Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15q11-q13 locus: Prader-Willi syndrome, Angelman syndrome, and 15q11-q13 duplication syndrome. Each of these disorders results from the loss of function or overexpression of at least 1 imprinted gene. This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders.
Key points
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Three distinct neurodevelopmental disorders are caused by copy number variation at human chromosome 15q11-q13: Prader-Willi syndrome (PWS), Angelman syndrome (AS), and 15q11-q13 duplication syndrome (Dup 15q syndrome).
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PWS and AS can also be caused by uniparental disomy, microdeletions and/or single gene mutations, and imprinting defects. An organized diagnostic strategy is required to confirm or fully exclude the diagnosis.
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PWS is characterized by infantile hypotonia and failure to thrive followed by obesity, hyperphagia, small stature, and behavioral issues. Early growth hormone (GH) treatment improves body habitus and stature.
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AS is characterized by severe intellectual disability, absent speech, epilepsy, and characteristic happy affect. This syndrome is caused by the loss of function of the maternal UBE3A gene.
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The Dup 15q syndrome is characterized by developmental delay, epilepsy, and autism. Duplications that lead to this syndrome are almost always of maternal origin.
Introduction
The 15q11-q13 region harbors several genes regulated by genomic imprinting, a phenomenon in which genes are expressed preferentially from 1 parental allele. As a result, genes subject to regulation by genomic imprinting are functionally haploid, having only a single functional copy. Three distinct neurodevelopmental disorders arise primarily from deletions or duplications at the 15q11-q13 locus: PWS, AS, and Dup15q syndrome. Each of these disorders results from the loss of function or overexpression of at least 1 imprinted gene. Each of them occur with a frequency of approximately 1/15,000 to 1/30,000 live births.
The deletions and duplications of chromosome 15q11-q13 that cause PWS, AS, or Dup15q syndrome are mediated by local DNA repeats that occur at the common breakpoints. There are 5 such elements, which are composed of breakpoints 1 through 5 (BP1–BP5). Deletions involving either BP1 or BP2 and BP3 are most common, while the duplications are more complicated, but can frequently involve BPs 4 and 5 and are discussed below. A map of the 15q11-q13 genetic region is shown in Fig. 1 . This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders.
Introduction
The 15q11-q13 region harbors several genes regulated by genomic imprinting, a phenomenon in which genes are expressed preferentially from 1 parental allele. As a result, genes subject to regulation by genomic imprinting are functionally haploid, having only a single functional copy. Three distinct neurodevelopmental disorders arise primarily from deletions or duplications at the 15q11-q13 locus: PWS, AS, and Dup15q syndrome. Each of these disorders results from the loss of function or overexpression of at least 1 imprinted gene. Each of them occur with a frequency of approximately 1/15,000 to 1/30,000 live births.
The deletions and duplications of chromosome 15q11-q13 that cause PWS, AS, or Dup15q syndrome are mediated by local DNA repeats that occur at the common breakpoints. There are 5 such elements, which are composed of breakpoints 1 through 5 (BP1–BP5). Deletions involving either BP1 or BP2 and BP3 are most common, while the duplications are more complicated, but can frequently involve BPs 4 and 5 and are discussed below. A map of the 15q11-q13 genetic region is shown in Fig. 1 . This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders.
Prader-Willi syndrome
Clinical Background of the Disease
PWS is characterized by hypotonia, failure to thrive with poor suck, hypogonadism, short stature with small hands and feet, hyperphagia leading to morbid obesity beginning during early childhood, developmental delay/intellectual disability, and behavioral issues, including obsessive-compulsive disorder ( Table 1 ). Characteristic facial features are also evident.
| Consistent (100%) | Frequent (80%) | Associated (20%–80%) |
|---|---|---|
| Hypotonia | Hypopigmentation | Speech articulation defects |
| Failure to thrive | Behavioral problems | Autism |
| Feeding difficulty | Developmental delay | — |
| Hypogonadism | Short stature, if untreated with growth hormone | — |
| Obesity, in absence of intervention | Distinctive facial features | — |
| Hyperphagia | Sleep disturbances | — |
| Small hands/feet | — |
Hypotonia
Hypotonia becomes evident during pregnancy as decreased fetal movement and atypical presentation at delivery. Assisted delivery and caesarean delivery are increased with PWS births. Hypotonia is nearly universal in infants with PWS, thus, a molecular test for PWS should be performed whenever neonatal hypotonia is observed. Infants with PWS are lethargic with reduced movement, often having a weak cry, poor suck, and failure to thrive. The infantile hypotonia improves, but mild to moderate hypotonia persists throughout life in children and adults with PWS.
Hypogonadism
Hypogonadism is often evident at birth as gonadal hypoplasia in both males and females. Males typically have a small scrotum and may have a small penis. Unilateral or bilateral cryptorchidism is frequent. Females often have a small labia minora and clitoris. Puberty can be delayed or disorganized in adolescents with PWS, and most adults are infertile. Hypogonadism is thought to result from both hypothalamic dysfunction resulting in low levels of gonadotropins (and therefore gonadal hormones) and primary gonadal deficiency.
Growth deficits
Growth deficits associated with PWS likely begin in utero. Infants with PWS are typically 15% to 20% smaller than their siblings. Short stature is often apparent in childhood and persists through adulthood. The lack of a pubertal growth spurt may exacerbate the growth deficit. Hands and feet are often particularly small, usually averaging below the fifth percentile. Growth deficits are caused, at least in part, by GH deficiency, which seems to result from hypothalamic-pituitary dysfunction. Indeed, GH replacement therapy improves body mass index (BMI) and muscle mass in children with PWS and may even improve body habitus in adults with PWS.
Hyperphagia and obesity
Individuals with PWS pass through a series of 7 nutritional phases relating to appetite and weight gain. The first phase, phase 0, occurs from the prenatal period to birth with reduced fetal movement and lower birth weight than their siblings. The second phase, phase 1a, occurs from birth to approximately 9 months and is characterized by failure to thrive with difficulty feeding and decreased appetite. The third phase, phase 1b, occurs from approximately 9 months to 2 years and is marked by improved feeding and appetite and appropriate growth. The fourth phase, phase 2a, occurs between approximately 2 and 4.5 years. This phase involves weight gain without increased appetite or excess calories. The fifth phase, phase 2b, occurs between approximately 4.5 and 8 years. This phase involves continued weight gain with increased appetite and calories; however, individuals in this phase can still feel full. The sixth phase, phase 3, lasts from approximately the age of 8 years to adulthood. This phase is characterized by extreme hyperphagia, and individuals rarely feel full. If food consumption is not limited, obesity is inevitable. The seventh and final phase, phase 4, occurs throughout adulthood. During this phase, appetite is no longer insatiable.
The cause of hyperphagia in PWS is poorly understood, although it is likely to result from hypothalamic dysfunction. It has been suggested that increased ghrelin levels may underlie hyperphagia in individuals with PWS ; however, there are no consistently identified hormonal abnormalities that explain the hyperphagic behavior in PWS. Nonetheless, it is not unusual for individuals in phase 3 to exhibit extreme food-seeking behaviors, including consumption of nonfood items, hoarding of food, or stealing money to buy food.
The cause of obesity in PWS is manifold. The onset of weight gain in phase 2a, before there is an increased appetite, suggests that individuals with PWS have lower caloric requirement. This low caloric requirement is partly because of the decreased resting energy expenditure caused by decreased activity and decreased lean muscle mass when compared with neurotypical individuals. Increased appetite and hyperphagia also contribute to obesity. The obesity in PWS primarily occurs in the abdomen, buttocks, and thighs; there is less visceral fat than would be expected. Obesity is the major cause of morbidity and mortality in PWS.
Developmental delay/intellectual disability
Motor development and language skills are delayed in most individuals with PWS, although nearly all individuals with PWS walk and can effectively communicate verbally. Individuals with PWS have mild to moderate intellectual disability, and poor academic achievement is typical and may be exacerbated by behavioral difficulties in addition to developmental and intellectual disability.
Behavioral difficulties
Up to 90% of individuals with PWS have characteristic behaviors including stubbornness, temper tantrums, manipulative behaviors, compulsivity, and difficulty with change in routine. Features similar to obsessive-compulsive disorder and skin picking are common. Some of the behaviors are consistent with autism, and indeed some individuals with PWS meet diagnostic criteria for autism. This situation may be more common in individuals with maternal uniparental disomy (matUPD). Psychosis is also prevalent in approximately 10% to 20% of adults with PWS.
Other features
Facial features associated with PWS include almond-shaped eyes; narrow, but prominent nasal bridge; high, narrow forehead; thin upper lip; and downturned mouth. Other features associated with PWS include sleep disorders such as sleep apnea, strabismus (60%–70%), scoliosis (40%–80%), light-colored hair and skin, striae, and tapering of fingers.
Recent Advances in Genetics and Pathomechanism of the Disease
PWS is caused by the loss of paternally inherited chromosome 15q11.2-q13. The loss of expression from this chromosomal region typically occurs by one of the following 3 mechanisms: (1) approximately 70% of individuals with PWS have a large deletion of the entire 15q11-q13 imprinted region, (2) approximately 25% of individuals with PWS have matUPD in which both copies of chromosome 15 have been inherited from the mother; and (3) less than 5% of individuals with PWS have an imprinting defect that causes paternal 15q11-q13 to behave as though it were inherited from the mother. However, there are no instances of a point mutation in any gene causing PWS, suggesting that PWS is a true contiguous gene syndrome, resulting from the loss of more than 1 gene.
In the vast majority of individuals with PWS, approximately 20 paternally expressed genes are missing, including Necdin ( NDN ), Makorin ring 3 ( MKRN3 ), Mage-like 2 ( MAGEL2 ), PWRN2, PWRN1 , Nuclear pore-associated protein 2 ( NPAP2 ), SNURF, SNRPN, SNORD109A, SNORD116, SNORD115, SNORD109B , and SNHG14 (formerly known as UBE3A-ATS ). Typical individuals with deletions of paternal NDN, MKRN3 , and MAGEL2 and with deletions of paternal SNORD115 and distal portions of SNHG14 have been identified, suggesting that these genes are not causative for PWS. Conversely, individuals with PWS have been identified with smaller, atypical deletions that have narrowed down the PWS critical region to a 91-kb region that includes SNORD109A, SNORD116 , and IPW . Mouse models further suggest that deletions of Snord116 are sufficient to cause PWS; however, no human patient with PWS caused by deletion of SNORD116 alone has been reported to date.
The SNORD genes that are located in 15q11.2-q13 are orphan CD box small nucleolar RNA (snoRNA) genes that have been reported to modify messenger RNAs (mRNAs) and ribosomal RNAs (rRNAs), as well as act as small interfering RNAs. SNORD116 is actually a cluster of 29 similar but not identical snoRNA genes that although evolutionarily related may affect different mRNAs and rRNAs. It is not known how loss of SNORD116 results in the phenotypic manifestations of PWS.
Diagnostic Strategy
Methylation analysis
DNA methylation analysis using Southern blot or methylation-specific polymerase chain reaction (PCR) diagnoses PWS in 99% of cases, including all 3 classes, paternal deletion, matUPD, and imprinting defect ( Fig. 2 ). The most widely used assays target the 5′ CpG island of the SNURF-SNRPN ( SNRPN ) locus, a region known as the imprinting center (IC). The promoter, exon 1, and intron 1 of SNRPN are unmethylated on the paternal allele and thus expressed, whereas they are methylated on the maternal, nonexpressed allele. A normal individual has both a methylated and an unmethylated SNRPN allele, whereas individuals with PWS have only the maternal methylated allele.
Methylation analysis allows for identification of patients with PWS, but it provides no information about the molecular class of the disease. As discussed, 65% to 75% of cases result from deletion at 15q11.2-q13, 20% to 30% result from uniparental disomy in which both copies of chromosome 15 are maternally inherited, and less than 5% are caused by some form of imprinting defect. Differentiation of the molecular class of PWS allows the physician to provide more accurate prognostic information and is crucial for accurate recurrence risk counseling. Testing should proceed in the order outlined below, from the most to the least common cause.
Search for a deletion
Fluorescence in situ hybridization (FISH) with an SNRPN probe is the most cost-efficient means of identifying a deletion. If done with simultaneous chromosomal analysis, rare cases caused by translocation or inversion are identified. Increasingly, chromosomal microarray analysis (CMA) is performed instead of FISH, and this method allows for accurate measurement of deletion size in addition to providing information about other genomic changes, if present. The extent of the deletion is expected to become increasingly important as the understanding of genotype-phenotype correlations in PWS grows. CMA is more expensive than FISH, but it is increasingly available and typically the first test done when a patient with a suspected genetic condition is evaluated, particularly if PWS was not initially considered. In this case, methylation testing is important as a confirmatory test, because identification of a deletion does not distinguish between PWS and AS, which may have considerable clinical overlap in the young child. In addition, CMA may identify rare patients who have deletions that do not include the IC.
Uniparental disomy testing
DNA polymorphism analysis of chromosome 15 loci on the proband and parents’ DNA identifies cases of matUPD in which both copies of chromosome 15 are maternally inherited.
Imprinting defect
Sequencing of the IC can be done in specialized laboratories. Mutations are found in 15% of those with imprinting defects, with the remainder caused by epimutations. Epimutations carry a low recurrence risk, whereas an IC mutation on the paternal allele may be associated with a 50% recurrence risk. Thus searching for a mutation provides important information to families about future risk.
Additional options
Multiplex ligation-dependent probe amplification (MLPA) testing is another increasingly popular option as a first-line test for diagnosis of PWS, particularly in Europe. MLPA testing has the ability to assess methylation at 5 sites in the PWS region, as opposed to 1 site in the standard methylation assay. This method also detects a deletion, if present, but cannot distinguish between UPD and imprinting defects.
Current Management
Diet and nutrition
Failure to thrive in infancy results from poor suck in the setting of hypotonia. Special nipples or gavage feeding are often required. Close monitoring of growth parameters is required in the first year of life. If failure to thrive is noted, despite adequate caloric intake, testing for hypothyroidism is indicated, because this is not uncommon in infancy.
As weight gain begins to increase from the age of 2 years, careful supervision of caloric intake is necessary. Weight gain often begins after the age of 2 years, although appetite increase is not typical until after the age of 4 years. It is important to monitor food intake, before the onset of obesity. Nutritional supervision to assess appropriate intake and supplementation of vitamin D, calcium, and other nutrients is recommended. Locking of cupboards and refrigerator is often necessary as appetite increases. Evidence suggests that early dietary intervention with a controlled prescribed diet as early as 14 months of age may result in a normal BMI. Continued monitoring of diet and weight is central to long-term health including avoidance of diabetes mellitus and other obesity-related complications.
Hormonal/endocrine
Treatment with GH is now recommended as the standard of care for children with PWS. Early treatment seems beneficial with normalization of height, increase in muscle mass, and decrease in fat mass. Treatment should begin between 4 months and 2 years of age because benefits in head circumference, gross motor and language development, and cognition have been demonstrated with early treatment. Owing to concern about the possibility of an increase in the rate of sudden death from upper airway obstruction in the first months of treatment, a sleep study is recommended before initiating treatment, 6 to 12 weeks after initiation of treatment, and on an annual basis thereafter. Children with PWS are at increased risk of obstructive and central apnea, and this risk may rise with GH treatment, possibly because of lymphoid hyperplasia. While receiving GH treatment, close monitoring for scoliosis, hypothyroidism, diabetes, and elevation of levels of insulinlike growth factor 1 is suggested. Treatment with GH may need to continue into adulthood, because recent studies suggest that BMI may increase significantly after cessation of GH therapy.
Cryptorchidism should be addressed with referral to urology and treatment if noted in infancy. Treatment of hypogonadism should be considered, with human chorionic gonadotropin (hCG) or testosterone, to assist with testicular descent, as well as scrotal and phallic development and growth. In early adolescence, replacement of sex hormones may be appropriate; low-dose estrogen or combined estrogen/progestin should be administered in girls beginning at the age of 11 to 12 years, particularly if there is amenorrhea/oligomenorrhea or low bone mineral density in the setting of low estradiol levels. Testosterone or hCG (increases endogenous testosterone production) should be administered in the setting of hypogonadism in boys beginning at the age of 12 to 13 years.
Monitoring of levels of free thyroxine in addition to that of thyrotropin should be done annually in childhood. Awareness of elevated risk for adrenal insufficiency is important because it may be present in up to 60% of children. Central adrenal insufficiency has been observed in PWS, although the frequency is unclear. Considering measuring adrenocorticotropic hormone (ACTH) and cortisol levels with illness is appropriate, and some have advocated stress dose steroids with illness or before surgery. Monitoring for type 2 diabetes mellitus is essential in adults.
Behavioral and educational
Physical therapy beginning in infancy assists with motor skills development with speech therapy often warranted by 2 years of age. Requirement for educational support should be anticipated including personal classroom aides and behavior management given the frequency of challenging behaviors such as tantrums as well as compulsive and stubborn behaviors. Serotonin reuptake inhibitors can be helpful for severe behavioral issues, including psychosis, which may emerge in adolescence. Adolescents and adults are often successful residing in a group home where attention to daily exercise and diet can be emphasized.
Other
Annual assessment for scoliosis should begin in the early childhood. Ophthalmologic evaluation for strabismus and impaired acuity should be done in the first year of life and continue thereafter. Given the increased risk for osteoporosis, bone density studies (dual energy X-ray absorptiometry studies) are recommended beginning in adolescence and continuing to adulthood.
Future potential therapies
Several medication trials are ongoing, aimed at addressing the hyperphagia and associated symptoms of PWS. Oxytocin nasal spray is being studied, because there is a reduction in oxytocin-producing neurons in the hypothalamic periventricular nucleus in individuals with PWS. A recent publication, however, did not demonstrate benefit in 30 individuals in an 18-week double-blind, placebo-controlled crossover trial. Other trials are ongoing. A trial of a candidate obesity drug called Beloranib is also underway. Belonarib is an inhibitor of methionine aminopeptidase-2 and works to reduce fatty acid synthesis, insulin levels, and food consumption. This drug also increases mobilization of fats and energy expenditure.
Recommendation for family counseling
Family counseling is recommended. Most deletions, UPD, and epimutations are associated with a low recurrence risk. However, IC mutations and some translocations may be associated with a 50% recurrence risk.
Angelman syndrome
Clinical Background of the Disease
AS is characterized by developmental delay, intellectual disability, absent speech, seizures, ataxic gait, easily excitable happy demeanor, and characteristic facies ( Table 2 ). This disorder has been referred to as happy puppet syndrome because of the ataxic gait and disposition of children with AS.
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