CHAPTER 15

In the office, primary pediatric health care professionals should observe a child’s physical manipulation of objects in the environment and expect to see much visual inspection, banging, mouthing, and throwing of objects between 4 and 10 months of age. During this time, infants begin to appreciate the association of “cause and effect,” wherein they recognize how their actions lead to a response in the environment. By 9 months of age, most infants will show mastery of this concept, realizing that they cause lights or sounds to occur when they activate a push-button toy, for example. Understanding cause and effect is a powerful first step for infants to realize the impact they can have in interacting with and causing change in their environment.

A major milestone during this sensorimotor phase of cognitive development is that of object permanence (Table 15.1). The understanding that an object exists even if one cannot see it is typically mastered by 9 months of age. Out of sight is not out of mind once object permanence is achieved, so a child will look for a toy that has been completely covered from view. Once object permanence has developed, an infant can retain a mental picture of a parent when the parent has left the room, so separation anxiety also emerges at about the same age. Mastery of object permanence can be observed during a child’s play or quickly elicited with a “peek-a-boo” game during a clinic visit.

One should be able to appreciate, either by observation or parent report, the development of a toddler’s ability to understand the functional use of objects. Knowing what the objects they encounter in the environment are used for is a cognitive milestone typically mastered by 12 to 15 months of age. A child of that age might put a hairbrush on her head, she may hold a phone to her ear, or she may hold a key to a doorknob. A child whose thinking skills have progressed to a developmental level of 18 months or more will begin to demonstrate representational play. In this phase of development, a child may put a hair brush to a baby doll’s head, pretending to brush its hair. Increased complexity comes at approximately the cognitive level of 2 to 3 years, wherein symbolic play emerges. Children are then capable of using objects to symbolize something else, so that they may place a stick to a baby doll’s hair, pretending it is a hairbrush. At this level of functioning, play can become more imaginary and pretend, with symbolic play allowing children to think beyond the objects in their immediate vicinity in order to develop their play themes. Although the ages of acquisition are not at all absolute, a child’s play can be a window into overall cognitive level, with the complexity providing some clues to a child’s overall thinking abilities.

Intellectual Disability

Intellectual disability (ID) is defined by impaired general mental abilities and adaptive skills, with these deficits causing a person functional impairment. With the American Psychiatric Association’s (APA) publication of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in May 2013, changes were made to the definition of ID.1 One notable change is the name of the disorder itself. Previous wording in medical literature and prior editions of the DSM used the term mental retardation; currently, intellectual disability is the generally accepted and preferred terminology. A subtitle term included in DSM-5 for this diagnosis is intellectual developmental disorder (IDD), to reference the fact that this is a diagnosis with symptoms presenting in the developmental period of life (not adulthood).

A second notable change with the DSM-5 was the specific definition of ID or mental retardation, which had been, for several decades, defined as an intelligence quotient (IQ) score that was 2 standard deviations (SDs) below the mean (IQ <70) combined with adaptive function that is 2 SDs below the mean. The DSM-5 definition puts relatively more emphasis on impairments in adaptive functioning instead of an IQ score in defining and diagnosing ID. An IQ score of 70 or below is still included in the supportive text for the ID definition in DSM-5, but it is no longer included as a primary diagnostic feature. Impairments in general mental abilities that begin during the developmental period are still symptoms of ID as described in DSM-5, but the diagnosis is based on the severity of the adaptive deficits.¹ Emphasis is placed not only on standardized assessment when making the diagnosis of ID, but also on clinical assessment. Interpretation of findings should be individualized within the context of a person’s sociocultural environment and accounting for other conditions that might better explain a poor performance on an IQ measure, such as sensory impairment or language disorder.

Measurements of IQ and adaptive function compare an individual’s performance or skill level to a same-aged sample from the general population. Population results therefore follow a “normal” or bell-shaped curve. Standard scores are based on a mean of 100 with a SD of 15. Most individuals (~95%) in a population will fall between a standard score of 70 and 130 (Figure 15.1). Adaptive function refers to how an individual functions in his or her environment and includes measures of socialization, communication motor skills, and activities of daily living, such as dressing and toileting. These adaptive functioning skills cluster into 3 main categories: conceptual, practical, and social. Skills included in the conceptual domain are those that tend to be more academic, such as reading, writing and math skills, but also include memory, language, problem-solving, and judgement in novel situations. The practical domain includes life skills, such as managing money, personal hygiene, occupational skills, and organizational skills. The social domain includes interpersonal communication skills, empathy, engagement in friendships, and social judgment. According to the APA, the level of severity of an ID diagnosis is defined by the level of impairment in adaptive functioning and the level of supports needed for day to day functioning.¹

The definition of ID published by the American Association on Intellectual and Developmental Disabilities (AAIDD) is similar to the APA’s. It is defined as a disability characterized by significant limitations in both intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills.2 AAIDD agrees that culture, language, communication, sensory, motor, and behavioral factors must be considered in an ID diagnosis. AAIDD also makes the point, however, that it is important to recognize that limitations often occur with strengths. Limitations are described in order to determine needed supports, and a person with intellectual disability can gain functional skills over time with appropriate support systems in place.^2,3

The diagnosis of ID is usually reserved for children 5 years of age or older due to the lack of good predictive validity for developmental and intelligence tests in younger children and the degree to which child development is changing in those early formative years. If a child younger than 5 years is failing to meet developmental milestones as expected, the APA defines this as global developmental delay (GDD).¹ This diagnostic category could also include children who are too young or older children who are otherwise unable to participate in standardized assessments of intellectual functioning. Repeated attempts at accurate standardized assessment over time is appropriate for children diagnosed with GDD to document improvements or ultimately to make a diagnosis of ID when appropriate.

Figure 15.1. Bell curve. From Carey WB, Crocker AC, Coleman WL, Elias ER, Feldman HM, eds. Developmental & Behavioral Pediatrics. Philadelphia, PA: Elsevier; 2009:764, with permission from Elsevier.

The medical evaluation of children with ID and GDD should include a careful history, including a 3-generation family history and a thorough physical examination, including head circumference, a dysmorphology exam, a neurological exam, and a skin exam for neurocutaneous stigmata4 (Table 15.2, Figure 15.2). A medical genetics evaluation should be offered to all families of an individual with ID or GDD. A specific diagnosis facilitates development of expectations for the future, access to family support organizations specific to the condition, education of primary pediatric health care professionals to monitor for potential associated medical and psychiatric comorbidities, education of families about potential research trials for targeted treatments, and genetic counseling in regard to risk of recurrence in future pregnancies. The diagnosis also often relieves parental anxiety about what they may have previously believed to have caused their child’s cognitive disability.

With permission from Moeschler JB, Shevell M; American Academy of Pediatrics Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014;134:e903–e918.

A parent or family’s “need to know” may vary greatly. Decisions about etiological evaluation should include shared decision-making. While the specific genetic workup to consider in individuals with ID/GDD is rapidly evolving, current expert consensus suggests that the initial diagnostic work up should include fragile X molecular genetic testing and chromosomal microarray analysis (CMA), with consideration of a karyotype if there is a family history of multiple miscarriages, or fluorescence in situ hybridization (FISH) (testing if a specific etiology, such as Williams syndrome (WS), is suspected.^4,5 In the past, the ability to identify the etiology of ID in an individual increased when there were greater than 3 dysmorphic features or if the level of functioning was lower.⁶ With the advent of new technology, such as whole-exome and whole-genome sequencing, the etiological yield in the future is likely to increase.

However, there are concerns regarding interpretation, cost, a potential to find a mutation with future clinical significance that is unrelated to ID or GDD, and the potential to miss epigenetic changes with these technologies. Currently, a CMA will be positive in about 6% of children with ID or GDD. This rate goes to 10% if the child has dysmorphic features. Fragile X DNA testing will be positive in about 2% to 3% of individuals with ID or GDD. A drawback to CMA is finding a copy number variation of unknown clinical relevance. A medical geneticist or certified genetic counselor should interpret abnormal values.⁴ If the initial workup is negative, testing for nonsyndromic X-linked ID genes and high-density X-CMA in males and MECP2 deletion, duplication, and sequencing in females should be considered. When microcephaly, macrocephaly, seizures, developmental regression, or neurological signs are present, magnetic resonance imaging (MRI) of the brain should be considered. A formal audiology evaluation is also indicated if the child has not had a hearing evaluation since birth. Ophthalmological examination and EEG should also be considered. Clinicians should also screen for medical conditions that frequently co-occur in children with ID, such as sleep problems, feeding problems, obesity, gastrointestinal disorders, and behavioral and psychiatric conditions.⁴

Adapted with permission from Moeschler JB, Shevell M, American Academy of Pediatrics Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134:e903–e918.

Metabolic testing for inborn errors of metabolism (IEM) is rarely positive in children with ID or GDD (0% to 5%), especially in the absence of “metabolic” symptoms, such as abnormal tone, ataxia, seizures, developmental regression or plateauing, failure to thrive, organomegaly, coarse facial features, abnormalities of skin or hair, or signs of hypothyroidism. Newborn screening typically identifies many children with treatable medical conditions; however, there are many treatable conditions that are not currently part of newborn screening, and the specific tests included in newborn screening vary from state to state. Controversy exists about the cost-benefit ratio of testing for rare metabolic disorders. A tiered approach to etiological workup is suggested.4,7 Van Karnebeek et al, based on a review of the available literature in 2013 and expert consensus, proposed a 2-tiered approach to testing for IEM. They discuss 89 treatable types of IEM. This tiered approach is primarily based on “availability, affordability, yield, and invasiveness.” Tier 1 tests, or nontargeted screening tests, include (1) blood tests for lactate, ammonia, plasma amino acids, total homocysteine, acylcarnitine profile, copper, and ceruloplasmin; and (2) urine tests for organic acids, purines and pyrimidines, creatine metabolism, oligosaccharides, and glycosaminoglycans (Figure 15.3). Other tests to consider are 7- and 8- dehydrocholesterol to screen for Smith-Lemli-Opitz syndrome and screening for congenital disorders of glycosylation. Some of these tests may be difficult to find outside of an academic center. Tests requiring cerebrospinal fluid (CSF) samples, or single tests per disease, are in the second tier, but these may be used in the first tier if clinically indicated.^4,7 First-tier tests recommended in the American Academy of Pediatrics (AAP) guidelines for the comprehensive evaluation of the child with ID or global developmental delays include (1) blood tests for plasma amino acids, total homocysteine, and acylcarnitine profile; and (2) urine tests for organic acids, purines and pyrimidines, creatine metabolism, oligosaccharides, and mucopolysaccharides.⁴

An app is available to help guide clinicians in the management of children with treatable causes of ID or GDD. The app is available at www.treatable-id.org. This app is free and accepted by members of the “rare disease community.”⁷ Potential treatments that may improve symptoms or slow progression of IEMs include appropriate management during illness or fasting, dietary interventions, cofactor supplements, vitamin supplements, substrate inhibition, stem cell transplants, and gene therapy.7 The evidence to support these treatments is variable and often relies on expert opinion due to low numbers of subjects and the progressive nature of the disorders. Many treatable IEMs may present later or without developmental regression or plateauing in children with ID/GDD. Disorders such as ornithine carbamoyltransferase deficiency, which is X-linked, may also present with milder symptoms in females.⁷ Finally, lead screening should be considered, especially in children with pica or who routinely mouth objects.

Figure 15.3. Two-tiered algorithm for diagnosis of treatable inborn errors of metabolism in intellectual developmental disorder. The first tier testing comprises group metabolic tests in urine and blood that should be performed in every patient with IDD of unknown cause. Based on the differential diagnosis generated by the patient’s signs and symptoms, the second tier test is ordered individually at a low threshold.

Adapted with permission from van Karnebeek CD, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab. 2014;111(4):428–438.

If no etiology is found after completing first- and second-tier genetic testing, metabolic screening, imaging, and neurophysiological testing (when indicated), additional testing such as MECP2 mutations in males and Rett/Angelman phenotype panels in males and females may be considered on the recommendation of a geneticist. In addition, due to the considerable progress being made with technology, consideration of newer methodologies, such as whole exome sequencing and multiplex ligation assay, should also be considered. Routine follow-up is suggested due to changes in technology, possible emergence of phenotypic features as the child grows, and ongoing research into the development of targeted treatments for some genetic disorders.4

Specific Etiologies of Intellectual Disability

In the following sections, the medical, developmental, and behavioral features of the most common genetic (Down syndrome), inherited (fragile X syndrome), and preventable (fetal alcohol spectrum disorders [FASDs]) etiologies of ID will be described. Other genetic disorders with characteristic behavioral phenotypes will then be discussed. Many of these are detected by specific FISH probes or by CMA, which is capable of detecting small deletions or duplications of genetic material.

– Down Syndrome/Trisomy 21

Down syndrome/trisomy 21 is the most common genetic cause of ID, occurring in 1 in 600 births. The incidence increases with maternal age. It is caused by an extra copy of chromosome 21. The physical phenotype is well recognized and includes hypotonia, microbrachycephaly, epicanthal folds, up-slanting palpebral fissures, Brushfield spots in the iris, flat nasal bridge, small mouth, small ears, excess skin at the nape of the neck, single transverse palmar creases, short incurving fifth fingers (clinodactyly), and a widened “sandal gap” between the first and second toes (Figure 15.4). Medical conditions, such as congenital heart disease, hearing and vision problems, hypothyroidism, obstructive sleep apnea, celiac disease, and hematologic problems, are commonly associated with Down syndrome, and patients should be monitored for these potential medical comorbidities⁸ (Table 15.3). Reactive airway disease may also be more frequent in children with Down syndrome⁹, and overweight and obesity are common, with rates up to 70%.¹⁰ Use of growth charts specific for children with Down syndrome are no longer recommended.⁸

Figure 15.4. Down syndrome. A 6-month-old with Down syndrome with up-slanting palpebral fissures, epicanthal folds, and protrusion of the tongue.

From Marion RW. Facial dysmorphism. In: McInerny TK, Adam HM, Campbell DE, Kamat DM, Kelleher JS, eds. American Academy of Pediatrics Textbook of Pediatric Care. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

The AAP has published “Health Supervision for Children With Down Syndrome” (Table 15.4).⁸ This policy statement provides essential information for management of individuals with Down syndrome. It is important for primary pediatric health care professionals and families to know that there is a broad range of cognitive and behavioral outcomes for children with Down syndrome, although a majority will have ID in a mild-to-moderate range. Children with Down syndrome classically tend to have fewer severe behavioral problems compared with other children with similar levels of ID, although approximately 10% will meet criteria for an autism spectrum disorder (ASD). Individuals with Down syndrome have an increased risk for depression and Alzheimer disease as they age.¹¹

– Fragile X Syndrome

The most common inherited cause of ID is fragile X syndrome. Fragile X syndrome is caused by a trinucleotide repeat expansion (CGG) within the fragile X mental retardation 1 (FMR1) gene.12 The FMR1 gene typically includes about 30 repeats. If the repeat size expands to 200 or more repeats, the gene will become methylated and silenced. This will result in a deficiency of FMR1 protein and the classic fragile X syndrome phenotype.¹³ The FMR1 protein is an RNA-binding protein that is found in most cells in the body.¹⁴ One role of FMR1 is to regulate metabotropic glutamate receptor 5 (mGluR5). Individuals who carry the premutation have 54 to 200 repeats.¹² Previously, individuals with the premutation were thought to be unaffected; however, there is mounting evidence for a specific phenotype in these individuals. Women with the premutation have a higher incidence of premature ovarian failure.¹⁵ Males with the premutation are at high risk for developing the fragile X–associated tremor/ataxia syndrome (FXTAS). FXTAS is a progressive neurodegenerative disorder that typically develops in male premutation carriers older than 50 years of age.¹⁶ Individuals with the premutation have normal levels of FMR1 protein but increased levels of messenger RNA.^17,18 Approximately 1 in 250 women and 1 in 800 to 1,000 men within the general population are premutation carriers.^19,20 The repeat number usually expands when passed from a woman with the premutation to her offspring but not when a man with the permutation passes the premutation to his daughters.

The presentation of the full mutation (>200 repeats) varies between males and females because females have 2 copies of the X chromosome and experience random X inactivation. The portions of the X chromosome that are not present on the Y chromosome are randomly inactivated in each cell. The phenotype in females will thus depend at least in part on the pattern of X inactivation.^21,22 If the pattern of inactivation is skewed in one direction or the other, the female may be minimally affected or more significantly affected. In general, females are more likely to be more mildly affected than males.²² Most males will present with ID in the mild-to-severe range.

The physical phenotype of fragile X syndrome in males is apparent prior to puberty but becomes more prominent after puberty. The phenotype includes macroorchidism, protuberant ears, a long, thin face, and a prominent jaw and forehead. Medical conditions frequently associated with fragile X syndrome include seizures, strabismus, otitis media, gastroesophageal reflux, mitral valve prolapse, and hip dislocation. The behavioral phenotype may include attention-deficit/hyperactivity disorder (ADHD), anxiety, sleep disturbance, perseverative language, hand flapping, gaze aversion, autism, and significant hypersensitivity to environmental stimuli.²³ Because the physical characteristics may not be present in young children, and because this is a relatively common disorder with a recurrence risk of 50%, specific DNA testing for fragile X syndrome is indicated in all children presenting with cognitive delays of unknown etiology.

Clinical guidelines have been established for health supervision in children with fragile X syndrome,24 and treatment of children with fragile X syndrome has been reviewed.²⁵ Clinical trials are also being conducted to evaluate “targeted treatments” for fragile X syndrome, such as metabotropic glutamate receptor antagonists.²⁶ Genetic counseling is warranted in a family with a child with fragile X syndrome because of the 50% recurrence risk and implications for other family members. For example, a child with fragile X syndrome’s mother and maternal grandfather may be at risk for issues associated with the premutation, such as FXTAS or premature ovarian failure. Families should also be informed about support groups.

– Fetal Alcohol Spectrum Disorders

FASDs are the most common preventable causes of ID and associated neurodevelopmental/neurobehavioral dysfunction in children. The FASDs include a broad range of outcomes that can be seen in individuals exposed to alcohol in utero. FASDs occur in about 1% to 5% of children.^27,28 There are several diagnostic schemas available. These include the updated clinical consensus guidelines for FASD developed by Hoyme et al and published in 2016.²⁹ The updated Hoyme guidelines clarify definitions for prenatal alcohol exposure and neurobehavioral dysfunction and update the definition of alcohol-related birth defects, the dysmorphology rating system, and the lip/philtrum guide for the North American white population. Despite the definition of prenatal alcohol exposure during pregnancy proposed by Hoyme et al, the AAP stipulates that no amount of alcohol during pregnancy is considered safe.³⁰ The Hoyme guidelines were intended to increase sensitivity to identify children with FASD by increasing head circumference, growth, and palpebral fissure percentile cutoffs from <3% to ≤10%.²⁹ The Hoyme guidelines also suggest that the diagnosis be made by a multidisciplinary team. Other diagnostic schemas for FASD include the Canadian guidelines for diagnosis,³¹ National Task Force on Fetal Alcohol Syndrome and Fetal Alcohol Effects (2004),³² and the FASD 4-digit diagnostic code.³³ The AAP also published a clinical report on FASD in 2015.³⁰

Prior to diagnosing an FASD, other disorders with similar developmental and dysmorphic features that should be considered and/or ruled out include Cornelia de Lange, Williams, 22q11.2 deletion, 15q duplication, Noonan, and Dubowitz syndromes, as well as exposures to teratogens such as valproic acid and toluene. The dysmorphology rating system was designed to help determine the need to explore other diagnoses.²⁹

Fetal Alcohol Syndrome

Fetal alcohol syndrome (FAS) refers to a full syndrome associated with prenatal alcohol exposure. The diagnosis can be made with or without confirmed maternal use of alcohol. The FAS diagnosis is made if all 4 of the following criteria are met: (1) at least 2 of 3 facial anomalies, including short palpebral fissures (≤10th percentile), thin upper lip, and smooth philtrum (the lip/philtrum guide is available for some races/ ethnicities. [see Figures 15.5, 15.6]); (2) poor prenatal or postnatal growth (height or weight ≤10th percentile); (3) at least 1 structural or functional brain abnormality, such as poor brain growth (head circumference ≤10th percentile), morphogenesis, or neurophysiology (recurrent nonfebrile seizures with no other known etiology); and (4) neurobehavioral impairment.29

Figure 15.5. (left) With permission from Hoyme HE, Kalberg WO, Elliott AJ, et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics. 2016;138(2):e20154256. (right) University of Washington Lip-Philtrum Guide 2 is used to rank upper lip thinness and philtrum smoothness for all other races with lips as full as African Americans. The philtrum is the vertical groove between the nose and upper lip. Guide 2 reflects the full range of lip thickness and philtrum depth with Rank 3 representing the population mean for African Americans. Ranks 4 and 5 reflect the thin lip and smooth philtrum that characterize the FAS facial phenotype. A separate Guide (Guide 1) is used for Caucasians and all other races with lips like Caucasians. Free digital images of these guides for use on smartphones and tablets can be obtained from astley@uw.edu. Copyright 2017, Susan Astley, PhD, University of Washington. Legend (for right figure) provided by Susan Astley, PhD.

Partial Fetal Alcohol Syndrome

A diagnosis of partial FAS (pFAS) can also be made with or without a confirmed history of maternal alcohol use. If there is adequate documentation of prenatal alcohol exposure, then the child must have at least 2 facial anomalies as described earlier for FAS and neurobehavioral impairment. If there is not adequate documentation of prenatal alcohol exposure, the child must have at least 2 characteristic facial anomalies, a growth deficiency or brain abnormality, and neurobehavioral impairment.29

Figure 15.6. Child presenting with the 3 diagnostic facial features of FAS: (1) short palpebral fissure lengths (distance from A to B), (2) smooth philtrum; and (3) thin upper lip. Copyright 2017, Susan Astley, PhD, University of Washington. Legend provided by Susan Astley, PhD.

Alcohol-Related Neurodevelopmental Disorder

A diagnosis of alcohol-related neurodevelopmental disorder (ARND) requires confirmation of prenatal alcohol exposure and neurobehavioral impairment. This diagnosis cannot be made until after 3 years of age.²⁹

Neurobehavioral Disorder with Prenatal Alcohol Exposure

A diagnosis of neurobehavioral disorder with prenatal alcohol exposure (ND-PAE) requires confirmation of prenatal alcohol exposure and neurobehavioral impairment in neurocognition, self-regulation, and adaptive functioning. This is a newly proposed mental health diagnosis intended to capture the behavioral and mental health effects of in utero exposure to alcohol in those with and without physical dysmorphia. Because of its relatively recent creation, the DSM-5 added ND-PAE as a diagnosis with the caveat that more study was needed.¹

Alcohol-Related Birth Defects

The diagnosis of alcohol-related birth defects requires confirmation of prenatal alcohol exposure and at least one major congenital malformation that has been associated with prenatal alcohol exposure in humans or animal models, such as malformations or dysplasias in cardiac, skeletal, renal, ocular, or auditory areas (eg, sensorineural hearing loss).²⁹

Individuals with an FASD may have significant difficulty with complex cognitive tasks and executive function (planning, conceptual set shifting, affective set shifting, response inhibition, and fluency). Some individuals with an FASD process information slowly and have difficulty with attention and short-term memory. Some individuals with FASDs do well with simple tasks but are challenged by more complex ones. Individuals with FASDs are also at risk for social difficulties and mood disorders.³⁴ People with an FASD are more vulnerable to being involved with the criminal justice system.³⁵

For children with an FASD, functional classroom assessments can be a very helpful supplement to psychoeducational evaluations. Methods that have been found to be helpful for individuals with FASD are visual structure (color code each content area), environmental structure (keep work area uncluttered, avoid decorations), and task structure (clear beginning, middle, and end). Cognitive control therapy is an intervention that has shown promising results for children with FASD.36 A review of current evidence for interventions was published in 2017.³⁷ Primary pediatric health care professionals have a critical role in the prevention of FASD through education of families and adolescents.³⁸

– Prader-Willi Syndrome

Prader-Willi syndrome is caused by a microdeletion on chromosome 15q11.2-q13 in an area that is imprinted. Imprinting refers to a gene being turned on or off depending on the parent of origin. The Prader-Willi/Angelman critical region was the first region of the human genome described to be affected by imprinting. A deletion in the same area gives a completely different phenotype (either Prader-Willi or Angelman syndrome) depending on the parent of origin. In 75% of children with Prader-Willi syndrome, the symptoms are caused by a deletion on the paternal chromosome; in 20% there are 2 copies of the maternal chromosome and no copy of the paternal chromosome 15 (uniparental disomy). In 5% there is a translocation or other structural anomaly of chromosome 15, and in 1% there is a problem with the imprinting center.³⁹ As with Angelman syndrome, there is some variation in the phenotype with different mechanisms.

Infants with Prader-Willi syndrome initially have failure to thrive and hypotonia. By age 2 years, the children begin to develop obesity and significant hyperphagia. They have hypogonadism and short stature. Consultation with an endocrinologist is indicated to consider the use of growth hormone, which has been found to have a positive impact on growth, muscle, bone mass, cognitive development, and metabolic parameters.⁴⁰ Sex hormone replacement is also sometimes recommended. Physical characteristics of children with Prader-Willi syndrome include almond-shaped eyes, a thin upper lip, and some may have hypopigmented skin, hair, and eyes (Figure 15.7).^39,41 Mean IQ scores of individuals with Prader-Willi have been reported in the mild range of ID (average IQ = 65), but cognitive abilities may extend from a low average range to the range of moderate ID.^41,42 They often have executive functioning deficits and impaired social cognition. They struggle specifically with Theory of Mind, which includes difficulty understanding the behavior and mental states of others and taking other’s perspective. Over 25% meet diagnostic criteria for ASD.42,43 Individuals with Prader-Willi syndrome often have obsessive-compulsive behaviors, including hyperphagia and skin picking. They can also have psychosis, a high pain tolerance, and disordered sleep.^39,41

Figure 15.7. Prader-Willi syndrome. A 3-month-old female who has Prader-Willi syndrome (left). Note the almond-shaped eyes and down-turned mouth. The same patient at approximately 3 years of age (right).

Reproduced with permission from Jonas JM, Demmer LA. Genetic syndromes determined by alterations in genomic imprinting pathways. NeoReviews. 2007;8(3);e120–e126.

– Angelman Syndrome

Angelman syndrome is also associated with the imprinted 15q11.2-q13 region on chromosome 15. There are 4 known mechanisms that lead to the Angelman syndrome phenotype: (1) a deletion at 15q11.2-q13 on the maternal chromosome; (2) paternal uniparental disomy, which means that the individual has 2 copies of the paternal chromosome 15 instead of one from each parent; (3) imprinting defects; and (4) mutations in the ubiquitin-protein ligase E3A gene (UBE3A). ⁴⁴ The phenotype can vary depending on the genotype, and individuals with the deletion tend to have the most severe phenotype. Angelman syndrome is characterized by 4 routinely present features: (1) severe cognitive impairment, (2) expressive language more impaired than receptive language, (3) movement and gait disorders, and (4) a happy demeanor/frequent laughter (Figure 15.8, Box 15.1). Features that are present in greater than 80% of individuals with Angelman syndrome are small head, seizures, and characteristic electroencephalogram (EEG) abnormalities⁴⁵ (Figure 15.8, Box 15.1).

Figure 15.8. Angelman syndrome. A female child with Angelman syndrome. Reproduced with permission from Jonas JM, Demmer LA. Genetic syndromes determined by alterations in genomic imprinting pathways. NeoReviews. 2007;8(3):e120–e126.

Box 15.1. Clinical Features of Angelman Syndrome^a

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