Genetic disorders: A pediatric perspective

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Genetic disorders: A pediatric perspective


Genetic disorders in children can result in a wide variety of movement impairments and disabilities. The resultant impact of certain genetic conditions on the child may be evident before or immediately after birth, whereas other conditions may not be diagnosed until later in life when problems manifest. In this chapter we discuss disorders of known genetic origin that physical and occupational therapists are most likely to encounter in therapy programs for children.

The Human Genome Project, completed in 2003,1 expanded knowledge about the genetic basis for disease and congenital malformations. The impact of this project is just being realized, with new research into diagnostic techniques and treatment options for genetic disorders. Pediatric health care professionals will be faced with questions from families who, in seeking diagnostic and prognostic information, are accessing the wealth of information both in the lay scientific press and on the World Wide Web (Box 13-1 and Table 13-1).



World wide web

1. Understanding Genetics

2. Human Genome Project Information

3. Genetics Fact Sheets, Centre for Genetics Education

4. Genetics Home Reference, National Library of Medicine (Bethesda, Md), 1993-2008

5. Family Village

6. Making Sense of Your Genes: A Guide to Genetic Counseling

7. American College of Medical Genetics

8. Genetics and Public Policy Center

9. National Newborn Screening and Genetics Resource Center

TABLE 13-1 image


AbleData Information about assistive technology (AT) products and rehabilitation equipment
AccessIT National Center on Accessible Information Technology in Education
Alliance for Technology Access Public education, information, referral; network of technology resources
Assistive Technology Industry Association Information on products and services
Assistive Technology Partners Information to assist persons with cognitive, sensory, and/or physical disabilities
Assistive Technology Training Online Project AT applications that help students with disabilities learn in elementary classrooms
Family Center on Technology and Disability Provides guide to AT and transition planning
National Public Website on Assistive Technology Features products by related functional area or disability, by activity, and by vendor
Protection and Advocacy for Assistive Technology Program _overview.htm Provides protection and advocacy services to help individuals with disabilities of all ages acquire, use, and maintain AT services or devices; website identifies each state’s program Information on AT products by categories
National Institute of Standards and Technology ( Authoritative information and guidance on measurement and standards for all industry sectors

An accurate diagnosis of a specific genetic disorder (syndrome or disease) is necessary for a prognosis to be provided, for eligibility for therapy and education services to be determined, and as a basis for genetic counseling for the child’s family.2 The diagnostic process for genetic disorders includes a combination of clinical assessments by the physician who collects the child’s medical history and a clinical geneticist who may construct a family history or “pedigree” to recognize disorders with familiar inheritance patterns. Molecular studies may confirm a clinical diagnosis, differentiate between diagnoses with similar clinical presentation, and identify the genetic cause of the disorder. Some genetic disorders are not easily identified, and laboratory testing can be extensive, prolonged, and often inconclusive; therefore pediatricians may refer children to occupational and physical therapy before the nature of their condition is fully known.2,3 Although sometimes far removed from the hospitals and specialized centers that perform genetic testing and diagnosis, the pediatric therapist is often able to contribute clinical evidence that will assist the diagnostic process.46 Furthermore, many genetic diseases and syndromes are increasingly survivable into adulthood; thus it is vital that physical and occupational therapists achieve competence in genetics and genomics in order to deliver care throughout the patient’s life span.6,7 An overview of the general categories and subtypes of genetic disorders is presented first. Specific examples of each type are given, along with a brief description of key diagnostic features and issues commonly addressed with medical and therapeutic intervention. A summary of impairments common to many pediatric genetic disorders is presented in the second section. The third section includes a discussion of the medical management of genetic disorders, genetic counseling, and the ethical implications of genetic screening and testing. The final section focuses on the physical or occupational therapist’s role in the clinical management of children with genetic disorders. The therapist’s role and responsibilities in developing competence in recognition, referral, and clinical practice when working with patients and families affected by a genetic disorder are discussed. Evaluation procedures, treatment goals and objectives, and general treatment principles and strategies are discussed from a family-centered perspective. A list of educational resources for clinicians and families is provided.

An overview: clinical diagnosis and types of genetic disorders with representative clinical examples

Genetic disorders are typically divided into four categories: chromosomal, single-gene, mitochondrial, and multi-factorial. Chromosomal disorders arise when there is an alteration in either the number or structure of chromosomes that exist in either autosomal or sex (X, Y) chromosomes.8 Numerical or large structural chromosomal abnormalities can be seen through a microscope; therefore a sample of the patient’s peripheral blood can be used in detection of disorders such as Down syndrome. When there is a suspicion of a clinical spectrum associated with some of the known chromosomal microdeletions, translocations, or inversions, direct deoxyribonucleic acid (DNA) analysis techniques such as fluorescence in situ hybridization (FISH) with use of specific sequence DNA probes can confirm a specific suspected diagnosis. Indirect DNA analysis techniques such as linkage analysis can be performed to confirm single-gene disorders when the gene or genomic region associated with the disorder is unknown.9

Of our 20,000 to 25,000 protein-coding genes,1 a single gene may be responsible for approximately 6000 known genetic traits. Approximately 4000 of these known traits are diseases or disorders.10 Single-gene disorders may be transmitted through three different patterns: autosomal dominant, autosomal recessive, and sex linked. Dominant refers to the case in which a mutated gene from one parent is sufficient to produce the disorder in offspring. Recessive refers to the case in which the disorder will not be expressed unless offspring inherited a mutated copy of that gene from both parents. It is incorrect to say that a gene is recessive or dominant; rather the trait, or disorder, is dominant or recessive.7

Inheritance is usually a term reserved for the transmission of a previously recognized family trait to subsequent offspring. However, many genetic disorders arise from new, spontaneous mutations in a gamete, the single egg cell from the mother or a sperm cell from the father. The remainder of the gametes from either parent are most likely normal. In this case their offspring will be the first in the family to display the sporadic disorder, and the faulty gene can then be passed onto subsequent generations. A disorder that results from a single copy of a mutated gene is referred to as a dominant disorder, even if it is acquired by a spontaneous mutation. Not all literature sources will include spontaneous mutations in the description of inherited disorders.

It is important to understand how a disorder was acquired, because the relative risks to other offspring for the disorder vary according to mode of transmission. For example, the risk of having another child with the same genetic disorder that occurred as a result of a spontaneous mutation is low. However, when one parent is affected by an inherited dominant mutation, the risk of passing that faulty gene onto each child is 50%.8

Most congenital malformations and many serious diseases that have an onset in childhood or adulthood are not caused by single genes or chromosomal defects; these are called multifactorial disorders.7,8

Mitochondrial disorders are caused by alterations in maternally inherited cytoplasmic mitochondrial DNA (mtDNA). The clinical manifestations of mtDNA-related disorders are extremely variable,11 and the occurrence is reportedly rare (5.0 per 100,000)8,12; however, collectively as a group of neuromuscular disorders, they account for substantial use of health care resources.12

Currently there are over 1000 genetic tests available in the United States.1 Specific DNA testing may soon be able to identify nearly all human genetic disorders. This not only allows for accurate and more complete diagnosis but should pave the way for the development of mechanisms for treatment, cure, and prevention of certain genetic conditions.4,5,8,9 Table 13-2 lists examples of specific disorders in categories of the most common pattern of inheritance by which each occurs.

TABLE 13-2 image


Autosomal Trisomy
Trisomy 21 1:740
Trisomy 18 1:5000
Trisomy 13 1:16,000
Sex Chromosome Aneuploidy
Turner syndrome 1:2500 females
Klinefelter syndrome 1:500-1000 males
Partial Deletion
Prader-Willi syndrome 1:10,000-30,000
Angelman Syndrome 1:12,000-20,000
Cri-du-chat syndrome 1:20,000-50,000
Autosomal Dominant
Neurofibromatosis type 1 1:3500
Tuberous sclerosis 1:5800
Osteogenesis imperfecta 6-7:100,000
Autosomal Recessive
Cystic fibrosis 1:2500-3500 Caucasians (highest ethnic incidence)
Spinal muscle atrophy 1:6000-10,000
Phenylketonuria 1:10,000-15,000
Hurler syndrome 1:100,000
Duchenne muscular dystrophy 1:3500
Fragile X syndrome 1:4000 males, 1:8000 females
Hemophilia A 1:4000-5000 males
Rett syndrome 1:10,000-22,000 females
Cleft lip with or without cleft palate 1:1000
Clubfoot (talipes equinovarus) 1:1000
Spina bifida 7:10,000
Mitochondrial myopathy Rare
Kearns-Sayre disease Rare


Chromosomal disorders

Cytogenics is the study of chromosomal abnormalities. A karyotype is prepared that displays the 46 chromosomes—22 pairs of autosomes arranged according to length, and then the two sex chromosomes that determine male or female sex. Modern methods of staining karyotypes enable analysis of the various numerical and structural abnormalities that can occur. Most chromosomal abnormalities appear as numerical abnormalities (aneuploidy) such as one missing chromosome (monosomy) or an additional chromosome, as in trisomy 21 (Down syndrome).8 Structural abnormalities occur in many forms. They include a missing or “extra portion” of a chromosome or a translocation error, which is an interchange of genetic material between nonhomologous chromosomes. The incidence of chromosomal abnormalities among spontaneously aborted fetuses may be as high as 60%.8,13 About one in 150 live-born infants have a detectable chromosomal abnormality; and in about half of these cases the chromosomal abnormality is accompanied by congenital anomalies, intellectual disability, or phenotypical changes that manifest later in life.8 Of the fetuses with abnormal chromosomes that survive to term, about half have sex chromosome abnormalities and the other half have autosomal trisomies.8

The following section provides a brief overview of common genetic disorders seen by physical and occupational therapists working with children.

Autosomal trisomies

Trisomy is the condition of a single extranuclear chromosome. Trisomies occur frequently among live births, usually as a result of the failure of the parental chromosomes to disjoin normally during meiosis. Trisomy can occur in autosomal or sex cells. Trisomies 21, 18, and 13 are the most frequently occurring trisomies; however, few children with trisomy 18 and 13 survive beyond 1 year of age.1

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 children21,22 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,2628 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 syndrome30,31 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 life42,43; 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

Sex chromosome aneuploidy

The human X chromosome is large, containing approximately 5% of a human’s nuclear DNA. The Y chromosome, much smaller, contains few known genes.8 Females, with genotype XX, are mosaic for the X chromosome, meaning that one copy of their X chromosome is inactive in a given cell; some cell types will have a paternally derived active chromosome, and others a maternally derived X chromosome. Males, genotype XY, have only one copy of the X chromosome; therefore diseases caused by genes on the X chromosome, called X-linked diseases (see section on sex-linked disorders), can be devastating to males and less severe in females.8 In the presence of abnormal numbers of sex chromosomes, neither male nor female individuals will be phenotypically normal.8 Two of the most prevalent sex chromosome anomalies are Turner syndrome and Klinefelter syndrome.

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 sensitivity61,62 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.6870

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

Partial deletion disorders

Deletions are one example of mutations that cause changes in the sequence of DNA in human cells. A sequence change that affects a gene’s function can cause the final protein product to be altered or not produced at all.

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

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