SA MEDICAL JOURNAL VOLUME 63 4 JUNE 1983 883 • The Prader-Willi syndrome In Cape Town R. BOTH WELL, L. MERCKEL In order to provide a perspective of the clinical, behavioural Summary and developmental aspects of the Prader-Willi syndrome the findings in I patient will be presented in full. A series of 9 patients in Cape Town with the Prader- Willi syndrome has been investigated in order to appraise possible aetiological factors and to deter- Case report mine the frequency and extent of somatic anomal- This female patient, aged 14 years, was the second offspring of ies. Contrary to pr~vious reports, no cytogenetic young non-consanguineous normal parents. The pregnancy was abnormalities could be detected. normal apart from a heavy fall in the third trimester, and fetal movements were comparable to those of an earlier pregnancy. S Atr Med J 1983; 63: 883-886. The infant was delivered at term, weighing 1420 g. The family history was non-contributory except that the maternal grand- mother had developed maturity-onset diabetes. The infant was nursed in an incubator for the first 8 weeks, and The cardinal features of the Prader-Willi syndrome (PWS) are as the sucking reflex was absent she was fed by nasogastric tube obesity, hypogonadism, cryptorchidism, mental retardation, during this period. Feeding difficulties persisted until the age of short stature and small hands and feet, preceded by a period of 8 months when she was started on a solid diet. Weight gain in the hypotonia in early infancy. Since it was first described in 1956 1 first year was very slow and hypotonia was very evident more than 150 cases have been reported in the literature. Investi- throughout. gation has been directed at the endocrine pathology,2-8 the radio- Her milestones were markedly delayed - she was able to roll logical abnormalities,9 lipid metabolism,lO.lI chromosomal sta- at 10 months, she sat at IS months and walked for the first time at tllS l2 and the mode of inheritance. 13 27 months. She said her first word at 20 months and could speak We have investigated 9 patients with the syndrome in order to sentences before the age of 3 years. She was described as having confirm the frequency of various reported clinical findings and been thin until the age of 5 years and 'plumpish' until the age of to determine whether there are other significant somatic fea- 10 years, after which she became very obese. She often searched tures. Chromosomal analyses were undertaken in each patient in for food but never ate food of poor quality. an attempt to confirm previously reported abnormalities. At the present time she anends a 'special school' where she is at the academic level of a normaI7-year-old. Socially she is much more advanced, having an outgoing, unselfconscious, self- Patients and methods assured personality. However, when thwarted she throws the occasional temper tantrum. The 9 previously diagnosed subjects in our study were all drawn When examined in 1981 her height was 120 cm, she weighed from the files ofthe Department of Human Genetics, University 45 kg, had a head circumference of 50,5 cm and was markedly of Cape Town. Five of the patients Wer~ White, while 4 were of obese, with a skinfold thickness above the 97th percentile accord- mixed ancestry. There were 3 males ami 6 females with ages ing to Tanner and Whitehouse's skinfold charts. ls She was ranging from 7 to 31 years. blonde and blue-eyed with an expressionless face and had a A history was obtained from a clOSe ri:lative and, where possi- narrow bifrontal diameter. Her eyes were almond-shaped with a ble, hospital records were scrutj~ized. A full clinical examination left-sided convergent strabismus. The mouth had a 'fish-like' included measurements of hei~ht, weight and head circumfer- configuration with down-turned edges, and the philtrum was ence. Hand measurements (palm, middle finger and ~otal hand smooth. The hands showed digital shortening with clinodactyly length) were underr;aken accorping to the method of Feingold of the fifth fingers. The dorsum of the hands and proximal and Bossertl 4 and expressed in terms of the normal values estab- phalanges appeared puffy and the fingers tapered distally. Pal- lished by these investigators. Skinfold thicknesses were mea- mar creases were normal. sured at the miptriceps region and in the subscapular area. A Laboratory investigations revealed a normal fasting blood blood glucose spot-test was performed in order to screen for glucose concentration. A limited skeletal survey revealed no hyperglycaemia. abnormality other than a diminished carpal bone age, while her Limited skeletal surveys were performed on 7 patients. This phalangeal bone age was consistent with chronological age. Pat- involved anteroposterior views of the hands, wrist, pelvis, knee, tern profile analysis revealed very short metacarpals and pha- femur", elbow and humerus. Pattern profile analysis was carried langes. out ori the hand radiographs to establish whether the carpal bones and phalanges were abnormally long. Chromosomal ana- lyses were performed on metaphase chromosomes by routine Results culture and harvesting techniques. The family histories, perinatal factors and developmental mile- stones of the 9 patients are listed in Table 1. Department of Human Genetics, University of Cape Town R. BOTHWELL, Medical Scudenr, University of the Witwatersrand, Johannesburg Family studies L. MERCKEL, Genetic Nursing Sister The average maternal age of 28 years and 4 months does not Dare received: 26 Augusl 1982. differ significantly from mean population maternal ages. Only 884 SA MEOIESE TYOSKRIF OEEL 63 4 JUNIE 1983 one mother was known to have had a miscarriage, and there were ci no reported cases ofsimilarly affected relatives. Two brothers of E case 4 died in the first few days of life - one apparently with o Ol ~ jaundice. The maternal grandmother in case 5 was a maturity- Q) ~ onset diabetic, as was the paternal grandmother in case 6. Many (fl >- '" o of the relative of case 3 were obese. o ('0. ('to. ("'-. ci E o Development N E (Xl o All our patients (excepting patient 9, for whom no history was Q) ~ 0""'", (fl >- <Xl ...... available) had a history of hypotonia in infancy. Associated with C"l E >->. o '" 0 ~ LL o z N ""~N this there were feeding difficulties in 5 out of 8 patients, which were sufficiently severe to necessitate tube-feeding for 3: variable w period. The sucking reflex soon appeared in the majoriry, but in ~ ci ci o EE 2 patients spoon-feeding was necessary throughout ~ancy. a: "'<0 The development of obesity is characteristically delayed in the c .,. ......... co Prader-Willi syndrome2.16.17 and this was the case with our z o (fl >->->. lA > patients. A number were described as thin children until 2-3 rn o ("0. C'. N+r- o NC"lan ...J years of age and only then did they start putting on weight. ...J Several showed a lack of satiation and constant foraging for food, ~ but 2 had a normal eating pattern. The quality of the food did not cl: seem to matter to 4 of the patients, all of whom raided the dustbin w C on occasions, while patient 7 had occasionally eaten cement, dead et a: Q. o birds and faeces. Some of these oddities are possibly due to the W mental retardation and behavioural problems rather than to an J: aberrant appetite. ~ ci J: E . ci . ~ o E 0 ~ E C"l E Personality rn ~ E ~~~ CIJ >- >- >. Temper tantrums, shyness, poor peer interaction and moodi- Z o z~ ~ N ~ w ness were common problems. The majority of these behavioural ~ et problems developed after the age of 4 years. Results of psycho- Q. ci metric tests were not available, but the IQ range of 40-60 E '" Z .,. an reported by Smith I would probably encompass the levels in our ~ Q) (fl ~ patients, with the exception of case 8, who was possibly in the Z 0 w '" >- ,...LL o ~ . , T borderline range. ~ Q. o ...J ci ci E E Somatotype W ~ C') '" ~ .,. Short stature was very evident with 7 of the 9 patients being C ~ >- .,. '" ......... >->->. lA lA C '" o below the third percentile for height. Conversely, the weight of Z 0 ~LL o M+ ~NC"l every patient was considerably higher than normal. It has often et > been claimed that the hands are small in relation to body size, but a: ci there was not a marked difference in terms of the percentile o E tn N charts for hand length and height. Skinfold thickness measure- <0 ......... ments clearly demonstrated the marked obesity of all our J: ~ ... E CIJ ,... N (fl >->->. (fl lA subjects. > ...J '" 0 o z~ N'+ NNC"l Other somatic abnormalities that occurred frequently were: ~ strabismus (6 out of9 patients), clinodactyly (8 patients), kypho- et LL ci sis and/or scoliosis (6 patients). A classic facies has been reported E in the literature,2.16.11 consisting of a delicate mouth, a high W .~ E M ...J Q) en c forehead, blue eyes and fair or auburn hair. Three ofour 5 White CD (fl e! >- E ... <I) ~ >. >. Cl) "E et '" .- c~ CIJ + a patients had this appearance, but none of those of mixed ancestry ~ 0 ,...LL c ("0. ("0. C'\I (") (") iii manifested this 'classic' facies. A more consistent feature was the E hands, which in 8 of our patients were puffy and soft over the <5 c: dorsum with proximal phalanges tapering distally. Sexual characteristics ::l "El The sexual characteristics of our male patients, who were 10, E 13 and 16 years ofage, were those of pre-adolescent males, and all c: ca ClQ) 3 had cryptorchidism. The penis ofthe 16-year-old was also very Clc:E short, being only 2 cm in length. c:i_ = .- - ca ... Ci5:i=U:: en Of our 6 female subjects, only case 5 (14 years and II months) and case 9 (31 years) were of postpubertal age. Case 5 had slight pubic hair growth and breast buds, while case 9 had mature breasts with scanty pubic hair in the female distribution. She had SA MEDICAL JOURNAL VOLUME 63 4 JUNE 1983 885 menstruated, shown considerable interest in the opposite sex and was on Depo-Provera. The age of menarche was not known. o '" 'iij E .2 o (5 ,.... 't:l Radiographic findings '" The results of our radiological skeletal survey are shown in Table n. The findings are unremarkable except for a bone age of CJ) ~>.> u;:;~z '" '" zz '" 0 ~-[ Cl~Z= '" ~ - '" '" 0> '" ::l 0>- .. C <J ::l a year or more below the chronological age in 7 of the 9 patients. In 2 the number of wormian bones in the skull was at the upper cl end of the normal range, and slightly increased in 1. E Pattern profile analysis on anteroposterior hand radiographs '" 'iij .2 was undertaken in all patients. This did not reveal a distinctive '0 u pattern in the length of the phalanges or metacarpals, although zz <Il zl marked shortening was apparent. .!!1 Six of our subjects (cases 2, 3, 4, 5, 7 and 9) were examined dentally, but none was found to suffer from severe dental caries o '" .2 E (5 as has been previously reported.2.9.I6.17 On the contrary, in this r-. '" <J respect the group compared favourably with the general popula- ID '" '" .... .. .. '" '" '" 0 ..c",..c Ul>->- Cl" a. tion. Moderately high arched palates were evident in 2 patients, but none had clefts. u~~z z~.~~ Z I Cytogenetic studies gave normal results in all our subjects and none showed the previously reported deletion in the long arm of cl E chromosome IS. r-. <D ID '" .. '" .. Ul>->- "'C'l('l u,....,.... zl Discussion CIJ The purpose of our study was documentation of the somatic, w a:: cl . radiographic and chromosomal findings in our series of 9 ::::l E0 patients, and a comparison of their manifestation with observa- I- ,.... E « ,....<D w Lt) (/) VJ tions in the literature. u. ID .. .. Ul>->- Previo~s reports have indicated?alN~h incidence of diabetes in ...J « "'o:ro:r u,....,.... I zl the familIes of patients With PWS.-· , Two ofour patients had a U family history of maturity-onset diabetes, but this does not differ Cl Q from the situation in the normal population. ...J Q '" 'iij The syndrome can be divided into two clinical phases. 17 .2 c cl (5 Initially there are the problems relating to hypotonia in the E perinatal period, such as the diminished fetal movements, an «" a:: a; ~ Z '" '" increased incidence of breech presentation, low Apgar scores, ~~ a. and marked neonatal floppiness with attendant sucking and W ...J Z::::l =~ zl swallowing problems. After several months tone usually improves en « and this was the situation with all our patients excepting case 5 I- (see case report), in whom the period of hypotonia was even more prolonged. The second stage of the syndrome is characterized by '" '(ij .2 delayed milestones, falling off in stature and onset of hyperpha- 'c" o '0 <J gia, often at 2-3 years, with the subsequent development of ZZ <Il zl obesity. Mental retardation usually becomes obvious, and behav- 7 ioural problems often become manifest. 2.I Our patients' mile- stones were consistent with those reported where, on average, sitting was achieved at 12 months, walking at 30 months (range 24-48 months) and talking at 42 months (range 20-60 months).2,17 IQ scores have ranged between 20 and normal, with an average of around 55,2 and the majority of patients were thus moderately 2 retarded. However, patients have been reported ,13 with normal zl intelligence and so there is reason to assume that the syndrome involves a broader spectrum than initially suggested and that ci mental retardation is not a prerequisite for diagnosis. I) E Although weight gain is usually excessive by 2 years, the onset of actual obesity is often not until 3-5 years of age. 2 The aetiology 'c" o '" E ZZ Z Z<ll of this extreme adiposity (which was well shown by our skinfold measurements) is uncertain. It is most likely due to the overeat- '" ing, which was very evident in the majority of our cases. Although some studies have failed to demonstrate any abnormal- '" c o .c ity in fat metabolism in the Prader-Willi syndrome,1O a tenfold c increase in adipose tissue lipoprotein lipase (AT-LPL) when compared with controls has been reported. AT-LPL has pre- '" '" :J: 'E ::l.. 0> C '" 't:l .. 0> C..c '0. viously been implicated in the causation of obesity. II The man- C Cii~ 0 <Il "'- IQ agement of the obesity has proved most difficult, and suggested regimens involve the use of a protein-sparing modified diet 20 and 886 SA MEDIESE TYDSKRIF DEEL 63 4 JUNIE 1983 the administration of naloxone, which probably acts by interfer- management of this fairly rare condition, but also clarify the ing with disordered hypothalamic and/or pituitary R-endorphin relationship between chromosomal rearrangements and dys- activity.21 morphic syndromes. Hypogonadism, which is a cardinal feature, was easily demon- strable in the male patients but was more difficult to demonstrate in the females. The? ~lf.l~gonadism is thought to be due to \V/e are grateful to Professor P. Beighton for his guidance during hypogonadorroplsm.-, , " Endocnne investigations Into pitUI- our survey, Dr M. Nelson and Mr R. Smart for the cytogenetic tary, thyroid and adrenal function have not revealed conclusive studies, Dr L. Stephen for the dental investigations and Gillian abnormalities. 2 ,5,8 The cause of the short stature has not been Shapley for preparing the manuscript. This survey was supported by grants to Professor P. Beighton established. from the University of Cape Town Staff Research Fund and the There are numerous additional features associated with the South African Medical Research Council. syndrome, such as strabismus, hypertelorism and epicanthic folds, a small bifrontal diameter, abnormal ear lobes, c1inodact- yly, syndactyly, slender tapering fingers, enamel defects, xeros- REFERENCES tomia, kyphoscoliosis and genu valgum. 2,5.13,18,19 Our findings are not at variance with those in the literature, Six of our patients I. Prader A, Labhart A, Willi H. Ein Syndrom \'On Adipositas, kleinwuchs, Kryprorchismen und Oligophrenie nach myotonieanigem Ztistand Un had kyphoscoliosis. It has been suggested that the high incidence Neugeborenenalter. Sch'weiz Med Wochen,chr 1956; 86: 1260. of kyphoscoliosis may result from a residual hypotonia. How- 2. Dunn HG. The Prader-Labhan-Willi svndrome: review of me literature and report of nine cases. Aaa Paedimr scalld 1968; suppl 186, 1-38. ever, although our patients showed poor muscular co-ordination 3. Forsman H, Hagberg B. Prader-Willi syndrome in boy of ten with prediabetes. and a broad-based unsteady gait, it was difficult to demonstrate ",ctu Puediutr 1964; 53: 70-78. 4. HamillOn CR jun, Scully RE, Kliman B. HypogonadOlropinism in Prader- clear-cut hypotonia, Willi syndrome. Introduction of puberty and spermarogenesis by clomiphene A recent radiological survey9 detected a number of non- cirrate. Alii] Med 1972; 52: 322-329. specific features, which included atrophic fat, infiltrated mus- 5. Jeffcoate WJ, Laurence BM, Edwards CRW, Besser GM. Endocrine function in the Prader-Willi svndrome. Clin Endocrillol 1980; 12: 81-89. cles, a small sella turcica, sutural abnormalities with increased 6. Kauli R, Prager-Le"'in R, Laron Z. Pubertal development in the Prader- numbers of wormian bones, scoliosis, coxa valga, small hands Labhart-Willi svndrome. Aaa PaediaLr Scu"d 1978; 67: 763-767. 7. Parra A, Cervantes C, Schultz RB. Immunoreactive insulin and growth hor- and feet, thin cortices in the metacarpals and a normal bone age, mone responses in patients with Prader-Willi syndrome. ] PediaJr 1973; 83: An earlier paper has referred to a delayed bone age;2 this was also 587-593. 8. Tolis G, Lewis W, Verdy 1\1, Friesen HG, Solomon S, Pagalis Geral. Anterior our finding in the majority of the patients, but we were unable to pituitan' function in rhe Prader-Labhart-Willi (PL W) syndrome.]Clill Endo-' confirm the other features, crinol Metab 1974; 39: 1061-1066. Our cytogenetic investigations failed to show the deletions in 9. Pearson KD, Steinbach HL, Bier DM. Roentgenographic manifestations of the Prader-Willi svndrome. Rudiology 1971; 100: 369-377. the long arm of chromosome 15 demonstrated by Ledbener el 10. Bier DM, Kaplan SL, Havel RJ. 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Am] Di, Child 1977; I31: 798-800. chance none of our patients had the deletion, it is also possible 14. Feingold M, Bossert WHo Normal values for selected physical parameters: an that our metaphase banding was unable to show up the defect. aid to syndrome delineation. Birth Defem 1974; 10: No. 13, 1-16. 15. Tanner JH, Whitehouse RH. Re"ised standards for triceps and sub-scapular High resolution banding may be more informative in the future. skinfolds in British children. Arch Dis Child 1975; 50: 142. With the weight of this evidence it seems very likely that a 16. Hall BD, Smith DW. Prader-Willi S\·ndrome. A resume of 32 cases including deletion in chromosome 15 is the cause of the P\\TS in many an instance of affected first cousins·, one of whom is of normal stature and intelligence.] Pediatr 1972; 81: 286-293. cases. Ledbetter el al. 12 suggest that those patients without 17. Zellweiger H, Schneider HJ. Syndrome of hYPolOnia-hypomentia-hypogo- the deletion may nevertheless have a cytogenetically undetect- nadism-obesity (HHHO) or Prader-Willi syndrome. Am] Dis Child 1968; 1150: 588-598. able deletion or inversion, a mosaic, a point mutation leading to 18. Smith DW. Recogllizuble Paller1lS of HI/mUll Malformatio". 2nd ed. Philadel- the same phenotype or they may be a phenocopy or be phia: WB Saunders, 1976: 106-107. 19. Landwirth J, Schwarrz AH, Grum JA. Prader-Willi syndrome. Am] Dis Child misdiagnosed. 1968; 116: 211-217. The PWS is a well-defined clinical entity with a probable 20. Bistrian BR, Blackburn G L, Stanbury JB. Metabolic aspects of a protein chromosomal basis, but the biochemical and growth defects are sparing modified fast in the dietary management of Prader-~rilli obesity. N Ellgl] Med 1977; 296: 774-779. poorly understood. A fuller understanding of the aberrant phy- 21. Kyriakides M, Silvers lOne T, Jeffcoate W, Laurance B. Effect of naloxone on siology of the syndrome may not only open doors to the better hyperphagis in Prader-WiIJi syndrome. LUllcet 1980; i: 876-877.