Trisomy 21 (down syndrome).

Trisomy 21 occurs in approximately 1 in every 700 live births, and its incidence is distributed equally between the sexes. 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. In the United States, the incidence of Down syndrome increases with advanced maternal age. 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. Down syndrome is the most common chromosomal cause of moderate to severe intellectual disability. 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 ( Fig. 11.2 ).

(A) A 10-month-old girl with Down syndrome. (B) A 21–month-old boy with the mosaic form of trisomy 18.

(Reprinted with permission of Tucker ME, Garringer HJ, Weaver DD. Phenotypic spectrum of mosaic trisomy 18: two new patients, a literature review, and counseling issues. Am J Med Genet A. 2007;143:505–517.)

Information compiled by the Centers for Disease Control and Prevention during 1968-2007 indicates that the median survival age of individuals with Down syndrome is 47 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. Half of all children with Down syndrome have congenital heart defects. ^, Congenital heart problems, respiratory infection, and leukemia are the most common factors associated with morbidity and mortality in childhood, whereas a possible increased tendency for premature cellular aging and Alzheimer disease may account for higher mortality rates later in life.

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 or hyperopia), astigmatism, or problems in accommodation. 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. ^, Obstructive sleep apnea has been reported to exist frequently in young children, and adults with Down syndrome. 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. 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. Children with Down syndrome also appear to have a higher risk of being overweight or obese, ^{, ,} which may be partly a result of the retarded growth and endocrine and metabolic disorders associated with trisomy 21. In a small population study of children with Down syndrome, Dyken and co-workers 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, which has been observed through radiography in up to 10% to 30% of individuals with this syndrome, ^, with and without neurological compromise. There is some controversy in the medical community regarding the necessity and efficacy of radiographic screening for the instability. ^, Proponents of radiographic screening argue that neurological symptoms of atlantoaxial instability may often go undetected in this population because symptoms are masked by the wide-based gait and motor dysfunction already associated with the disorder. If the child is unable to verbalize complaints or 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 anesthesia and participate in recreational sports such as the Special Olympics. Symptomatic instability can result in spinal cord compression, leading to myelopathy with leg weakness, decreased walking ability, spasticity, or incontinence. Although reportedly rare, there have been cases where atlantoaxial dislocation has resulted in quadriplegia.

Several researchers have explored the neuropathology associated with Down syndrome. Changes in brain shape, size, weight, and function occur during the prenatal and infant development of babies with Down syndrome, with important differences apparent by 6 months of age. The relatively small size of the cerebellum and brain stem was reported by Crome and Stern in the 1970s. Marin-Padilla 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-Mdzewska 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. Crome reported lesser brain weight in comparison with normal persons. Finally, Benda noted a lack of myelinization of the nerve fibers in the precentral area, frontal lobe, and cerebellum of infants with Down syndrome. According to McGraw, 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.

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. 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. Only 10% of infants born with trisomy 18 survive past the first year of life; female and non-Caucasian children survive the longest. The survival of girls averages 7 months, and the survival of boys averages 2 months. Individuals surviving past infancy most often have the mosaic form, and there is high variance in phenotype (see Fig. 11.2 ).

Individuals with trisomy 18 generally have far more serious organic malformations than seen in those with Down syndrome. 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 the typical life-span. 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.

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

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 ^, As in the other trisomic syndromes, advanced maternal age is correlated with the incidence of trisomy 13. Fewer than 10% of individuals with trisomy 13 survive past the first year of life ^, ; girls and non-Caucasian infants appear to survive longer. ^, Individuals surviving past infancy most often have the mosaic form, and there is high variance in phenotype. 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.

Trisomy 13 is characterized by microcephaly, deafness, anophthalmia or microphthalmia, coloboma, and cleft lip and palate. As in trisomy 18, infants with trisomy 13 frequently have serious cardiovascular and urogenital malformations and typically have severe to profound intellectual disability. Skeletal deformities and anomalies include flexion contractures of the fingers and polydactyly of the hands and feet. Rocker-bottom feet have also 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.

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. ^, Turner syndrome is the most common chromosomal anomaly among spontaneous abortions. ^, 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. Three characteristic impairments of the syndrome are sexual infantilism, a congenital webbed neck, and cubitus valgus. 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. ^, 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. Congenital heart disease is present in 20% to 30% of individuals with Turner syndrome, with a smaller number of cardiovascular malformations in individuals with the mosaic form ; 33% to 60% of individuals with Turner syndrome have kidney malformations. Hypertension is common even in the absence of cardiac or renal malformations.

There are numerous types 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, deformity of the medial tibial condyles, idiopathic scoliosis, and deformities resulting from osteoporosis.

Sensory impairments include decrease in gustatory and olfactory sensitivity ^, and deficits in spatial perception and orientation, 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. 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. 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. ^,

Klinefelter syndrome.

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

Most individuals with karyotype XXY have normal intelligence, a somewhat passive personality, and a reduced libido. Eighty-five percent of individuals with nonmosaic karyotype are sterile. Individuals with karyotypes 48,XXXY and 49,XXXXY tend to display a more severe clinical picture. Individuals with 48,XXXY karyotype usually have severe intellectual disability, along with multiple congenital anomalies, including microcephaly, hypertelorism, strabismus, and cleft palate. Skeletal anomalies include radioulnar synostosis, genu valgum, malformed cervical vertebrae, and pes planus. According to a 2010 systematic review of the literature, the neurocognitive outcomes of people with Klinefelter syndrome include problems of delayed walking in children, persistent deficits in fine and gross motor development, and problems in motor planning. ^, 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 in which they found cortical thinning in areas of the motor strip associated with impaired control of the upper trunk, shoulders, and muscles involved in speech production.

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. Although approximately 70% of individuals with cri-du-chat syndrome are female, there is an unexplained higher prevalence of older males with this disorder. 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, but now life expectancy is nearly normal with routine medical care.

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

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

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. ^, PWS has an incidence of 1 in 15,000 to 30,000, and AS has an incidence of 1 in 12,000 to 20,000. ^, 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 ( Fig. 11.3 ).

The Effect of imprinting on chromosome 15 deletions.

(A) Inheritance of the deletion from the father produces Prader-Willi syndrome. ( B) Inheritance of the deletion from the mother produces Angelman syndrome.

(From Jorde L, Carey J, Bamshad M, et al. Medical Genetics. 3rd ed. St. Louis: Mosby; 2005.)

PWS results from a failure of expression of paternally inherited genes in the PWS region of chromosome 15. Conversely, AS results when the maternal contribution in the 15q11.2-q13 region is lost. 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.

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

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

Angelman syndrome, named after 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 these children. Individuals often display spontaneous bouts of laughter accompanied by hand-flapping movements and a characteristic walking posture of arms overhead and flexed elbows. ^{, ,} Infants with AS 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 ^, ; molecular studies can also confirm the disorder before all of the clinical criteria for this diagnosis are met.

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 ubiquitin protein ligase, an enzyme involved in the normal process of removing damaged or unnecessary proteins from 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. 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. 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. ^, 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 ^, and is hypothesized to be associated with exposure to radiation and other environmental teratogens ^, in the preconception, gestational, and postpregnancy periods. ^,

With advancements in medical treatment protocols for pediatric patients, 5-year survival rates have improved to 80%. Children aged 1 to 9 years at diagnosis have a better prognosis than infants, adolescents, or adults diagnosed with ALL. Survival rate statistics since the approval of the gene therapy drug tisagenlecleucel for children and adults up to age of 25 years with B-cell ALL are expected to change from previously reported survival rates. Numerous forms of translocation mutations are 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. ^, Other translocations that result in hyperdiploidy (more than 50 chromosomes)—in particular within chromosomes 4, 10, and 17—may confer a more favorable outcome.

Frequent 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. 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 as early involvement of the CNS has important prognostic implications. Cytogenetic studies will be performed to aid in the selection of treatment protocols and determination of prognosis.

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.

Osteogenesis imperfecta.

OI is a spectrum of diseases that result from deficits in collagen synthesis associated with single-gene defects, most commonly of COL1A1 and COL1A2, which are located on chromosomes 17 and 7, respectively. OI is characterized by brittle bones resulting from impaired quality, quantity, and geometry of bone material and hyperextensible ligaments. ^, Deafness, resulting from otosclerosis, is found in 35% of individuals by the third decade of life. New knowledge about this disease from molecular genetic studies and bone histomorphometry has expanded the classification subtypes of OI into types I through VIII. ^, 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. 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. OI types V and VI account for only 5% of cases, and type VII has been found only in Native Canadian population to date. In 2007, an autosomal recessive OI, designated type VIII, was characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses. This section compares and contrasts 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. Ninety percent of dominant forms of OI can be confirmed by DNA analysis. 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 sclerae, mild to moderate bone fragility, joint hyperextensibility, and hearing loss in young adulthood. There are no significant deformities; individuals with this type may not sustain fracture until they are ambulatory, and the incidence of fractures decreases with age. Type IV OI is characterized by more severe bone fragility and joint hyperextensibility than in type I. Bowing of long bones, scoliosis, dentinogenesis imperfecta, and short stature are common. ^{, ,}

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

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. 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. ^{, ,} The long bones of the lower extremities are most susceptible to fractures, particularly between the ages 2 to 3 years and 10 to 15 years, after which the frequency of fractures diminishes. Intramedullary rods inserted in the tibia or femur may minimize recurrent fractures.

Type II, the most severe form, is most often lethal before or shortly after birth, although there are a few cases of children living up to 3 years. ^, Infants with type II OI have multiple fractures, often in utero, and underdeveloped lungs and thorax; therefore many die from respiratory complications soon after birth. Most type II cases are the result of spontaneous mutations. As 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.

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. ^{, ,} Aquatic therapy can be a valuable treatment strategy for children with OI. ^,

Tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is characterized by a triad of impairments: seizures, intellectual disability, and sebaceous adenomas; however, there is a wide variability in expression, with some individuals displaying skin lesions only. 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 being a contributing factor. TSC affects both sexes equally, with a frequency of one in 5800 births. Mutations in the TSCI and TSC2 genes are known to cause tuberous sclerosis. The normal function of these genes is to regulate cell growth; if they are defective, cellular overgrowth and noncancerous tumor formation can occur. Tumor formation in the CNS is responsible for most of the morbidity and mortality due to TSC, followed by renal disease associated with the formation of benign angiomyolipomas. Diagnostic criteria for TSC have been established, and the determination can be made clinically; results of genetic testing are currently viewed as corroborative. 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. Sebaceous adenomas first appear at the age of 4 to 5 years, with early individual brown, yellow, or red lesions of firm consistency in the nose and upper lip. These isolated lesions may later coalesce to form a characteristic butterfly pattern on the cheeks. Also known as hamartomas (tumor-like nodules of superfluous tissue), the skin lesions are present in 83% of individuals with tuberous sclerosis.

Delayed development is another characteristic during infancy, 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. 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. 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. Surgical excision of seizure-producing tumors has been successful in some cases.

Other associated impairments include retinal tumors and hemorrhages, glaucoma, and corneal opacities. 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.

Neurofibromatosis.

Three genetically distinct disorders that cause tumors to grow in the nervous system compose the neurofibromatosis group. There are three recognized forms of NFM: neurofibromatosis 1 (NFM1), neurofibromatosis 2 (NFM2), and schwannomatosis. This section focuses on NFM1 and NFM 2. Neurofibromas or connective tissue tumors of the nerve fiber fasciculus impede the development and growth of neural cell tissues ^, and are the hallmark feature of NFM1. Neurofibromas are noncancerous, and malignant changes are rare in children, but an increased risk of malignancy has been observed in adult patients with NFM1, and this is a major contributor to decreased average life expectancy, which is shortened by approximately 15 years. Tumors typically increase in number with the rising age. About half of all cases of NFM are caused by a sporadic mutation in parental germ cells or during fetal development. Schwannomas are the main tumor type of NFM2 and classically appear bilaterally on the vestibular nerves. ^, NFM1 is also known as von Recklinghausen disease. Compared with type II, type I is more common (one per 3000 births) and usually identified in younger children. It is associated with mutations in the NF1 gene, which produces a protein called neurofibromin, the complete function of which is not yet understood. However, it 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. Infants usually appear normal at birth, but initial café-au-lait spots appear by the age of 3 years in 95% of affected individuals ( Fig. 11.4 ). Cognitive impairment is the most common neurological complication of NFM1 and is postulated to be caused by altered expression of neurofibromin in the brain and/or by brain lesions, which appear hyperintense on MRI. 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. These lesions—commonly found in the basal ganglia, internal capsule, thalamus, cerebellum, and brain stem ^, —tend to disappear in adulthood and often do not cause other overt neurological symptoms. Fewer than 10% of these individuals are mentally retarded, but about 30% to 60% of affected children have mild and nonprogressive learning disabilities. ^, 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.

A 4-year-old boy with neurofibromatosis and the characteristic café-au-lait spots on his trunk.

In older children and adolescents, pain, itching, and stinging can occur from cutaneous neurofibromas. 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. One percent to 5% of children aged 0 to 6 years develop symptoms associated with optic pathway glioma. ^, Neurofibromatous vasculopathy interferes with arterial and venous circulation in the brain. ^{, ,} Hydrocephalus occurs in some individuals. ^, Hypertension is common and may develop at any age, and cardiovascular disease is a major cause of premature death. ^{, ,} Headaches are a commonly reported symptom in children, adolescents, and adults with neurofibromatosis. ^{, , ,}

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. 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. Differences in leg length have also been noted and may contribute to scoliosis. NFM2 occurs less frequently than NFMI (one in 25,000 to 40,000 births) and is caused by a mutation in the gene encoding the protein neurofibromin 2, also called Merlin . 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. Contrary to first descriptions of NFM1 and NFM2, café-au-lait spots are seldom a singular feature of NFM2 ; rather, signs and symptoms of tinnitus, hearing loss, and balance dysfunction usually appear during adolescence or in early 20s. ^, Problems with visual acuity caused by strabismus and refractive errors are common in young children. NFM2 may be underrecognized in children up to 10 years of age because early hearing loss and tinnitus are present in only 20% of cases; 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.

Cystic fibrosis.

CF is one of the most common autosomal recessive disorders and is more often seen in Caucasians, affecting one in 2000 to 4000. The CF gene has been mapped to chromosome 7 and its protein product, CF transmembrane regulator (CFTR). CFTR is involved in the regulation of chloride channels of the bowel and lung, which are 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. 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. Newborn screening tests for CF are required in all states in the United States.

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 are the basis for the sweat chloride test used in diagnosis. The most serious impairment in CF is obstruction of the lungs by thick mucus, which leads to chronic pulmonary obstruction, infections that destroys lung tissue, and eventual death from pulmonary disease in 90% of these individuals.

Improved survival rates in recent decades are the 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. Modern and less labor-intensive devices such as those that provide positive expiratory pressure (PEP device) may not be as effective at clearing secretions as conventional chest physiotherapy, but patient and caregiver compliance with a regular program may be improved. 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 prevent secondary impairments of adolescence and adulthood, such as stress incontinence in young women caused by excessive coughing, ^, chronic back pain, and osteopenia and osteoporosis. New gene therapy research in the United Kingdom to treat CF appears promising; however, application of its results has not been approved to date.

Massery describes the relationship between respiration, postural control, and secondary impairments in the musculoskeletal and neuromuscular systems that develop in individuals with CF. She addresses the threefold problems faced by such patients: (1) lung dysfunction leading to increased respiratory demand, (2) increased workload of respiration as a deforming force on the immature musculoskeletal 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 they 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.

Hurler syndrome (mucopolysaccharidosis I, severe type).

Hurler syndrome is an inborn error of metabolism that results in the abnormal storage of mucopolysaccharides in many different tissues of the body. The incidence is estimated to be 1 in 100,000 live births for the severe forms and 1 in 500,000 for milder forms. IDUA is the only gene currently known to be associated with this multisystemic disorder.

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

Characteristic physical features are caused by the storage of glycosaminoglycans (GAGs) 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. Some individuals with the physical characteristics of Hurler syndrome have normal intelligence, but most have progressive and profound intellectual disability.

Spastic paraparesis or paraplegia and ataxia have been observed in individuals with Hurler syndrome. 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. Defective ossification centers of the vertebral bodies result in spinal deformity, complications of nerve entrapment, atlanto-occipital instability, and restricted cervical range of motion. Conductive and sensorineural hearing loss is common. Delayed motor milestones have been noted as early as 10 months of age, with severe disabilities occurring with increasing age. Adaptive equipment is often needed, and most children with Hurler syndrome become wheelchair users in their later years.

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. 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. ^, If untreated, this metabolic error results in mental and growth retardation, seizures, and pigment deficiency of hair and skin. 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. It is estimated that one of every 50 individuals is heterozygous for PKU.

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. If PKU is untreated, the affected child may go on to develop hypertonicity (75%), hyperactive reflexes (66%), hyperkinesis (50%), or tremors (30%) in addition to intellectual disability. IQ levels generally fall between 10 and 50, although rare cases of untreated individuals with normal intelligence have been reported.

A simple blood plasma analysis, which is mandatory for newborn infants in all 50 US states, can detect the presence of elevated phenylalanine levels in nearly 100% of cases. 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. Follow-up management by an interdisciplinary team consisting of a nutritionist, psychologist, and appropriate medical personnel is advised in addition to special diet. Individuals with poor compliance with the recommended diet have a greater risk of osteopenia in adulthood.

Spinal muscle atrophy.

SMA (5q SMA) is characterized by progressive muscle weakness due to degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei. ^, Diagnosis of SMA is based on molecular genetic testing for deletion of the SMN1 gene (named for “survival of motor neuron 1”), located at 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. The overall disease incidence of SMA is 5 in 10,000 live births.

The clinical classifications of SMA are still evolving. ^{, ,} At present, four subtypes (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.

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

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

SMA type 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. Seventy percent of children diagnosed with SMA type II are alive at 25 years of age.

Children with SMA type II can usually sit independently if placed but cannot stand unsupported. Bulbar weakness with swallowing difficulties, poor weight gain, and diaphragmatic breathing are common. Finger trembling is almost always present. ^, Joint contractures are present in most individuals. Severe kyphoscoliosis that requires bracing and/or surgery often develops, but patients are at risk of postanesthesia complications. Respiratory failure is the major cause of morbidity and mortality. Nocturnal oxygen desaturation and hypoventilation occur before daytime hypercarbia and are early indications of the need for ventilator support.

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

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

Variants of SMA occur in individuals with similar phenotypes and clinical diagnostic features on EMG testing that are not associated with the deletion of SMN1. Genetic testing for SMN gene deletion achieves up to 95% sensitivity and nearly 100% specificity. 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. Traditional strength measurements are not practical for children with SMA. The Gross Motor Function Measure has excellent reliability on studies of gross motor evaluation in this population. ^, Consensus guidelines on pulmonary care, including assessment, monitoring, and treatment; feeding and swallowing and gastrointestinal dysfunction and nutrition; and orthopedic management have been published by the Standard of Care Committee for Spinal Muscle Atrophy. In 2004, at the University of Massachusetts Medical School, it was discovered that the drug nusinersen (Spinraza) could treat the symptoms of SMA by correcting SMN2 exon 7 splicing. Twelve years later, in December 2016, the drug was approved for patient use. Before 2016 there were no drugs to effectively treat the symptoms of SMA. ^, Studies of long-term treatment efficacy of the drug will be important, with a remaining concern regarding its affordability.

Hemophilia.

Hemophilia is a bleeding disorder caused by a deficient clotting process. Affected individuals will have hemorrhage in 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. 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.

Hemophilia A is reported to affect 1 in 4000 to 5000 males worldwide. Hemophilia B is less common, affecting 1 in 20,000 males worldwide. 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). The proportions of cases that are severe, moderate, and mild are about 50%, 10%, and 40%, respectively. 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 even after mild trauma. Bleeding from tongue or lip lacerations is often persistent.

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. Children are especially vulnerable to bleeding episodes owing to the nature of their physical activity combined with periods of rapid growth.

Treatment includes guarding against trauma and replacement with factor VIII derived from human plasma or recombinant techniques. 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 have almost completely eliminated the threat of infection. Although replacement therapy is effective in most cases, 30% of treated individuals with hemophilia A and 3% of those with hemophilia B have neutralizing antibodies that decrease its effectiveness. Before treatment with clotting factor concentrates was available, the average life expectancy was 11 years ; currently, excluding death from HIV, life expectancy for those with severe hemophilia who receive adequate treatment is 63 years. Factor replacement therapy is credited for increasing the ease and safety of vigorous exercise and sports participation for such individuals. The benefits of regular exercise are the same as those for unaffected individuals and outweigh the risks in treated persons. A 2002 pilot study by Tiktinsky and colleagues 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 1 in 4000 males and one in 8000 females. 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.

Developmental milestones are slightly delayed in affected males. 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. Penetrance (the proportion of individuals with a mutation that actually exhibit clinical symptoms) in the female is reported to be only 30%. Other impairments include epilepsy, emotional lability, attention-deficit/hyperactivity disorder (ADHD), and clinical autistic disorder in 30% of males. ^, Life-span is normal for individuals with this condition.

Lesch-nyhan syndrome.

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

The prevalence of LNS is 1 in 380,000 individuals. 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.

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

The prenatal and perinatal course is typical for affected individuals. Hypotonia and delayed motor skills are noticeable by the age of 3 to 6 months. Dystonia, choreoathetosis, and opisthotonus indicative of extrapyramidal involvement emerge during the first few years of life. Many children are initially diagnosed with athetoid cerebral palsy when pyramidal signs such as spasticity, hyperreflexia, and abnormal plantar reflexes emerge. 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 year. Because of the extreme self-mutilation that characterizes this disorder, it has been questioned whether these children have normal pain perception. Although they have the abnormal catecholamine metabolism seen in other patients with congenital pain insensitivity, 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 device even when the device may be one that would not physically prevent biting, such as a glove or bandaid. 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. 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. 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. Growth retardation is also apparent, along with moderate to severe intellectual disability. 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 the second or third decade of life.

Rett syndrome.

RS is inherited in an X-linked pattern and affects females almost exclusively, as it is most often lethal in boys before 2 years of age. Males may inherit RS with an extra X chromosome in many or all of the body’s cells. The estimated incidence is one in 15,000 to 20,000 females It has been reported that 99% of all cases of RS are the result of sporadic mutations. ^, 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. ^, Several variants of RS exist; they have overlapping features with classic RS but may have a much milder or more severe course.

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. ^, Most girls survive into adulthood. 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. 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. Retarded growth and muscle wasting are observed in most girls, likely associated with poor food intake and gastrointestinal problems.

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. Initially hypotonia may be evident, but with advancing age, spasticity of the extremities develops. 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.

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. ^, Heel cord tightening and hip instability have also been identified as areas of potential concern. 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, is also associated with RS. Interventions reported in the literature have focused on splinting, behavioral modification techniques to teach self-feeding skills, aquatic therapy, occupational therapy, music therapy, physical therapy, ^{, , ,} and the first two combined in a dual-intervention approach.