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 pater- nal 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 leth- argy, 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 .-- *.... ...... .s~~~~~~~~~~~~ .. A.. zrI im xl, 0 i.-. - v;.4 .i.. I *. ~':3 -.-I.- 1:1 ... 1- d., SW ',.,.. s s KS X r:- I E ... :s, a i: .|w w #.b ..,-g'S.i 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 nor- mal 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 pa- tients 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