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1.5 THE PRADER-WILLI SYNDROME IN CAPE TOWN - The Prader-Willi Powered By Docstoc
					                                                                                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
         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.    ("'-.

                      E                                                                           o                Development
                                                                                                 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 >->.
         '"        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


 >                                                                                                                 patients. A number were described as thin children until 2-3
 rn                                         o    ("0.   C'.    N+r-                  o
 ...J                                                                                                              years of age and only then did they start putting on weight.
                                                                                                                   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
 C                                                                                                                 on occasions, while patient 7 had occasionally eaten cement, dead
 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
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                                                 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
Z       .,.       an                                                                                               reported by Smith I would probably encompass the levels in our
         (fl      ~                                                                                                patients, with the exception of case 8, who was possibly in the
Z 0
w '"
                  ,...LL                    o                 ~
                                                                 .    ,
                                                                                                                   borderline range.
                  E                                                                                     E          Somatotype
~       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
>                                                                                                                  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-
                                                                                          .........                ments clearly demonstrated the marked obesity of all our
J:      ~                                               ...

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        0                                  o    z~            N'+                        NNC"l
                                                                                                                      Other somatic abnormalities that occurred frequently were:
~                                                                                                                  strabismus (6 out of9 patients), clinodactyly (8 patients), kypho-
                  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
                                                .~ E
...J    Q)                                                                                       en          c     forehead, blue eyes and fair or auburn hair. Three ofour 5 White
CD      (fl       e!
                                                E ...                                    <I)

                                                                                         ~       >. >.

et      '"                                      .-
                                                                      +                                      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
                                                                                                                   dorsum with proximal phalanges tapering distally.

                                                                                                                   Sexual characteristics
                                                                                                       "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
                                                                                                                   3 had cryptorchidism. The penis ofthe 16-year-old was also very
                                                                                         Clc:E                     short, being only 2 cm in length.
                                                                                         .- -
                                                                                             ca ...
                                                                                                       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                                    '"
                                                                                        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
                                                                                         '"     '"

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                                                                                                                                                '" 0>
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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
was undertaken in all patients. This did not reveal a distinctive                                                    '0
pattern in the length of the phalanges or metacarpals, although                                      zz              <Il            zl
marked shortening was apparent.
   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                            '"
                                                                                         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
                                                                                   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
chromosome IS.                                                                          r-.
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                                                                                         ..     '"
                                                                                  u,....,....                                       zl
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    .. ..
   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
from the situation in the normal population.                              ...J
   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; ~  Z
increased incidence of breech presentation, low Apgar scores,                                             ~~ a.
and marked neonatal floppiness with attendant sucking and
                                                                          ...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
delayed milestones, falling off in stature and onset of hyperpha-                                         'c"
                                                                                                           o          '0
gia, often at 2-3 years, with the subsequent development of                                          ZZ               <Il           zl
obesity. Mental retardation usually becomes obvious, and behav-
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
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                               '"
                                                                                                     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-
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
                                                                                                                                    't:l   ..
viously been implicated in the causation of obesity. II The man-
                                                                                                                       <Il          "'-
agement of the obesity has proved most difficult, and suggested
regimens involve the use of a protein-sparing modified diet 20 and

 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
                                                                         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. The Prader-Willi syndrome regulation of fat
al. 12 A series presented by these workers at the Genetics Confer-            transpon. Diabe1eS 1977; 26: 874-881.
                                                                          11. Schwartz RS, Bransell JD, Berman EL. Elevated adipose tissue lipoprotein
ence in Israel in 1981 revealed 23 out of a series of 45 Prader-              lipase in the pathogenesis of obesity in the Prader-Willi syndrome. TraIlS Assoc
Willi subjects with a deletion of chromosome 15 with break-                   Am Phvsicians 1979; 92: 89-95.
points at 15qll and 15q 13. A few of their subjects showed some          12. Ledbeiter DH, Riccardi VM, Airlast SD, Strobel RJ, Keenan BS, Crawford
                                                                              JD. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N
other abnormality involving chromosome 15. Other series have                  Engl] Med 1980; 304: 325-329.
shown only a 2-5% incidence I Although it is conceivable that by         13. Clarren SK, Smith DW. Variable severity and recurrence risk. 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.