical classifications of SMA are still evolving.^153,154,156 At present, four subtypes (types I to IV) are well accepted, and a fifth, type 0, is being explored. The subtypes are based on age at symptom onset and expectations for maximum physical function, the latter being more closely related to life expectancy.¹⁵⁶

SMA type 0 is characterized by extreme muscle weakness apparent before 6 months of age that likely had a prenatal onset.^153,154 Some infants have a prenatal history of decreased fetal movements during the third trimester.¹⁵³

SMA I, otherwise known as Werdnig-Hoffmann disease or acute infantile SMA,¹⁰ has an onset before 6 months of age.^153,156 Incidence is estimated to be one in 20,000 live births.¹⁰ It is characterized clinically by severe hypotonicity, generalized symmetrical muscle weakness, absent deep tendon reflexes, and markedly delayed motor development. Intellect, sensation, and sphincter functioning, however, are normal.¹⁵³ Children usually cannot sit without support and have poor head control.¹⁵⁶ They have a weak cry and cough and problems with swallowing, feeding, and handling oral secretions.¹⁵⁴ The diaphragm is spared, but combined with weakness in intercostal muscles, infants exhibit paradoxical breathing, abdominal protrusion, and a bell-shaped trunk with chest wall collapse.¹⁵⁴ Overall, this pattern of chest wall weakness and poor respiratory function contributes to the greatly increased susceptibility to pulmonary infection, which usually results in death before the age of 2 years.^10,154,155

SMA II, otherwise known as intermediate or chronic infantile SMA, has an onset at age 6 to 18 months and is associated with delayed motor milestones.¹⁵⁶ Seventy percent of children diagnosed with SMA II are alive at 25 years of age.¹⁵³

Children with SMA II can usually sit independently if placed but never stand unsupported.¹⁵⁴ Bulbar weakness with swallowing difficulties, poor weight gain, and diaphragmatic breathing are common.¹⁵⁵ Finger trembling is almost always present.^153,154 Joint contractures are present in most individuals. Kyphoscoliosis of severity to require bracing and/or surgery often develops, but patients are at risk of postanesthesia complications.¹⁵⁴ Respiratory failure is the major cause of morbidity and mortality. Nocturnal oxygen desaturation and hypoventilation occur before daytime hypercarbia and are early indications of need for ventilator support.¹⁵⁴

SMA III is characterized by onset of symptoms in childhood after 18 months.¹⁵³ It is also known as juvenile SMA or Kugelberg-Welander syndrome.¹⁰ These individuals have a normal life span and usually attain independent ambulation and maintain it until the third or fourth decade of life.¹⁵³ Lower extremities are often more severely affected than the arms. Strength is often not sufficient for stair climbing, and balance problems are common.¹⁵³ Muscle aches and joint overuse symptoms are frequently reported.¹⁵⁴

SMA IV typically has an onset at older than 10 years of age and is associated with a normal life expectancy and no respiratory complications.^154,156 Individuals maintain ambulation during the adult years.¹⁵⁴

Variants of SMA occur in individuals with similar phenotypes and clinical diagnostic features of electromyography (EMG) that are not associated with deletion of SMN1.¹⁵⁶ Genetic testing for SMN gene deletion achieves up to 95% sensitivity and nearly 100% specificity.¹⁵⁴ For cases that remain unclear, a clinical diagnosis may be accomplished through EMG and muscle biopsy, which reveal neurogenic atrophy. Key physical signs are common: symmetrical weakness in the more proximal musculature versus distal, and lower extremity weakness that is greater than in the arms.¹⁵⁴ Traditional strength measurements are not practical for children with SMA. The Gross Motor Function Measure¹⁵⁷ has excellent reliability in studies of gross motor evaluation in this population.^154,158 Consensus guidelines on pulmonary care including assessment, monitoring, and treatment; feeding and swallowing, gastrointestinal dysfunction and nutrition; and orthopedic management have been published by the Standard of Care Committee for Spinal Muscle Atrophy.¹⁵⁴ Currently there are no efficacious drugs to effectively treat the symptoms of SMA.^160,161

Hemophilia.

Hemophilia is a bleeding disorder caused by a deficient clotting process. Affected individuals will have hemorrhage into joints and muscles, easy bruising, and prolonged bleeding from wounds. The term hemophilia refers to hemophilia A (coagulation factor VIII deficiency) and hemophilia B or Christmas disease (coagulation factor IX deficiency). There are numerous other clotting diseases, and some that were once referred to as hemophilia are now genomically distinguished. For example, von Willebrand disease has a distinctly different genetic basis from hemophilia; it follows an autosomal recessive or autosomal dominant pattern and involves mutation of the von Willebrand factor (VWF) gene, located on chromosome 12. VWF plays a role in stabilizing blood coagulation factor VIII.¹⁶² Hemophilia A and B occur as X-linked recessive traits owing to mutations of genes F8 and F9, respectively, both of which are located on the X chromosome.^163,164

Hemophilia A is reported to affect one in 4000 to 5000 males worldwide.¹⁶³ Hemophilia B is less common, affecting one in 20,000 males worldwide.¹⁶⁴ Hemophilia can affect females, though in milder form. The severity and frequency of bleeding in hemophilia A are inversely related to the amount of residual factor VIII (less than 1%, severe; 2% to 5%, moderate; and 6% to 35%, mild).¹⁶³ The proportions of cases that are severe, moderate, and mild are about 50%, 10%, and 40%, respectively.¹⁶⁵ The joints (ankles, knees, hips, and elbows) are frequently affected, causing swelling, pain, decreased function, and degenerative arthritis. Similarly, muscle hemorrhage can cause necrosis, contractures, and neuropathy by entrapment. Hematuria and intracranial hemorrhage, although uncommon, can occur after even mild trauma. Bleeding from tongue or lip lacerations is often persistent.⁸

Hemophilia is usually diagnosed during childhood, with the most severe cases diagnosed in the first year of life: bleeding from minor mouth injuries and large “goose eggs” from minor head bumps are the most frequent presenting signs in untreated children.¹⁶³ Children are especially vulnerable to bleeding episodes owing to the nature of their physical activity combined with periods of rapid growth.¹⁶³

Treatment includes guarding against trauma and replacement with factor VIII derived from human plasma or recombinant techniques.⁸ In the late 1970s to mid 1980s it was estimated that half of the affected individuals in the United States contracted hepatitis B or C or human immunodeficiency virus (HIV) infection when treated with donor-derived factor VIII. The initiation of donor blood screening and use of heat treatment of donor-derived factor VIII has almost completely eliminated the threat of infection.⁸ Although replacement therapy is effective in most cases, 30% of treated individuals with hemophilia A and 3% of individuals with hemophilia B have neutralizing antibodies that decrease its effectiveness.^163,164 Before treatment with clotting factor concentrates was available, the average life expectancy was 11 years¹⁶³; currently, excluding death from HIV, life expectancy for those with severe hemophilia who receive adequate treatment is 63 years.¹⁶³ Factor replacement therapy is credited for increasing the ease and safety of vigorous exercise and sports participation for individuals.¹⁶⁶ The benefits of regular exercise are the same as for unaffected individuals and outweigh the risks in treated persons.¹⁶⁷ A 2002 pilot study by Tiktinsky and colleagues¹⁶⁷ found decreased episodes of bleeding in a population of young adults with a long-term history of resistance training that began in adolescence.

Fragile X syndrome.

FXS is the most common sex-linked inherited cause of intellectual disability, affecting one in 4000 males and one in 8000 females.¹⁶⁸ Males manifest a more severe form than females. A fragile site on the long arm of an X chromosome is present, with breaks or gaps shown on chromosome analysis. A region of the X chromosome, named FMR1, normally codes for proteins that may play a role in the development of synapses in the brain. Mutations of this region are errors of trinucleotide repeats, in which the number of CGG triplets at this region is expanded, thereby making the gene segment unable to produce the necessary protein.¹⁶⁸

Developmental milestones are slightly delayed in affected males.¹⁶⁸ Eighty percent of males are reported to have intellectual disability, with IQs of 30 to 50 being common but ranging up to the mildly retarded to borderline range.¹⁶⁸ Penetrance (the proportion of individuals with a mutation that actually exhibit clinical symptoms) in the female is reported to be only 30%.⁸ Other impairments include epilepsy, emotional lability, attention-deficit/hyperactivity disorder (ADHD), and clinical autistic disorder in 30% of males.^168,169 Life span is normal for individuals with this condition.¹⁶⁸

Lesch-nyhan syndrome.

Also known as hereditary choreoathetosis,¹⁷⁰ LNS leads to profound neurological deterioration. First described in 1964 by Lesch and Nyhan,¹⁷¹ it is associated with a mutation in the HPRT1 gene on the X chromosome. This gene codes for an enzyme, hypoxanthine guanine phosphoribosyltransferase, which allows cells to recycle purines, some of the building blocks of DNA and ribonucleic acid (RNA).¹⁷² Without this gene’s normal function, there is an overproduction of uric acid (hyperuricemia),¹⁷² which accumulates in the body. High uric acid levels are thought to cause neurological damage.^170,172

The prevalence of LNS is one in 380,000 individuals.¹⁷² Females born to carrier mothers have a 25% chance of inheriting the mutation. There are rare reports of females demonstrating this syndrome as a result of X chromosome inactivation. Most female carriers are considered to be asymptomatic, but some may have symptoms of hyperuricemia in adulthood.¹⁷²

LNS is detectable through amniocentesis, and genetic counseling is advisable for parents who have already given birth to an affected son.¹⁷³

The prenatal and perinatal course is typical for affected individuals. Hypotonia and delayed motor skills are noticeable by age 3 to 6 months.¹⁷² Dystonia, choreoathetosis, and opisthotonus indicative of extrapyramidal involvement emerge during the first few years of life.¹⁷² Many children are initially diagnosed with athetoid cerebral palsy when pyramidal signs such as spasticity, hyperreflexia, and abnormal plantar reflexes emerge.¹⁷² Most children never walk. A hallmark of the disease is severe and frequent self-injurious behaviors such as lip and finger biting, which emerge in almost all affected children by their third birthday.¹⁷² Because of the extreme self-mutilation that characterizes this disorder, it has been questioned whether these children have normal pain perception.¹⁷⁴ Although these children have the abnormal catecholamine metabolism seen in other patients with congenital pain insensitivity,¹⁷⁵ behaviors documented in children with LNS suggest that they do sense pain, demonstrated by their apparent relief when they are restrained from hurting themselves. Children may actually request the restraining device¹⁷⁶ even when the device may be one that would not physically prevent biting, such as a glove or bandaid.¹⁷² A reported survey of parents of children with LNS indicated that parents often find behavioral programming techniques helpful in modifying aggression toward self or others.¹⁷⁶ However, there is no consensus on the best kind of behavioral treatments, as any reward, either positive or negative, may increase the frequency of self-injury.¹⁷⁷ Some parents have reported that they elected tooth extraction as a means to prevent biting. Other impairments in children with LNS include severe dysarthria and dysphagia. Bilateral dislocation of the hips may occur as a result of the spasticity.¹⁷² Growth retardation is also apparent, as well as moderate to severe intellectual disability.¹⁰ Individuals may have gouty arthritis and kidney and bladder stones.

Blood and urine levels of uric acid have been decreased successfully through the administration of allopurinol, with a resultant decrease in kidney damage. With current management techniques, most individuals survive into their second or third decade of life.¹⁷²

Rett syndrome.

RS is inherited in an X-linked pattern and it affects females almost exclusively, as it is most often lethal in boys before age 2 years. Males may inherit RS with an extra X chromosome in many or all of the body’s cells.178–181 The estimated incidence is one in 15,000 to 20,000 females.^10,182 It has been reported that 99% of all cases of RS are the result of sporadic mutations.^181,183 Most cases of RS, called classic RS, are caused by mutations in the MECP2 gene, which is responsible for directing proteins critical for normal synaptic development; however, it is unclear how these mutations lead to all the signs and symptoms of the syndrome.^181,184 Several variants of RS exist; they have overlapping features with classic RS but may have a much milder or more severe course.¹⁸¹

Classic RS is characterized by apparently normal development during the first 6 months of life, followed by a short period of developmental plateau, and then rapid deterioration of language and motor skills typically occurring at 6 to 18 months of age.^181,185 Most girls survive into adulthood.¹⁸¹ The hallmark of the syndrome is that during the period of regression, previously acquired purposeful hand skills are also lost and replaced by stereotypical hand movements. These nonspecific hand movements have been described as hand wringing, clapping, waving, or mouthing. Virtually all language ability is lost, although some children may produce echolalic sounds and learn simple manual signing. Evidence of minimal receptive language skills may be observed. Autistic behaviors, inconsolable crying and screaming, and bruxism are common features of individuals with RS.¹⁸¹ Almost all individuals with RS function in the range of severe to profound intellectual disabilities.

Head circumference is normal at birth, and its increase may decelerate in early childhood, but microcephaly is not a consistent feature of RS.¹⁸¹ Retarded growth and muscle wasting are observed in most girls, likely associated with poor food intake and gastrointestinal problems.¹⁸¹

Almost one fourth of girls with RS never develop independent ambulation skills; otherwise the onset of walking is usually delayed until about 19 months of age.¹⁸⁶ Initially hypotonia may be evident, but with advancing age, spasticity of the extremities develops.¹⁸⁷ Increased muscle tone is usually observed first in the lower extremities, with continued greater involvement than in the upper extremities. Peripheral vasomotor disturbances, especially in the lower limbs, are often noted.¹⁸¹

Scoliosis, which is often severe enough to require surgical correction, occurs in most girls by adolescence, characterized by a long C-shaped thoracolumbar curve, kyphoscoliosis, and an early onset of posterior pelvic tilt and abducted shoulder girdles.^{186,188–192} Heel cord tightening, and hip instability have also been identified as areas of potential concern.¹⁸⁸ Abnormal EEG and seizures occur in 70% of individuals with RS in the first 5 years of life. Cranial CT results are normal or show mild generalized atrophy. Breathing dysfunction, including wake apnea and intermittent hyperventilation,¹⁸⁶ is also associated with RS. Interventions reported in the literature have focused on splinting,¹⁹³ behavioral modification techniques to teach self-feeding skills,¹⁹⁴ aquatic therapy,¹⁹⁵ occupational therapy,¹⁹⁶ music therapy,¹⁹⁷ physical therapy,^{181,190,191,197} and the first two combined in a dual-intervention approach.¹⁹⁸