Syndrome of the Month

JMed Genet 1997;34:917-923 917 Syndrome of the month

Prader-Willi syndrome

Suzanne B Cassidy

Abstract 1 5q (genetic heterogeneity) and it is typified by Prader-Willi syndrome is a complex dis- a distinctive behavioural phenotype."7 order affecting multiple systems with Approximately 1 in 10 000-15 000 subjects many manifestations relating to hypotha- is diagnosed with PWS8 and it occurs in both lamic insufficiency. Major findings in- sexes and all races. Unfortunately, diagnosis is clude infantile hypotonia, developmental still delayed in many cases despite the availabil- delay and mental retardation, behaviour ity of clinical diagnostic criteria.' Appropriate disorder, characteristic facial appear- management can have a significant positive ance, obesity, hypogonadism, and short impact on health and quality of life, but stature. Obesity and the behavioural controlling the characteristic obesity and diffi- problems are the major causes ofmorbid- cult behaviour constitutes a major challenge, ity and mortality. requiring cooperative input from geneticists, Prader-Willi syndrome is caused by primary care physicians, endocrinologists, nu- abnormalities of the imprinted region of tritionists, psychologists, psychiatrists, and proximal 15q and results from absence of teachers, as well as families and other care the normally active paternal genes in this givers. region. Such absence results from paternal interstitial deletion, maternal unipa- Clinical findings and natural history rental disomy, or a mutation or other Although many of the manifestations of PWS abnormality in the imprinting process. are related to functional hypothalamic defi- Diagnostic identification of all causes ciency, the clinical appearance in infancy has become available in recent years, per- differs considerably from that in childhood and mitting early detection and institution of adulthood.4" appropriate management. This testing has permitted recent identification of HYPOTONIA some phenotypic differences among af- Hypotonia ofprenatal onset is nearly uniformly fected subjects of different race and present and is probably the cause of decreased between those with deletions and unipa- fetal movement, frequent abnormal fetal posi- rental disomy as a cause. tion, and difficulty at the time of delivery often (3Med Genet 1997;34:917-923) necessitating caesarean section.4 The neonatal central hypotonia is almost invariably associ- Keywords: Prader-Willi syndrome; imprinting; proxi- ated with poor sucking, with consequent failure mal 15q; uniparental disomy to thrive and the necessity for nasogastric or other special feeding techniques. Infantile lethargy, with decreased arousal and weak cry, are Prader-Willi syndrome (PWS) is a complex, also prominent findings, leading to the neces- multisystem disorder first described in 1956.' sity to awaken the child to feed. A gastrostomy Twenty-five years later it captured the interest tube is rarely necessary since this problem is ofgeneticists because it was the first recognised transient. Reflexes may be decreased or absent. microdeletion syndrome identified by high Neuromuscular electrophysiological and bi- resolution chromosome analysis.2 PWS is now opsy studies are normal or non-specific and the known to be one of the most common hypotonia gradually improves. Motor mile- microdeletion syndromes, one of the most fre- stones are delayed and average age of sitting is Department of quent disorders seen in genetics clinics, and the Genetics and Center 12 months and walking is 24 months. Adults for Human Genetics, most common recognised genetic form of remain mildly hypotonic with decreased mus- Case Western Reserve obesity. It is also the first recognised human cle bulk and tone. University and genomic imprinting disorder and the first University Hospitals of recognised as resulting from uniparental HYPOGONADISM Cleveland, 11100 disomy.' PWS thus occupies an important Euclid Avenue, Hypogonadism is prenatal in onset' and is evi- Lakeside 1500, place in the contemporary history of human dent at birth as genital hypoplasia, It is Cleveland, OH 44106, genetic disorders. It is, in addition, manifested by cryptorchidism, scrotal hypopla- USA distinguished by being a syndrome caused by sia (small, hypopigmented, and poorly rug- S B Cassidy several different genetic alterations of proximal ated), and sometimes a small penis in males, 918 Cassidy

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Figure 1 Evolution of the phenotype ofPWS in a patient with a lSq deletion: (A) 11 months, (B) 2½12years, (C) 3¼12years, (D) 7years, (E) 13years, (F) 27years. See textfor description ofphenotypicfindings. (All photographs reproduced with permission.) and by hypoplasia of the labia minora and stimulated, treatment with pituitary or gonadal clitoris in females. These findings persist hormones can improve secondary sex throughout life, though spontaneous descent of characteristics.49 testes has been observed up to adolescence. Hypogonadism is also evident in abnormal HYPERPHAGIA AND OBESITY pubertal development. While pubic and axil- The proportion offat mass to lean body mass is lary hair may develop early or normally, the high even in thin infants with PWS,'0 remainder of pubertal development is delayed presumably because of hypotonia and the sub- and usually incomplete. Adult males only sequent decreased muscle bulk. However, occasionally have voice change, male body significant obesity generally begins after hyper- habitus, or substantial facial or body hair. In phagia has its onset, often between the ages of females, breast development generally begins 1 and 6 years. Food seeking behaviour, with at a normal age, but there is usually amenor- hoarding of or foraging for food, eating of rhoea or oligomenorrhoea. Menarche may unappealing substances such as garbage, pet occur as late as the 30s, particularly in food, and frozen food, and stealing of food or association with significant weight loss. In both money to buy food, are common. A high males and females, sexual activity is rare and threshold for vomiting may complicate binge- infertility is the rule. ing on spoiled food from the garbage or such The hypogonadism is hypothalamic in origin items as boxes of sugar or frozen uncooked and gonadotrophins, oestrogen, and testoster- meat, and toxicity from ineffective Ipecac used one are generally deficient.4 9 Since the pitui- to induce vomiting has occurred. The obesity is tary gland and gonads are normal but under- central in distribution with relative sparing of Prader-Willi syndrome 919

SHORT STATURE Birth weight and length are usually within normal limits, but the early period of failure to thrive may result in both weight and length being below the 3rd centile. Short stature, if not apparent in childhood, is almost always present by the second half of the second decade, associated with lack of a pubertal growth spurt. Average height is 155 cm for males and 148 cm for females. African- Americans tend to be taller.'9 Growth hormone deficiency has been shown in most tested patients with PWS, and treatment with growth hormone increases height and lean body mass, often resulting in decreased body mass index.9 22

DEVELOPMENTAL DELAY/MENTAL RETARDATION In addition to the gross motor delay described above, language development is also delayed. Verbal skills are an ultimate strength in most patients, though speech is often poorly articu- lated, having a nasal/slurred character. Cogni- tive abnormalities are evident and most patients are mildly retarded (mean IQ 60s-low 70s).6 23 Approximately 40% have borderline Figure 2 A 41 year old with PWS. See textfor description retardation or low normal intelligence and ofphenotypic findings. about 20% have moderate retardation. Aca- demic performance is poor for cognitive ability. Specific patterns of cognitive strength and the distal extremities, and even subjects who weakness have begun to emerge, frequently are not overweight tend to deposit fat on the with relative strength in reading, visual-spatial abdomen, buttocks, and thighs (figs 1 and 2). skills, and long term memory, and weakness in Obesity is the major cause of morbidity and arithmetic, sequential processing, and short mortality in PWS and longevity may be nearly term memory.7 Coming to clinic with a book of normal if it is avoided. 12 13 Cardiopulmonary word search puzzles can almost be considered a compromise results from excessive obesity, as diagnostic sign for PWS and unusual skill with can type II diabetes mellitus, hypertension, jigsaw puzzles is common. thrombophlebitis, and chronic leg oedema. Sleep apnoea occurs at increased frequency. BEHAVIOURAL PROBLEMS The hyperphagia is the result of a hypotha- A characteristic behavioural profile becomes lamic abnormality resulting in lack of evident in early childhood, with temper tan- satiety.'4 '1 In addition, there is a decreased trums, stubbornness, controlling and manipu- caloric requirement,'6 probably related to lative behaviour, obsessive-compulsive charac- hypotonia and decreased activity. teristics, and difficulty with change in routine. 7 Lying, stealing, and aggressive behaviour are common. True psychosis is DYSMORPHIC APPEARANCE evident in young adulthood in approximately Characteristic facial features, including narrow 5-10% of patients. Behavioural and psychiatric bifrontal diameter, almond shaped palpebral problems interfere the most with quality of life fissures, narrow nasal bridge, and downturned in adulthood. mouth with a thin upper lip, are either present from birth or evolve over time'7 (figs 1 and 2). MISCELLANEOUS CHARACTERISTICS Small, narrow hands with a straight ulnar bor- A variety of more minor findings are unique to der and sometimes tapering fingers, and short, this condition, including thick, viscous saliva often broad feet are usually present by the age that may predispose to dental caries and of 10, with an average adult foot length of 20.3 contribute to articulation abnormalities, high cm in females and 22.3 cm in males.'8 African- pain threshold, skin picking and high threshold Americans are less likely to have small hands for vomiting. Sleep disturbances, especially and feet.'9 A characteristic body habitus, excessive daytime sleepiness and oxygen de- including sloping shoulders, heavy mid section, saturation in REM sleep, are common even in and genu valgum with straight lower leg the absence of obesity.25 Osteoporosis is borders, is usually present from toddlerhood frequent. (figs 1 and 2). Hypopigmentation for the family, manifested as fairer skin, hair, and eye col- Management our, occurs in about a third of affected Management of PWS is largely problem subjects.20 Strabismus is often present.2' oriented. Early intervention and special educa- Scoliosis/kyphosis are common, the former tion, followed by supportive employment, are occurring at any age, and the latter developing appropriate to address the developmental in early adulthood (fig 2). disabilities. Physical, occupational, and speech 920 Cassidy

PWs A' S virtually all families studied in which there has been a recurrence of PWS, have neither KD151l ZNF127 D15S11 PW71 SNRPN IPW UBE: GABRB3 GABRG3 )+tel deletion nor UPD, but rather have a very small ~3A - cen- p0 ~~~/telX D15S13 D15S10 GABRA5 P deletion in the centre controlling imprinting within 15ql 1-q13, the imprinting centre S IC 0 200 kb (IC).6 7 03 Methylation is one mechanism by lines indicate the two common which genomic imprinting can occur, and Figure 3 Genetic map of the l5qll-q13 region. Jagged, has been shown for several proximal and one common distal breakpoints, circles indicate genes and reference markers, methylation genes and bars indicate critical regions involved in PWS, Angelfman syndrome (AS), and the identified within the PWS/AS region.27 imprinting centre (IC), the centromere (cen), and telomer-e (tel). See text for details ofgenes It is of interest that a clinically very different and the ICfunction. (Map contributed by Robert D Nichoils, PhD and Nancy Rebert, is the result of Case Western Reserve University). disorder, Angelman syndrome, an oppositely imprinted gene in the same therapies can be b)eneficial at all ages. The region of chromosome 15.3 36 Thus, approxi- obesity can be contirolled with a well balanced mately 60% of patients with Angelman syn- low calorie diet of:about 1000-1200 kcal/day, drome have the same 1 5ql 1-qi 3 deletion, but regular exercise (30 minutes per day is an occurring in the maternally derived chromo- appropriate goal), aand environmental modifi- some. Paternal uniparental disomy is seen in cation, such as loc:king kitchen cabinets and 3-5%. In approximately 10% there is an close supervision tcZ avoid access to food. So imprinting mutation and the remaining cases, a far, no medication Eias had long term effective- category that has not been reported in PWS, ness in controlling appetite. Recent evidence have a presumed single gene mutation. Re- shows great benefit from growth hormone cently, mutations in the UBE3A gene have replacement. Sex Iiormone replacement will been identified in a small number of these improve secondary{ sex characteristics and patients.37 38 theoretically will improve osteoporosis, but tes- A number of genes have been mapped within tosterone treatment is sometimes associated the PWS/Angelman syndrome region and oth- with an increase in

Table 1 Summary of the clinical diagnostic criteriafor (alpha satellite) probe which can serve as a Prader-Willi syndrome (adaptedfrom Holm et al7). The diagnosis should be strongly suspected in children under 3 control, and a method to detect a cryptic trans- years ofage with five points, threefrom major criteria, or in location involving chromosome 15 (which those above 3years with eight points,fourfrom major would predispose to unbalanced rearrange- criteria. The original diagnostic criteria, developed before the availability ofsensitive and specific genetic testing, ments or UPD, and thus increase the chance of included a major criteria ofchromosome 15 deletion or recurrence).52 other chromosome 15 anomaly Uniparental disomy can be detected with PCR using informative microsatellite markers Major criteria (1 point each) from the PWS/AS region by studying both par- Infantile central hypotonia Infantile feeding problems/failure to thrive ents and the child.52 56 Using additional mark- Rapid weight gain between 1 and 6 years ers from other chromosomes can confirm cor- Characteristic facial features Hypogonadism: genital hypoplasia, pubertal deficiency rect paternity. Developmental delay/mental retardation Prenatal detection is possible. FISH is Minor criteria (112 point each) indicated when a cytogenetic 15q deletion is Decreased fetal movement and infantile lethargy Typical behavioural problems suspected on chorionic villus sampling (CVS) Sleep disturbance/sleep apnoea or amniocentesis. If trisomy 15 is detected on Short stature for the family by age 15 years CVS and the fetus survives, parent of origin Hypopigmentation Small hands and feet for height age (methylation analysis or microsatellite marker) Narrow hands with straight ulnar border studies are indicated and validated.56-59 FISH Esotropia, myopia and parent oforigin studies are also indicated if Thick, viscous saliva Speech articulation defects an inherited or de novo translocation involving Skin picking chromosome 15 is detected prenatally. Supportive criteria (no points) Parents should be studied in cases with High pain threshold an Decreased vomiting identified imprinting mutation, since a healthy Temperature control problems parent can carry this abnormality and be at Scoliosis/kyphosis Early adrenarche increased risk for recurrence.34 Prenatal detec- Osteoporosis tion through identification of the mutation or Unusual skill with jigsaw puzzles maternal only methylation pattern in a fetus is Normal neuromuscular studies possible.59 The American Society of Human Genetics/ retardation/developmental delay is associated American College of Medical Genetics Test with obesity are included in the differential and Technology Transfer Committee has diagnosis, including Bardet-Biedl syndrome, developed and published a statement regarding Albright hereditary osteodystrophy, and Cohen the status of genetic testing for PWS and syndrome.47 Mental retardation disorders in Angelman syndrome.52 which obesity is an occasional finding, such as fragile X and Angelman syndromes, may also Recurrence risk be confused with PWS. Acquired hypothalamic *PWS resulting from either the common large injury from accidents, tumours, or surgical deletion in the absence of a structural chromo- complications can closely mimic PWS. some abnormality or from UPD has not been Currently, the most efficient molecular diag- reported to recur. However, a paternal bal- nostic test for PWS is determination of the anced insertion or gonadal mosaicism is possi- parent specific methylation imprint within the ble, and therefore a recurrence risk of approxi- PWS/AS region using Southern hybridisation mately 1% or less is appropriate for genetic and methylation sensitive probes (SNRPN and counselling purposes. UPD is caused by PW7 1).34 41 48-52 If the methylation pattern is non-disjunction, as evidenced by advanced characteristic of maternal only inheritance, maternal age in this group,28 29 and by docu- PWS is confirmed, and if not, PWS resulting mentation of trisomy 15 on CVS and maternal from deletion, UPD, or an imprinting mutation UPD at birth.60 Since non-disjunction can is ruled out. Newer techniques using PCR to- recur, a recurrence risk of 1% is appropriate for 56 62 hs detect the methylation status of SNRPN53 or genetic counselling purposes. In those SNRPN expression54 have been developed, but families with a detected imprinting mutation are not yet in widespread use. Determination of (small deletion) or with a presumed imprinting whether the PWS is the result of deletion, mutation based on maternal only methylation UPD, or an imprinting mutation is important pattern when other testing fails to indicate primarily for genetic counselling purposes and deletion or uniparental disomy, a recurrence to identify those few cases with a translocation risk of up to 50% pertains, as this is likely to be or inherited microdeletion. an imprinted dominant mutation, occurring in High resolution cytogenetic analysis can the paternal grandmother's germline.34 often detect the 15qi 1-q13 deletion; however, there is an unacceptably high false negative and Conclusion false positive rate using this technique, and it is In summary, PWS is a multisystem disorder no longer considered sufficient for diagnostic with considerable clinical variability. It is purposes.49 50 52 55 Fluorescence in situ hybridi- caused by absence of expression of as yet sation (FISH) using probes within the unelucidated genes within 15qi 1-q13 from the PWS/AS critical region (SNRPN or DI 5SI 1) normally active paternal copy, with cases is the definitive diagnostic test for the common resulting from paternal interstitial deletion, sized deletion causing PWS. It is best accom- maternal uniparental disomy, and imprinting plished in conjunction with a probe outside the mutations. Recently, testing through detection critical region, optimally a 15 centromeric of parent of origin of SNRPN has allowed 922 Cassidy

diagnostic confirmation in virtually all cases. 25 Hertz G, Cataletto M, Feinsilver SH, Angulo M. Develop- mental trends of sleep-disordered breathing in Prader-Willi Continued analysis of known but anonymous syndrome: the role of obesity. Am J Med Genet 1995;56: genes within this region, and search for 188-90. 26 Greenswag LR, Alexander RA, eds. Management of Prader- additional genes, will probably provide infor- Willi syndrome. 2nd ed. New York: Springer-Verlag, 1995. mation about genes contributing to normal 27 Nicholls RD. Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndrome: a review. Am _J hypothalamic function or regulation. Although Med Genet 1993;46:16-25. symptomatic management is available, more 28 Robinson WP, Bottani A, Yagang X, et al. Molecular, cytogenetic and clinical investigations of Prader-Willi definitive treatment will probably await reversal syndrome patients. Am 7 Hum Genet 1991 ;49: 1219-34. of imprinting in this region. 29 Mascari MJ, Gottlieb W, Rogan PK, et al. The frequency of uniparental disomy in Prader-Willi syndrome. N Engl J Med 1992;326:1599-607. I thank Robert D Nicholls, PhD and Nathaniel Robin, MD for 30 Reis A, Klein-Vogler U, Dittrich B, et al. Imprinting critically reviewing parts of the manuscript, Nancy Rebert for mutations suggested by abnormal DNA methylation providing the gene map, and Florence Stewart for secretarial patterns in familial Angelman and Prader-Willi syndromes. assistance. I am very appreciative of long term assistance by Am _J Hum Genet 1994;54:741-7. clinic coordinators, especially Shauna Heeger, MS, and many 31 Sutcliffe JS, Nakao M, Christian S, et al. Deletions of a dif- collaborators. I am particularly grateful to the families of ferentially methylated CpG island at the SNRPN gene patients affected with PWS for their continuing support and define a putative imprinting control region. Nat Genet participation in Prader-Willi syndrome clinics and clinical 1994;8:52-8. research. In particular, appreciation goes to those who are will- 32 Buiting K, Saitoh S, Gross S, et al. Inherited microdeletions ing to have photographs published. in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 1994;9:395-400. 33 Saitoh S, Buiting K, Rogan PK, et al. Minimal definition of 1 Prader A, Labhart A, Willi H. Ein Syndrom von Adipositas, the center and fixation of a Kleinwuchs, Kryptochismus und Oligophrenie nach myot- imprinting chromosome oniertgem Zustand im Neugeborenalter. Schweiz Med 15ql1 -q13 epigenotype by imprinting mutations. Proc Natl Wochenschr 1956;86:1260-1. Acad Sci USA 1996;93:7811-15. 2 Ledbetter DH, Riccardi VM, Airhart SD, Strobel RJ, 34 Saitoh S, Buiting K, Cassidy SB, et al. Clinical spectrum and Keenen SB, Crawford JD. 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54 Wevrick R, Francke U. Diagnostic test for the Prader-Willi 58 Christian SL, Smith ACM, Macha M, et al. Prenatal syndrome by SNRPN expression in blood. Lancet 1996; diagnosis of uniparental disomy 15 following trisomy 15 348:1068-9. mosaicism. Prenat Diagn 1996;16:323-2. 55 Delach JA, Rosengren SS, Kaplan L, Greenstein RM, Cas- 59 Kubota T, Aradhya S, Macha M, et al. Analysis ofparent-of- sidy SB, Benn PA. Comparison of high resolution chromo- origin specific DNA methylation at SNRPN and PW71 in some banding and fluorescence in situ hybridization tissues: implication for prenatal diagnosis. Jf Med Genet (FISH) for the laboratory evaluation of Prader-Willi 1996;33:1011-14. syndrome and Angelman syndrome. Am Med Genet 60 Cassidy SB, Lai L, Erickson RP, et al. Trisomy 15 with loss 1994;52:85-91. of the paternal 15 as a cause of Prader-Willi syndrome due 56 Ledbetter DH, Engel E. Uniparental disomy in humans: to maternal disomy.Am JHum Genet 1992;51:701-8. development of an imprinting map and its implications for 61 Purvis-Smith SG, Saville T, Manass S, et al. Uniparental prenatal diagnosis. Hum Mol Genet 1995;4:1757-64. disomy 15 re§ulting from correction of an imitial trisomy 57 Robinson WP, Langlois S, Schuffenhauer S, et al. Cytoge- 15. Am JHum Genet 1992;50:1348-50. netic and age-dependent risk factors associated with unipa- 62 Kennerknecht I. Differentiated recurrence risk estimations rental disomy 15. Prenat Diagn 1996;16:323-32. in the Prader-Willi syndrome. Clin Genet 1992;41:303-8.