American Journal of Medical Genetics 42:220-230 (1992)
Conference Report: First International Scientific Workshop on Prader-Willi Syndrome and Other Chromosome 15q Deletion Disorders
Suzanne R . Cassidy Section of Genetics/Dysmorphology, Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona College of Medicine, Tucson
Key words:
Prader-Willi syndrome, Angelman syndrome, chromosome deletion, 15qdeletion. genetic imprinting, disomy, contiguous gene syndrome, growth hormone, sleep disorder, diagnostic criteria
INTRODUCTION Everyone must have a day that they can point to as a major turning point in their career; I certainly do. It was the day t.hat Judy Hall announced to the genetics fellows at the University of Washington (of which I was one) that a small deletion had been identified in several patients with Prader-Willi syndrome at Baylor College of Medicine, using the newly developed method of prometaphase banding. She asked whether any of us would be interested in coordinating a study of the patients in Dr . Vanja Holm's Prader-Willi syndrome clinic, in collaboration with Dr. Horace Thuline, who as director of the State of Washington's cytogenetics laboratory had already begun using this high resolution technology. Having a long-standing interest in karyotype-phenotype This correlation, I volunteered. complex and utterly fascinating disorder has been the major focus of my Received for publication June 21,1991; revision received August 5, 1991.
Address reprint requests to: Suzanne B. Cassidy, M.D. Associate Professor of Pediatrics, Section of Genetics/ Dysmorphology, Univ. of Arizona College of Medicine, Tucson, AZ 85724
0 1992 Wiley-Liss, Inc.
clinical research interest since that day. I cannot imagine this focus bringing me to a more exciting point that it did when I saw my organizational efforts culminate in the international scientific workshop on Prader-Willi Syndrome and Other Chromosome 15q Deletion Disorders, which was held on May 2 and 3, 1991 in The Netherlands. The response to letters of inquiry about the desirability of such a meeting and the invitations to key speakers was most encouraging. The response to the call for abstracts was overwhelming; more than 70 abstracts, most of high scientific quality, were submitted. This level of research productivity indicated that the topics of Prader-Willi syndrome, Angelman syndrome, and the unique genetic relationship that they share, are of major interest to professionals in molecular genetics and cytogenetics, in clinical genetics, endocrinology, child development, neurology, rehabilitation, psychiatry and psychology, and genetic counseling.
Prader-Willi Conference Report Perhaps the most gratifying part of the meeting was seeing laboratory and clinical researchers from 15 countries in four continents represented among the participants, and even more countries and continents represented among the professional and parent observers. Many of the participants knew each other in print only, and were delighted to meet for the first time. Several international research collaborations were established during informal discussions at the meeting, and a few vigorously argued differences of opinion will likely result in newly energized research efforts. The workshop ended with initiation of plans for another such international meeting on the same topics within the next three to four years. Efforts to understand the genetics of Prader-Willi and Angelman syndromes, with their implications for unraveling genetic imprinting and for shedding light on normal and abnormal brain development, have advanced dramatically in the 11 years since the 15q deletion was first discovered. There is still much to learn, and an international scientific workshop is an outstanding forum in which to stimulate such learning. INTERNATIONAL SCIENTIFIC WORKSHOP ON PRADER-WILL1 SYNDROME AND OTHER CHROMOSOME 15q DELETION DISORDERS DeLeeuwenhorst Congress Center, Noordwijkerhout, The Netherlands Thursday, May 2, 1991 First Session: H i s t o r y , Phenotype and Genetics
Cytogenetics of Prader-Willi Syndrome and Angelman Syndrome: Ellen Magenis, Oregon Health Sciences University, Portland, OR, USA Second Session: Holecular Genetics Moderator: Bernhard Horsthemke The Irregular Inheritance of Angelman and Prader-Willi Syndromes: Marcus Pembrey, University of London, England, UK Microdissection and Molecular Analysis sf Proximal 15q: Bernhard Horsthemke, University of Essen, Germany Genome Imprinting and the Role of Epigenetic Inheritance During Development: M. Azim Surani, Institute of Animal Physiology and Genetics Research, Cambridge, England, UK Characterization of cDNA Clones Corresponding to Genomic Loci Rearranged in PWS Patients. CA Gregory, AJ Kirkilionis, JL Hamerton. Possible Genomic Imprinting at the Angelman Syndrome Gene Locus. N Niikawa and J-I Hamabe. Molecular Analysis in Angelman Syndrome and Prader-Willi Syndrome, and Potential Mouse Models. RD Nicholls, W Gottlieb, MJ Mascari, EM Rinchik, GS Pail DJ Driscoll, MG Butler, RT Zori, PE Neumann, MF Waters, JL Zackowski, B Horsthemke, RL Ladda, and CA Williams.
Prader-Willi Syndrome in 1956 and 1991: Andrea Prader, University of ZGrich, Switzerland
Clinical, Molecular, and Cytogenetic Survey of Potential Prader-Willi Syndrome Patients. WP Robinson, J Balakrishnan, F Binkert, A Bottani, M Machler, Z Yagang, A Prader, and A Schinzel.
Overview of Prader-Willi Syndrome: Suzanne B. Cassidy, University of Arizona, Tucson, AZ, USA
Third Session: Cytogenetics and C l i n i c a l Genetics
Moderator: Suzanne B. Cassidy
Moderator: Ellen Magenis
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Xosaicism for Deletion 15qll-ql3 in Sporadic and Familial Cases. SR Patil, B Hauschildt, D Wilson, C Headley, M Greally, J Hanson, and T Donlon .
A Multicenter Italian Study of PraderWilli Syndrome. A Salvatoni and the Obesity Study Group of The Italian Society of Paediatric Endocrinology and Diabetology.
Prader-Willi Syndrome and Angelman Syndrome in Two Female Cousins as a Result of a Familial Translocation. DFCM Smeets, MR Nelen, BCJ Hamel, APT Smits, HJM Smeets, JHM Bollen, and BA van Oost.
Prader-Willi Syndrome in Norway. Lofter4d and A Heiberg.
An Australian Collaborative Study of Prader-Willi Syndrome Individuals and Their Families. A Smith, S White, G Warne, P Montgomery, J Nelson, H Beange, J Pearn, J Henderson, and KJ Trent.
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A Comparison of Characteristics in 33 Japanese and 83 American PraderWilli Syndrome Patients. JM Hariehett, N Matsuo, T Nagai, N Niikawa, and H Tonoki. Sixth Session: Clinical Aspects Prader-Willi Syndrame. 11.
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Moderator: Vanja Holm Implications for the Recurrence Risk in the Prader-Willi Syndrome on the Basis o€ Proposed Genomic Imprinting. I Kennerknecht. Friday, May 3, 1991 Fourth Session: Physiology of Clinical Features Moderator: Suzanne B. Cassidy Hormone Physiology and Therapy in Prader-Willi Syndrome: Martin Ritzgn, Karolinska Institute, Stockholm, Sweden. Mechanisms of Appetite Control and Their Abnormality in Prader-Willi Syndrome: Tony Holland , Bethlem Royal Hospital, Beckenham, England, UK Fifth
Session: Clinical Aspects Prader-Willi Syndrome. I.
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Growth Hormone Evaluation and Treatment in Prader-Willi Syndrome. M Angulo, M Castro-Magana, J Uy, and W Rosenfeld. Diminished 24 Hour Urinary Growth Hormone Excretion in Patients with Prader-Willi Sydrome. S Blichfeldt, K Main, M Ritzen, and NE Skakkebaek. Studies of Body Composition in Patients with Prader-Willi Syndrome: Implications for Management. W Klish, B Brown, T Lin, P Lee, and F Greenberg. Total Energy Expenditure in the PraderWill: Syndrome. PSW Davies, C Joughin, TJ Cole, MBE Livingstone, and ND Barnes. Scoliosis Surgery in the Prader-Willi Syndrome. MW Jones. Seventh Session: Psychological an Behavioral Aspects of Prader-Willi Syndrome
Moderator: Jean-Pierre Fryns Moderator: Louise Greenswag Diagnostic Criteria for Prader-Willi Syndrome. VA Holm, SB Cassidy, MG Butler, JM Hanchett, F Greenberg, BY Whitman, LR Greenswag. A Family Focused Care Model for PraderWilli Syndrome in Norway. A Heiberg, K Storhaug, C Aashamar, and €3 Lofter$d.
Psychological Characteristics and Intervention Strategies in PraderWilli Syndrome: Paul MG Curfs, Pedological Institute DeHondsberg, The Netherlands.
Prader-Willi Conference Report History, Cbrrent Use, and Impact of Mood Altering and Behavior Change Medication in 114 Individuals with Prader-Willi Syndrome. BY Whitman and LR Greenswag. Psychological Profile in Patients with Prader-Willi Syndrome. M Borghgraef and J-P Fryns. Behavioral and Emotional Problems in Youngsters with Prader-Willi Syndrome. PMG Curfs, FC Verhulst, and J-P Fryns.
Eighth Session: Clinical Aspects of Angelman Syndrome
Characterization of YAC and cDNA Clones from the PWSjAS Chromosomal Region. K Buiting, V Greger, and B Horsthemke. Prader-Willi Syndrome: Deletion of DNA Probes Mapped to 15qll-13 in a Cytogenetically Normal Patient. BG Koussef f, OT Mueller , PR Papenhausen, and M Torres. Molecular Deletions in Prader-Willi Syndrome and in Angelman Syndrome. J-I Hamabe and N Niikawa. DNA Studies in Prader-Willi and Angelman Syndrome. H Smeets, M Nelen, A Smits, D Smeets, A AkkermansScholten, I van de Burgt, and B van Oost.
Moderator: Ellen Magenis Angelman Syndrome: A Clinical Update: Patrick Willems, University of Aritwerp , Belgium Angelman Syndrome in the Adolescent and Young Adult. J Clayton-Smith. Clinical Findings in Angelman Individuals Without a Molecular Deletion or Uniparental Disomy. R Zori, RD Nicholls, DJ Driscoll, and CA Williams. Genetic Counseling for Angelman Syndrome When the Proband has a Cytogenetic or Molecular Deletion. J Hendrickson, L Marfatia, K Kovak, E Magenis, and C Williams. Panel Discussion: Current Understanding A b u t Diagnosis and Recurrence Risks of Prader-Willi and Angelman syndrames
Panel Members: Timothy Donlon (Leader), Marcus Pembrey, Ellen Magenis, Bernhard Horsthemke
wsms MOLECULAR GENETICS AND CYTOGENETICS OF PFZADER-WILL1 AND ANGELMAN SYNDROMES
Molecular Analysis of the Prader-Willi Syndrome. RJ Trent, F Volpato, A Smith, R Lindeman, G Warne and E Haan. Long Range Mapping of the Prader-Willi Chromosome Region Using Pulsed Field Gel Electrophoresis. T Woodage, R Lindeman, A Smith and RJ Trent. Maternal Origins of 15qll-13 Deletions in Three Unrelated Patients with Angelman Syndrome: Further Evidence for Genomic Imprinting. D Bettio, D Gardino, N Rizo, and G Simoni. Deletion of Chromosome 15qll-13 in Two Groups of Patients with Different Consistency with Prader-Willi Syndrome. D Giardino, D Bettio, N Rizzi, and G Grugni. Cytogenetic and Molecular Analyses in Prader-Willi and Angelman Patients. Correlation or Discrepancy? E Wesbyvan Swaay, JO Van Hemel, DJJ Halley, and ES Sachs. Molecular Investigation of the DNA Mutations Leading to Angelman Syndrome. J Beuten, P Coucke, IM Buntinx, B Van der Auwera, and PJ Willems. DNA Studies in Sibs with PWS. M Anvret, A Martony, KH Orstavik, and K Brsndum-Nielson.
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Evaluation of Improved G-Banding for the Detection of Deletions in Patients with Angelman Syndrome. KJ Mangelschots, BC Van Roy, FP Speleman, IM Buntinx, PJ Willems, and JE L>umon. Twins and the Prader-Willi Syndrome: A Study of Two Cases. A Smith, R Mclvor, J Dunstan, A Kearney, and RJ Trent. Genetic Aspects of Angelman Syndrome: Evidence for Genomic Imprinting. K Schmidt, K Sperling, RD Wegner, B Horsthemke, and J Kunze.
CLINICAL ASPECTS OF SYNDROME
PRADER-WILL1
Prader-Willi Syiidrome in Northern Ireland. FJ Priest, NC Nevin, A Hughes, and I Rennie.
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Comparison of Growth Pattern of Prader-Willi Syndrome Between Japanese and Caucasian. T Nagai, N Matsuo, Y Fukushima, H Totoki, and N Niikawa.
Incidence o€ Altered Glucose Tolerance in Patients with Prader-Willi Syndrome. G Grugni, A Ardizzi, G Guzzaloni, and F Morabito. Small Ovaries Without Primary Follicles and Other Characteristics in 12 Cases of Prader-Willi Syndrome. C Dacou-Voutetakis, Th Papanicolaou, J Pagalos, M Korvesi, D Chiotis, and A Vourou. Sleep and Breathing Patterns in Adult Patients with Prader-Willi Syndrome. M Cataletto, G Hertz, S Feinsilver, and M Angulo. Abnormalities of Sleep and Arousal in Prader-Willi Syndrome. KH Warton, K Levine, and JA Hobson. The Sl-eep-WakeContinuum in the PraderWilli Syndrome. B HelbingZwanenburg, M Damen, and w\C Kamphuisen.
Hyperthermia in Infants with PraderWilli Syndrome. MS Wise, H Zoghbi, M Edwards, LK Byrd, AE Guttmacher, and F Greenberg. Antero-Posterior Cephalometric Analysis of the Craniofacial Complex in Prader-Willi Syndrome. AE Poole, RM Munoz, and SB Cassidy.
PSYCHOLOGICAL AND BEHAVIORAL ASPECTS OF PRADER-WILL1 SYNDROME
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Cognitive, Behavioral and Genetic Study of Prader-Willi Syndrome : University of Birmingham Collaborative Study. C Hardy, MW Kilpatrick, T Webb, S Bundey, DJ Clarke, J Corbett, and P Sturmey.
Intelligence and Cognitive Profile in Prader-Willi syndrome. PMG Curfs, A Wiegers, M Borghgraef, and J-P Fryns . Cognition and Behavior in Prader-Willi Syndrome. DJ Clarke and JE Doherty (in collaboration with: T Webb, C Hardy, M Kilpatrick, S Bundey, J Corbett, and P Sturmey). Sexual Feelings and Fantasies in PraderWilli Syndrome Girls. P Bregani, P Brambilla, C Ripamonti, C Chisalberti, L Tomasini, D Cella, and G Chiumello. Emotional Implications in Prader-Willi Syndrome Subjects' Food Behavior. P Bregani, P Brambilla, C Ripamonti, C Pani.goni, C Chisalberti, L Tomasini, and G Chiumello. Self Trauma in Prader-Willi Syndrome. JM Hanchett .
CLINICAL ASPECTS OF ANGELMAN SYNDROME Clinical. Evaluation of the Angelman Syndrome in Belgium and The Netherlands. IM Buntinx, BJ Willems, KJ Mangelschots, RC Hennekam, OF Brouwer, J Beuten, and JE Dumon.
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Prader-Willi Conference Report Morphometric Analysis of Facial Features in Patients with Angelman Syndrome. JL Frias, GB Schaefer, B Gray, and CA Williams. Five Young Children with 15q Deletion Lacking the Prader-Willi or Angelman Syndrome Phenotype. VA Holm. Neonatal Diagnosis of de1(15)(qll-13) Without Prader-Willi Phenotype. F Greenberg, J Parke, R Zeller, E Mizrahi, and DH Ledbetter. HISTORY, PHENOTYPE, NATURAL HISTORY AND CYTOGENETICS The workshop was honored to begin with the historical perspective of Professor Andrea Prader (University of Zirich), a senior pediatric endocrinologist who first recognized the pattern of human malformation which constitutes the Prader-Willi syndrome (PWS). He included pictures of Drs. Labhart and Willi, the co-workers on his pivotal paper in 1956. He particularly remarked on the dramatic changes in the genetic understanding and the level of interest in this disorder in recent years. The members of the audience for this workshop were very diverse in their areas of expertise and familiarity with the various aspects of PWS; included among them were academic physicians of several different specialties, molecular geneticists, cytogeneticists, and psychologists. In order to provide a common framework of knowledge about PWS and abnormalities of chromosome 15q, Suzanne Cassidy (University of Arizona) provided a broad overview of the phenotype, natural history, and what is known of the etiology of PWS. This included the discovery of the chromosomal deletion of 15q, its paternal origin, recent findings of maternal disomy in chromosomally normal cases, and the determination that maternal deletion causes the clinically dissimilar disorder Angelman syndrome (AS), whose features were briefly described. Ellen Magenis (Oregon Health Sciences University) then reviewed in greater detail the refinement of the
chromosome anomalies present in PWS and AS, providing a comparison indicating nearly total overlap. The improvement of high resolution cytogenetic technology and the methods of detecting parental origin for the two disorders was presented. She did suggest that subtle differences indicate that the genetic locus for the two disorders may be different. Additional clinical details of AS were also provided from her considerable experience.
APPROACHES TO MOLECULAR GENETICS AND GENOMIC IMPRINTING Bernhard Horsthemke (University of Esseri) described his approach to unraveling the molecular genetics of 15q, indicating that this was the vital first step in using reverse genetics to determine the genes whose abnormality result in PWS and AS, and thence their functions, as well as to delineate the molecular extent of the deletion. He uses the technique of physical microdissection to produce a microclone library, then forms probes which can be sequenced. Polymerase chain reaction (PCR) is used to identify loci and clones, using yeast artificial chromosomes (YACs). Over 5000 overlapping clones in 15q11.2-13 have been isolated, and a restriction map made. Two specific clones appear in multiple copies in proximal 15q and vary in number among individuals, possibly conferring instability to this region. Azim Surani (Institute of Animal Physiology and Genetics Research, Cambridge) focused on genomic imprinting. This epigenetic marking process leads to functional differences between the two types of parental genomes, conferring preferential activity on one of the homologous parental alleles. Using mouse androgenones and gynogenones, rescuing them from lethality in chimeras, he has identified regions of the mouse genome which harbor imprinted genes and demonstrated their phenotypic effects The mouse distal chromosome 7 region is homologous to the human proximal 15q and is highly subject to imprinting effects. This region contains Insulin-like Growth Factor 2 (Igf2), which is involved in embryonic growth and is preferentially a
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repressed .in the maternally derived genome. This system of studying mouse transgenes is valuable in unraveling the effects of human imprinting. Marcus Pembrey (University of London) described the theoretical mechanisms for production of disomy, including trisomy 15 (nondisjunction) with later loss of one chromosome, combination of dizygous and nullizygous zygotes, and combination of a normal and nullizygous zygote with later duplication of the normal 15. He provided evidence suggesting that the entire chromosome 15 is disomic in disomy cases. A family was described in which a rearranged chromosome 15 is segregating and first cousins were produced in which one has AS and the other PWS (in whom a paternal deletion is also present). This situation suggests that rearranged 15s can induce deletions. His study of 84 patients with As suggests significantly differing recurrence risks depending upon whether deletion, disomy, or normal 15s are present. There are far more recurrences in families with AS than with PWS, in which recurrence is rare. The sibling pairs had neither deletion nor disomy. In nbout half the pairs both had received the same parental 15s, but in the other half there were different paternal 15s and the same maternal 15s, excluding an autosomal recessive gene on 15 as the cause in those cases. Recurrence risk is quite low in deletion and disomy cases (less than 2 % ) , but much higher in cases where both these abnormalities have been excluded.
MOLECULAR GENETICS AND CYTOGENETICS Carolyn Gregory (University of Manitoba) described her studies screening a cDNA human fetal brain library and zoo blots using two loci from the Prader-Willi Chromosome Region (PWCR). Conservation of the genomic loci and the cDNA sequences are limited to primates and some but not all human cell types. Interestingly, this message was detected in human fetal brain tissue but not adult brain. Norio Niikawa (Nagasaki University) presented an interesting family in which three siblings with AS were all hemizygous for the paternal
allele of one 15q probe, and their mother was hemizygous for a different allele of this probe, which represented absence of her father's allele. All but one of the other probes in 15q were heterozygous in all tested individuals. Thus, the same submicroscopic deletion occurri-ng in the paternally derived chromosome (the maternal grandfather's) caused no phenotypic change, whereas when it occurred in the maternally derived chromosome (the mother's), it caused AS in the offspring. Not only does this family confirm the importance of imprinting in the cause of AS, but the absence of PWS in the mother despite the paternal deletion implies that the loci for PWS and AS are different.
Rob Nicholls (University of Florida) investigated the genetics of 15q by studying the families of 27 patients with AS and 17 with PWS. Parental origins and the presence of disomy were confirmed. Of the PWS cases, everyone had either deletion (71%) or some other chromosome anomaly involving 15 ( 8 % ) , or had disomy (21%). Some without a chromosomal deletion had a molecular deletion. Of 27 AS patients studied, only one had disomy, and 2 0 had deletion. Clones derived from human 15q were mapped to mouse chromosome 7, and mapping order was determined. Maternal meiosis I nondisjunction is the most likely mechanism in the cause of maternal disomy, presumably through a trisomic intermediate. Patients with either syndrome with a deletion tend to be hypopigmented, as are mice disomic for chromosome 7, suggesting that a gene involved in the pigment system is affected by gene dosage and not genomic imprinting. Wendy Robinson (University of &rich) presented her molecular studies of 36 patients with possible PWS. Distinction between patients on the basis of clinical criteria correlated with molecular testing in showing that all typical patients had either deletion or disomy. Disomy appeared to be for the entire chromosome 15, confirming other studies. Most strikingly, in disomy cases the parental age was advanced (about 8 years older than the deletion cases), pointing to maternal nondisjunction leading to trisomy with subsequent loss of the paternal chromosome as a mechanism in the disomic cases. The advanced maternal age in
Rader-Willi Conference Report disomy cases was confirmed by Nicholls from his studies. CYTOGENETICS AND CTJNICAL GENETICS Mosaicism for 15q deletion was initially thought to exist, then was later thought to result from variability of the proximal 15q region. Shiva Patil (University of Iowa) presented 3 sporadic patients and 2 familial cases in which chromosomal mosaicism for 15q was convincing. Of the sporadic cases, two had intellectual limitations and were small, but did not have evident PWS or AS. In the familial cases, the mothers had mosaicism for del 15q and the affected child had del 15q in all cells but did not have typical A S or PWS phenotype. The mosaicism could not be confirmed with molecular studies. Cytogenetic mosaicism must be carefully scrutinized. Dominique Smeets (University of Nijmegen) presented a family in which a balanced 6;15 translocation was present in two brothers, one of whom had a daughter with PWS and the other a daughter with AS. While the unaffected translocation carriers had normal molecular findings in 15q, the child with PWS had a molecular deletion in the translocation chromosome, and the cousin with AS had paternal disomy for 15 but no deletion. Thus, unequal crossing-over had likely occurred during meiosis in the PWS child. This suggests that the presence of translocations involving 15 may significantly increase the risk for deletion and disomy, adding further evidence to the study of Pembrey mentioned earlier. Looking at all the published data of approximately 800 PWS patients, including 7 fcmilies with recurrence, lngo Kennerknecht (University of Ulm) used sib and proband methods to study recurrence risks. None of the familial cases have had deletion or disomy. He proposed a mechanism in which maternal imprinting and paternal erasure of the imprint could account for the findings in PWS. In familial cases, he proposed that female transmitters would have normal children for a "dysfunctional" PWS genefregion, whereas male transmitters would have 50% affected children. He proposed
recurrence risks of 0.4% in an isolated case of PWS and 50% recurrence risk when more than one sib was affected. Arabella Smith (Children's Hospital, Camperdown, Australia) presented an Australian collaborative study looking for recurrence in 144 families with PWS. Among 266 living sibs there was no recurrence. There was only one familial recurrence, in third cousins, which could have been explained by coincidence. There were four sets of twins, all like-sex, all but one of which was discordant. There was no increase in fetal wastage. Many of the molecular findings were confirmed in presented as posters.
genetic studies
PHENOTYPE, NATURAL HISTORY, AND EPIDEMIOLOGY OF PWS Martin Ritzgn (Karolinska Institute) reviewed current knowledge about the endocrine findings in Pws. In addition to the well-described hypothalamic insufficiency leading to hypogonadotrophic hypogonadism, he noted that premature adrenarche but not gonadarche was common. His study of 8 PWS patients and 11 obese controls found differing FSH and LH response to GNRH, but no difference in melatonin or prolactin secretion, cortisol levels or thyroid hormones. There was no difference either in growth hormone response to stimulation, but those with PWS have lower spontaneous secretion of growth hormone following sleep. Insulin secretion following glucose load was prolonged in PWS. He recommended treatment of males with testosterone to increase muscle mass, independence, maturity and concentration. Tony Holland (Bethlem Royal Hospital, Kent) reviewed mechanisms of satiety in light of apparent absence of appropriate satiety in PWS. His studies in 13 obese adults with PWS indicated that they achieve satiety but only after three times more calories than controls (average: 1500 cal lunch), and their hunger returns much more quickly. Following a controlled meal, secretion of cholecystokinin (a satiety agent) is significantly higher in PWS versus controls, suggesting a possible
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alteration receptors.
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The d i f f i c u l t i e s o f d i a g n o s i n g PWS l e d a y r o u p o f 6 c l i n i c a l experts i n t h i s d i s o r d e r t o convene t o d e v e l o p c o n s e n s u s d i a g n o s t i c c r i t e r i a f o r PWS. The c r i t e r i a , p r e s e n t e d b y Vanja H o l m ( U n i v e r s i t y o f Washington), were based on a s c o r i n g s y s t e m which i n c l u d e d b o t h major and minor manifestations, s e p a r a t e d by t h e i r s p e c i f i c i t y and f r e q u e n c y . A s e p a r a t e s e t of c r i t e r i a was d e v e l o p e d f o r t h o s e below a g e 3 years, since t h e c l i n i c a l presentation i s so d i f f e r e n t a t t h a t t i m e . T e s t i n g of t h e s e c r i t e r i a on o v e r 100 p a t i e n t s r e f e r r e d f o r possible PWS i n d i c a t e d t h a t t h e t e s t s were e f f e c t i v e i n i n c l u d i n g t h e t y p i c a l PWS p a t i e n t s and e x c l u d i n g t h o s e f e l t n o t t o have t h i s c o n d i t i o n by the experienced testers. Christian Aashamar (Frambu H e a l t h C e n t e r , Norway) d e s c r i b e d t h e Norwegian s y s t e m of a t w o week r e s i d e n t i a l e d u c a t i o n a l and medical program f o r e n t i r e f a m i l i e s a f f e c t e d by conditions causing d i s a b i l i t y , including PWS. This provides support and i n f o r m a t i o n f o r p a r e n t s and siblings, a s s e s s m e n t and t e a c h i n g o f a f f e c t e d i n d i v i d u a l s , and a n i d e a l o p p o r t u n i t y f o r c l i n i c a l research. Bjqrn Lofterqd (Moss H o s p i t a l , Norway) t h e n p r e s e n t e d h i s p e r s o n a l and s u r v e y s t u d i e s on a l l c h i l d r e n w i t h PWS i n Norway known t o t h e Frambu C e n t e r . The i n c i d e n c e of PWS i n Norway i s 1/14,000, a f i g u r e v e r y close t o t h e only published epidemiologic s t u d y ( f r o m North D a k o t a ) . T h e r e w a s a h i g h f r e q u e n c y i n t h e Norwegian PWS p a t i e n t s of poor s h o r t term memory and h y p e r o p i a , and a lower f r e q u e n c y of s e i z u r e s and d i a b e t e s t h a n i n t h e published l i t e r a t u r e . A l e s s a n d r o S a l v a t o n i ( H o s p i t a l of Varese) pre se n t e d a m u l t i c e n t e r I t a l i a n s t u d y of 77 c h i l d r e n w i t h PWS. There were 4 p a t - i e n t s w i t h d i a b e t e s (two i n s u l i n d e p e n d e n t ) . Approximately 40% had an e l e v a t e d c h o l e s t e r o l and 14% an elevated triglyceride. I n t h e i r study, t h o s e w i t h o u t a 1Sq d e l e t i o n had a h i g h e r i n c i d e n c e of s h o r t s t a t u r e and less hypogonadism. Jeanne Hanchett ( R e h a b i l i t a t i o n I n s t i t u t e of P i t t s b u r g h ) p r e s e n t e d a c o m p a r a t i v e s t u d y between J a p a n e s e and American c h i l d r e n w i t h PWS. The f o r m e r had been o u t p a t i e n t s and t h e l a t t e r were i n p a t i e n t s a t h e r c e n t e r and
may have had more s e v e r e problems t h a n a v e r a g e . While many a b n o r m a l i t i e s were oE similar incidence in the two populations, obesity, skin picking, s p e e c h problems and b e h a v i o r problems occurred a t s t a t i s t i c a l l y significantly h i g h e r f r e q u e n c y among t h e Americans. C u l t u r a l and g e n e t i c d i f f e r e n c e s i n t h e t w o c o u n t r i e s are l i k e l y e x p l a n a t i o n s . Growth hormone deficiency and t r e a t m e n t were a major f o c u s of t h e c l i n i c a l p r e s e n t a t i o n s . Moris Angulo (Winthrop University, New York) p r e s e n t e d d a t a on 19 c h i l d r e n w i t h PWS (4 non-obese), all of whom had n e u r o s e c r e t o r y ( s p o n t a n e o u s 24 h o u r ) growth hormone d e f i c i e n c y . Treatment of 10 p a t i e n t s w i t h hGH r e s u l t e d in s i g n i f i c a n t i n c r e a s e i n growth, i n c r e a s e i n somatomedin-C and d e c r e a s e i n weight o v e r p e r i o d s up t o 4 y e a r s . Susanne B l i c h f e l d t ( R i g s h o s p i t a l e t , Copenhagen) d e s c r i b e d s t u d i e s of 24-hour u r i n a r y growth hormone e x c r e t i o n i n 12 c h i l d r e n and 9 a d u l t s w i t h PWS, compared w i t h 584 c o n t r o l c h i l d r e n and 110 a d u l t s . L e v e l s were below t h e mean i n o v e r 80% a t a l l a g e s , and below t h e 3 r d c e n t i l e i n 33% of c h i l d r e n , e s p e c i a l l y t h o s e under age 10. F r a n k Greenberg ( B a y l o r C o l l e g e of Medicine) u s e d t o t a l body e l e c t r i c a l c o n d u c t i v i t y (TOBEC) as a measure of f a t f r e e mass t o d e m o n s t r a t e t h a t PWS p a t i e n t s had s i g n i f i c a n t l y lower l e a n body mass t h a n obese c o n t r o l s w i t h similar p e r c e n t fat. Two p a t i e n t s t r e a t e d w i t h hGH showed s i g n i f i c a n t i n c r e a s e i n l e a n body mass o v e r t i m e . P e t e r D a v i e s (Dunn N u t r i t i o n U n i t , Cambridge) measured e n e r g y e x p e n d i t u r e i n 19 c h i l d r e n w i t h PWS b y i n d i r e c t c a l o r i m e t r y and found t h a t a l l were below t h e normal mean and a b o u t h a l f were less t h a n 2 s t a n d a r d d e v i a t i o n s below t h e mean compared with c o n t r o l s . T h i s i s d u e t o b o t h l o w basal metabolic rate and l o w p h y s i c a l a c t i v i t y . M e 1 J o n e s ( U n i v e r s i t y of L i v e r p o o l ) c o n d u c t e d an i n t e r n a t i o n a l s u r v e y of c o m p l i c a t i o n s of s c o l i o s i s s u r g e r y i n 33 PWS p a t i e n t s . H e found a h i g h rate of problems, i n c l u d i n g 55%e x c e s s b l e e d i n g , 27% s o f t b o n e s ( i n 4 cases too s o f t t o h o l d r o d s ) , 15% r e s p i r a t o r y problems, and 15% sepsis. Anticipation of p o t e n t i a l problems w a s recommended.
S e v e r a l posters i n d i c a t e d s i g n i f i c a n t
Prader-Willi Conference Report sleep disturbance in PWS, including hypoventilation, excessive daytime sleepiness, sleep-onset REM, and cataplexy. Cephalometric alterations were also described. PSYCHOLOGICAL AND BEHAVIORAL ASPECTS OF PWS Psychological characteristics and intervention strategies in PWS were reviewed by Paul Curfs (Pedological Institute DeHondsberg, Netherlands). Literature survey of data on 575 patients showed 5% severe mental retardation, 25% moderate, 33% mild, 20% borderline, and 5% with IQ in the normal range. Adults were not different from children, which speaks against reported decreased intelligence over time. A Be1,gian-Dutchcollaborative study did IQ subtesting on 55 patients. Neither performance or verbal scores were consistently higher, though many had more than 15 points difference between the two scores. Block design and other performance scores seemed to be particular strengths, but there was no specific pattern of weakness. Behavior problems were very common. Barbara Whitman (St. Louis University) presented data from a 144 patient survey o n medication usage in PWS. Of the 37% who took psychotropic or drugs for behavior, anxiety depression at some time, 40% lived at home and 60% in a residential setting. Those on medications tended to weigh less. Many of these were also taking medication for stomach distress. Martine Borghgraef (University of Leuven, Belgium) studied the psychological profile in 12 people with PWS. She documented that temper tantrums tended to develop at 3 to 5 years, and social problems at 6 to 9 years. Early diagnosis and education of families and patients was recommended to improve outcome for behavior and obesity. Agnes Wiegers (Pedological Institute DeHondsberg) presented behavioral studies on 27 patients living at home. Significant behavi.or and emotional problems were noted in all ages and sexes, particularly in externalizing and internalizing. Patients tended to be hyperactive and immature. LQ did not affect behavior problems.
Many of the presented emotional , behavioral and intelligence findings were emphasized in other studies presented as posters.
CLINICAL ASPECTS OF ANGELMAN SYNDROME Patrick Willems (University of Antwerp) presented data on 44 patients from the Belgian-Dutch collaborative Angehan syndrome project. Growth is normal in AS, though infantile feeding problems are common. Hyperlordosis, flexed arms, and wide-based jerky gait are common. Absent speech is found in 100%. Characteristic abnormal EEG and seizures occur in over 90%, the latter usually well controlled with medication and improving with age. Typical facial findings of prognathism and macrostomia are more evident after age 5 years. A low threshold for laughter occurs in 86%, and mild microcephaly in 77%. Recurrence risk was 4%, and 60% of the patients in 4 studies had a 15q deletion. There were no clinical differences between deletion and familial cases. The absence of an autosomal recessive gene on chromosome 15 for AS in familial cases is supported by data indicating that parental alleles are not always the same. Jill Clayton-Smith (Institute of Child Health, London) presented data on 17 patients ages 10-24 years. Scoliosis was found in 23%, and 3 patients became nonambulatory with time. Most had up to 5 words and even more could use some sign language. Seizures ceased in a third during the second decade. Puberty appeared normal. Retching was particularly noted in girls, as was some obesity developing with age. Early sleep problems later improve. Many developed some self-help skills. Roberto Zori (University of Florida) sought clinical differences between patients without deletion or disomy and those with these anomalies. The only differences among 5 such patients compared with 21 with deletion was that 2 did not have seizures, and 2 were tall and had normal head circumference. Jill Hendrickson (University of Florida) presented genetic studies among 46 patients with AS and 15q deletion in
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llorida and Oregon. Ten had no siblings. There were Gl siblings among the other 36, as well as 9 maternal and 6 paternal half-sibs, and none had AS. One girl had a mother with some changes of AS (ataxia,brachycephaly, motor delay) who did not have a deletion. There were affected first cousins (different sexes) who both had maternal del 15, though in one case it was inherited through the father. They conclude that sibling recurrence is below 5% in deletion cases. Poster presentations on AS provided morphometric analysis of the facial abnormaliti.es, and added some findings including recurrent upper airway infections, hypopigmentation, and orset of seizures between 10 and 31 months.
PANEL DISCUSSION The panel discussion focused on summarizing the molecular findings in PWS and AS and determining appropriate sibling recurrence risks based on these findings. The general consensus was that in PWS 77% have a paternal 15q deletion or some other chromosome anomaly involving 15, and 23% have maternal disomy. No typical patient has neither. Recurrence risk is below 1% in deletion cases (none reported), and unknown in disomy cases, but still probably below 2%. In AS, 60% have maternal 15q deletion, 4% have paternal disomy, and the remainder have neither. Recurrence risk is below 2% in & nova deletion cases and empirically 18% in nondeletion cases with disomy excluded. Guesses at appropriate recurrence risks in other situations include 5-10% in deletion or disomy cases in which there is a rearranged parental chromosome 15, 2% in the few disomy cases, and 50% once a recurrence has already occurred in siblings. Theories for the cause in familial non-deletion cases include maternally derived mutation, which may be dominant, or a submicroscopic deletion.
ACKNOWLEDGEMENTS Many people contributed to make this workshop successful. I want to thank the members of the Scientific Advisory Committee for their assistance in identifying speakers and selecting abstracts (Nicholas Barnes, Tim Donlon, Jean-Pierre Fryns, VanLja Holm, Martin Ritzen, Martinus Niermeijer and Evelyn Wesby-van Swaay). Particular gratitude is due to Henk Moezelaar, head of the Dutch PWS association, for the local arrangements, and to Jean PhillipsMartinsson, head of the Swedish PWS association, for using international contacts to identify people with interest in PWS. The PWSA (US) provided a grant to assist in planning of the conference, and contributions were made by the March of Dimes/Birth Defects Foundation (Grant No. 4-237) and by Vivigen. Major support for this workshop was provided by an Advanced Research Workshop Award from NATO. I am grateful to Maryann Wagner for her invaluable administrative and secretarial assistance.
Conference Report: First International Scientific Workshop on Prader-Willi Syndrome and Other Chromosome 15q Deletion Disorders
Suzanne R . Cassidy Section of Genetics/Dysmorphology, Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona College of Medicine, Tucson
Key words:
Prader-Willi syndrome, Angelman syndrome, chromosome deletion, 15qdeletion. genetic imprinting, disomy, contiguous gene syndrome, growth hormone, sleep disorder, diagnostic criteria
INTRODUCTION Everyone must have a day that they can point to as a major turning point in their career; I certainly do. It was the day t.hat Judy Hall announced to the genetics fellows at the University of Washington (of which I was one) that a small deletion had been identified in several patients with Prader-Willi syndrome at Baylor College of Medicine, using the newly developed method of prometaphase banding. She asked whether any of us would be interested in coordinating a study of the patients in Dr . Vanja Holm's Prader-Willi syndrome clinic, in collaboration with Dr. Horace Thuline, who as director of the State of Washington's cytogenetics laboratory had already begun using this high resolution technology. Having a long-standing interest in karyotype-phenotype This correlation, I volunteered. complex and utterly fascinating disorder has been the major focus of my Received for publication June 21,1991; revision received August 5, 1991.
Address reprint requests to: Suzanne B. Cassidy, M.D. Associate Professor of Pediatrics, Section of Genetics/ Dysmorphology, Univ. of Arizona College of Medicine, Tucson, AZ 85724
0 1992 Wiley-Liss, Inc.
clinical research interest since that day. I cannot imagine this focus bringing me to a more exciting point that it did when I saw my organizational efforts culminate in the international scientific workshop on Prader-Willi Syndrome and Other Chromosome 15q Deletion Disorders, which was held on May 2 and 3, 1991 in The Netherlands. The response to letters of inquiry about the desirability of such a meeting and the invitations to key speakers was most encouraging. The response to the call for abstracts was overwhelming; more than 70 abstracts, most of high scientific quality, were submitted. This level of research productivity indicated that the topics of Prader-Willi syndrome, Angelman syndrome, and the unique genetic relationship that they share, are of major interest to professionals in molecular genetics and cytogenetics, in clinical genetics, endocrinology, child development, neurology, rehabilitation, psychiatry and psychology, and genetic counseling.
Prader-Willi Conference Report Perhaps the most gratifying part of the meeting was seeing laboratory and clinical researchers from 15 countries in four continents represented among the participants, and even more countries and continents represented among the professional and parent observers. Many of the participants knew each other in print only, and were delighted to meet for the first time. Several international research collaborations were established during informal discussions at the meeting, and a few vigorously argued differences of opinion will likely result in newly energized research efforts. The workshop ended with initiation of plans for another such international meeting on the same topics within the next three to four years. Efforts to understand the genetics of Prader-Willi and Angelman syndromes, with their implications for unraveling genetic imprinting and for shedding light on normal and abnormal brain development, have advanced dramatically in the 11 years since the 15q deletion was first discovered. There is still much to learn, and an international scientific workshop is an outstanding forum in which to stimulate such learning. INTERNATIONAL SCIENTIFIC WORKSHOP ON PRADER-WILL1 SYNDROME AND OTHER CHROMOSOME 15q DELETION DISORDERS DeLeeuwenhorst Congress Center, Noordwijkerhout, The Netherlands Thursday, May 2, 1991 First Session: H i s t o r y , Phenotype and Genetics
Cytogenetics of Prader-Willi Syndrome and Angelman Syndrome: Ellen Magenis, Oregon Health Sciences University, Portland, OR, USA Second Session: Holecular Genetics Moderator: Bernhard Horsthemke The Irregular Inheritance of Angelman and Prader-Willi Syndromes: Marcus Pembrey, University of London, England, UK Microdissection and Molecular Analysis sf Proximal 15q: Bernhard Horsthemke, University of Essen, Germany Genome Imprinting and the Role of Epigenetic Inheritance During Development: M. Azim Surani, Institute of Animal Physiology and Genetics Research, Cambridge, England, UK Characterization of cDNA Clones Corresponding to Genomic Loci Rearranged in PWS Patients. CA Gregory, AJ Kirkilionis, JL Hamerton. Possible Genomic Imprinting at the Angelman Syndrome Gene Locus. N Niikawa and J-I Hamabe. Molecular Analysis in Angelman Syndrome and Prader-Willi Syndrome, and Potential Mouse Models. RD Nicholls, W Gottlieb, MJ Mascari, EM Rinchik, GS Pail DJ Driscoll, MG Butler, RT Zori, PE Neumann, MF Waters, JL Zackowski, B Horsthemke, RL Ladda, and CA Williams.
Prader-Willi Syndrome in 1956 and 1991: Andrea Prader, University of ZGrich, Switzerland
Clinical, Molecular, and Cytogenetic Survey of Potential Prader-Willi Syndrome Patients. WP Robinson, J Balakrishnan, F Binkert, A Bottani, M Machler, Z Yagang, A Prader, and A Schinzel.
Overview of Prader-Willi Syndrome: Suzanne B. Cassidy, University of Arizona, Tucson, AZ, USA
Third Session: Cytogenetics and C l i n i c a l Genetics
Moderator: Suzanne B. Cassidy
Moderator: Ellen Magenis
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Xosaicism for Deletion 15qll-ql3 in Sporadic and Familial Cases. SR Patil, B Hauschildt, D Wilson, C Headley, M Greally, J Hanson, and T Donlon .
A Multicenter Italian Study of PraderWilli Syndrome. A Salvatoni and the Obesity Study Group of The Italian Society of Paediatric Endocrinology and Diabetology.
Prader-Willi Syndrome and Angelman Syndrome in Two Female Cousins as a Result of a Familial Translocation. DFCM Smeets, MR Nelen, BCJ Hamel, APT Smits, HJM Smeets, JHM Bollen, and BA van Oost.
Prader-Willi Syndrome in Norway. Lofter4d and A Heiberg.
An Australian Collaborative Study of Prader-Willi Syndrome Individuals and Their Families. A Smith, S White, G Warne, P Montgomery, J Nelson, H Beange, J Pearn, J Henderson, and KJ Trent.
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A Comparison of Characteristics in 33 Japanese and 83 American PraderWilli Syndrome Patients. JM Hariehett, N Matsuo, T Nagai, N Niikawa, and H Tonoki. Sixth Session: Clinical Aspects Prader-Willi Syndrame. 11.
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Moderator: Vanja Holm Implications for the Recurrence Risk in the Prader-Willi Syndrome on the Basis o€ Proposed Genomic Imprinting. I Kennerknecht. Friday, May 3, 1991 Fourth Session: Physiology of Clinical Features Moderator: Suzanne B. Cassidy Hormone Physiology and Therapy in Prader-Willi Syndrome: Martin Ritzgn, Karolinska Institute, Stockholm, Sweden. Mechanisms of Appetite Control and Their Abnormality in Prader-Willi Syndrome: Tony Holland , Bethlem Royal Hospital, Beckenham, England, UK Fifth
Session: Clinical Aspects Prader-Willi Syndrome. I.
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Growth Hormone Evaluation and Treatment in Prader-Willi Syndrome. M Angulo, M Castro-Magana, J Uy, and W Rosenfeld. Diminished 24 Hour Urinary Growth Hormone Excretion in Patients with Prader-Willi Sydrome. S Blichfeldt, K Main, M Ritzen, and NE Skakkebaek. Studies of Body Composition in Patients with Prader-Willi Syndrome: Implications for Management. W Klish, B Brown, T Lin, P Lee, and F Greenberg. Total Energy Expenditure in the PraderWill: Syndrome. PSW Davies, C Joughin, TJ Cole, MBE Livingstone, and ND Barnes. Scoliosis Surgery in the Prader-Willi Syndrome. MW Jones. Seventh Session: Psychological an Behavioral Aspects of Prader-Willi Syndrome
Moderator: Jean-Pierre Fryns Moderator: Louise Greenswag Diagnostic Criteria for Prader-Willi Syndrome. VA Holm, SB Cassidy, MG Butler, JM Hanchett, F Greenberg, BY Whitman, LR Greenswag. A Family Focused Care Model for PraderWilli Syndrome in Norway. A Heiberg, K Storhaug, C Aashamar, and €3 Lofter$d.
Psychological Characteristics and Intervention Strategies in PraderWilli Syndrome: Paul MG Curfs, Pedological Institute DeHondsberg, The Netherlands.
Prader-Willi Conference Report History, Cbrrent Use, and Impact of Mood Altering and Behavior Change Medication in 114 Individuals with Prader-Willi Syndrome. BY Whitman and LR Greenswag. Psychological Profile in Patients with Prader-Willi Syndrome. M Borghgraef and J-P Fryns. Behavioral and Emotional Problems in Youngsters with Prader-Willi Syndrome. PMG Curfs, FC Verhulst, and J-P Fryns.
Eighth Session: Clinical Aspects of Angelman Syndrome
Characterization of YAC and cDNA Clones from the PWSjAS Chromosomal Region. K Buiting, V Greger, and B Horsthemke. Prader-Willi Syndrome: Deletion of DNA Probes Mapped to 15qll-13 in a Cytogenetically Normal Patient. BG Koussef f, OT Mueller , PR Papenhausen, and M Torres. Molecular Deletions in Prader-Willi Syndrome and in Angelman Syndrome. J-I Hamabe and N Niikawa. DNA Studies in Prader-Willi and Angelman Syndrome. H Smeets, M Nelen, A Smits, D Smeets, A AkkermansScholten, I van de Burgt, and B van Oost.
Moderator: Ellen Magenis Angelman Syndrome: A Clinical Update: Patrick Willems, University of Aritwerp , Belgium Angelman Syndrome in the Adolescent and Young Adult. J Clayton-Smith. Clinical Findings in Angelman Individuals Without a Molecular Deletion or Uniparental Disomy. R Zori, RD Nicholls, DJ Driscoll, and CA Williams. Genetic Counseling for Angelman Syndrome When the Proband has a Cytogenetic or Molecular Deletion. J Hendrickson, L Marfatia, K Kovak, E Magenis, and C Williams. Panel Discussion: Current Understanding A b u t Diagnosis and Recurrence Risks of Prader-Willi and Angelman syndrames
Panel Members: Timothy Donlon (Leader), Marcus Pembrey, Ellen Magenis, Bernhard Horsthemke
wsms MOLECULAR GENETICS AND CYTOGENETICS OF PFZADER-WILL1 AND ANGELMAN SYNDROMES
Molecular Analysis of the Prader-Willi Syndrome. RJ Trent, F Volpato, A Smith, R Lindeman, G Warne and E Haan. Long Range Mapping of the Prader-Willi Chromosome Region Using Pulsed Field Gel Electrophoresis. T Woodage, R Lindeman, A Smith and RJ Trent. Maternal Origins of 15qll-13 Deletions in Three Unrelated Patients with Angelman Syndrome: Further Evidence for Genomic Imprinting. D Bettio, D Gardino, N Rizo, and G Simoni. Deletion of Chromosome 15qll-13 in Two Groups of Patients with Different Consistency with Prader-Willi Syndrome. D Giardino, D Bettio, N Rizzi, and G Grugni. Cytogenetic and Molecular Analyses in Prader-Willi and Angelman Patients. Correlation or Discrepancy? E Wesbyvan Swaay, JO Van Hemel, DJJ Halley, and ES Sachs. Molecular Investigation of the DNA Mutations Leading to Angelman Syndrome. J Beuten, P Coucke, IM Buntinx, B Van der Auwera, and PJ Willems. DNA Studies in Sibs with PWS. M Anvret, A Martony, KH Orstavik, and K Brsndum-Nielson.
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Evaluation of Improved G-Banding for the Detection of Deletions in Patients with Angelman Syndrome. KJ Mangelschots, BC Van Roy, FP Speleman, IM Buntinx, PJ Willems, and JE L>umon. Twins and the Prader-Willi Syndrome: A Study of Two Cases. A Smith, R Mclvor, J Dunstan, A Kearney, and RJ Trent. Genetic Aspects of Angelman Syndrome: Evidence for Genomic Imprinting. K Schmidt, K Sperling, RD Wegner, B Horsthemke, and J Kunze.
CLINICAL ASPECTS OF SYNDROME
PRADER-WILL1
Prader-Willi Syiidrome in Northern Ireland. FJ Priest, NC Nevin, A Hughes, and I Rennie.
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Comparison of Growth Pattern of Prader-Willi Syndrome Between Japanese and Caucasian. T Nagai, N Matsuo, Y Fukushima, H Totoki, and N Niikawa.
Incidence o€ Altered Glucose Tolerance in Patients with Prader-Willi Syndrome. G Grugni, A Ardizzi, G Guzzaloni, and F Morabito. Small Ovaries Without Primary Follicles and Other Characteristics in 12 Cases of Prader-Willi Syndrome. C Dacou-Voutetakis, Th Papanicolaou, J Pagalos, M Korvesi, D Chiotis, and A Vourou. Sleep and Breathing Patterns in Adult Patients with Prader-Willi Syndrome. M Cataletto, G Hertz, S Feinsilver, and M Angulo. Abnormalities of Sleep and Arousal in Prader-Willi Syndrome. KH Warton, K Levine, and JA Hobson. The Sl-eep-WakeContinuum in the PraderWilli Syndrome. B HelbingZwanenburg, M Damen, and w\C Kamphuisen.
Hyperthermia in Infants with PraderWilli Syndrome. MS Wise, H Zoghbi, M Edwards, LK Byrd, AE Guttmacher, and F Greenberg. Antero-Posterior Cephalometric Analysis of the Craniofacial Complex in Prader-Willi Syndrome. AE Poole, RM Munoz, and SB Cassidy.
PSYCHOLOGICAL AND BEHAVIORAL ASPECTS OF PRADER-WILL1 SYNDROME
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Cognitive, Behavioral and Genetic Study of Prader-Willi Syndrome : University of Birmingham Collaborative Study. C Hardy, MW Kilpatrick, T Webb, S Bundey, DJ Clarke, J Corbett, and P Sturmey.
Intelligence and Cognitive Profile in Prader-Willi syndrome. PMG Curfs, A Wiegers, M Borghgraef, and J-P Fryns . Cognition and Behavior in Prader-Willi Syndrome. DJ Clarke and JE Doherty (in collaboration with: T Webb, C Hardy, M Kilpatrick, S Bundey, J Corbett, and P Sturmey). Sexual Feelings and Fantasies in PraderWilli Syndrome Girls. P Bregani, P Brambilla, C Ripamonti, C Chisalberti, L Tomasini, D Cella, and G Chiumello. Emotional Implications in Prader-Willi Syndrome Subjects' Food Behavior. P Bregani, P Brambilla, C Ripamonti, C Pani.goni, C Chisalberti, L Tomasini, and G Chiumello. Self Trauma in Prader-Willi Syndrome. JM Hanchett .
CLINICAL ASPECTS OF ANGELMAN SYNDROME Clinical. Evaluation of the Angelman Syndrome in Belgium and The Netherlands. IM Buntinx, BJ Willems, KJ Mangelschots, RC Hennekam, OF Brouwer, J Beuten, and JE Dumon.
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Prader-Willi Conference Report Morphometric Analysis of Facial Features in Patients with Angelman Syndrome. JL Frias, GB Schaefer, B Gray, and CA Williams. Five Young Children with 15q Deletion Lacking the Prader-Willi or Angelman Syndrome Phenotype. VA Holm. Neonatal Diagnosis of de1(15)(qll-13) Without Prader-Willi Phenotype. F Greenberg, J Parke, R Zeller, E Mizrahi, and DH Ledbetter. HISTORY, PHENOTYPE, NATURAL HISTORY AND CYTOGENETICS The workshop was honored to begin with the historical perspective of Professor Andrea Prader (University of Zirich), a senior pediatric endocrinologist who first recognized the pattern of human malformation which constitutes the Prader-Willi syndrome (PWS). He included pictures of Drs. Labhart and Willi, the co-workers on his pivotal paper in 1956. He particularly remarked on the dramatic changes in the genetic understanding and the level of interest in this disorder in recent years. The members of the audience for this workshop were very diverse in their areas of expertise and familiarity with the various aspects of PWS; included among them were academic physicians of several different specialties, molecular geneticists, cytogeneticists, and psychologists. In order to provide a common framework of knowledge about PWS and abnormalities of chromosome 15q, Suzanne Cassidy (University of Arizona) provided a broad overview of the phenotype, natural history, and what is known of the etiology of PWS. This included the discovery of the chromosomal deletion of 15q, its paternal origin, recent findings of maternal disomy in chromosomally normal cases, and the determination that maternal deletion causes the clinically dissimilar disorder Angelman syndrome (AS), whose features were briefly described. Ellen Magenis (Oregon Health Sciences University) then reviewed in greater detail the refinement of the
chromosome anomalies present in PWS and AS, providing a comparison indicating nearly total overlap. The improvement of high resolution cytogenetic technology and the methods of detecting parental origin for the two disorders was presented. She did suggest that subtle differences indicate that the genetic locus for the two disorders may be different. Additional clinical details of AS were also provided from her considerable experience.
APPROACHES TO MOLECULAR GENETICS AND GENOMIC IMPRINTING Bernhard Horsthemke (University of Esseri) described his approach to unraveling the molecular genetics of 15q, indicating that this was the vital first step in using reverse genetics to determine the genes whose abnormality result in PWS and AS, and thence their functions, as well as to delineate the molecular extent of the deletion. He uses the technique of physical microdissection to produce a microclone library, then forms probes which can be sequenced. Polymerase chain reaction (PCR) is used to identify loci and clones, using yeast artificial chromosomes (YACs). Over 5000 overlapping clones in 15q11.2-13 have been isolated, and a restriction map made. Two specific clones appear in multiple copies in proximal 15q and vary in number among individuals, possibly conferring instability to this region. Azim Surani (Institute of Animal Physiology and Genetics Research, Cambridge) focused on genomic imprinting. This epigenetic marking process leads to functional differences between the two types of parental genomes, conferring preferential activity on one of the homologous parental alleles. Using mouse androgenones and gynogenones, rescuing them from lethality in chimeras, he has identified regions of the mouse genome which harbor imprinted genes and demonstrated their phenotypic effects The mouse distal chromosome 7 region is homologous to the human proximal 15q and is highly subject to imprinting effects. This region contains Insulin-like Growth Factor 2 (Igf2), which is involved in embryonic growth and is preferentially a
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repressed .in the maternally derived genome. This system of studying mouse transgenes is valuable in unraveling the effects of human imprinting. Marcus Pembrey (University of London) described the theoretical mechanisms for production of disomy, including trisomy 15 (nondisjunction) with later loss of one chromosome, combination of dizygous and nullizygous zygotes, and combination of a normal and nullizygous zygote with later duplication of the normal 15. He provided evidence suggesting that the entire chromosome 15 is disomic in disomy cases. A family was described in which a rearranged chromosome 15 is segregating and first cousins were produced in which one has AS and the other PWS (in whom a paternal deletion is also present). This situation suggests that rearranged 15s can induce deletions. His study of 84 patients with As suggests significantly differing recurrence risks depending upon whether deletion, disomy, or normal 15s are present. There are far more recurrences in families with AS than with PWS, in which recurrence is rare. The sibling pairs had neither deletion nor disomy. In nbout half the pairs both had received the same parental 15s, but in the other half there were different paternal 15s and the same maternal 15s, excluding an autosomal recessive gene on 15 as the cause in those cases. Recurrence risk is quite low in deletion and disomy cases (less than 2 % ) , but much higher in cases where both these abnormalities have been excluded.
MOLECULAR GENETICS AND CYTOGENETICS Carolyn Gregory (University of Manitoba) described her studies screening a cDNA human fetal brain library and zoo blots using two loci from the Prader-Willi Chromosome Region (PWCR). Conservation of the genomic loci and the cDNA sequences are limited to primates and some but not all human cell types. Interestingly, this message was detected in human fetal brain tissue but not adult brain. Norio Niikawa (Nagasaki University) presented an interesting family in which three siblings with AS were all hemizygous for the paternal
allele of one 15q probe, and their mother was hemizygous for a different allele of this probe, which represented absence of her father's allele. All but one of the other probes in 15q were heterozygous in all tested individuals. Thus, the same submicroscopic deletion occurri-ng in the paternally derived chromosome (the maternal grandfather's) caused no phenotypic change, whereas when it occurred in the maternally derived chromosome (the mother's), it caused AS in the offspring. Not only does this family confirm the importance of imprinting in the cause of AS, but the absence of PWS in the mother despite the paternal deletion implies that the loci for PWS and AS are different.
Rob Nicholls (University of Florida) investigated the genetics of 15q by studying the families of 27 patients with AS and 17 with PWS. Parental origins and the presence of disomy were confirmed. Of the PWS cases, everyone had either deletion (71%) or some other chromosome anomaly involving 15 ( 8 % ) , or had disomy (21%). Some without a chromosomal deletion had a molecular deletion. Of 27 AS patients studied, only one had disomy, and 2 0 had deletion. Clones derived from human 15q were mapped to mouse chromosome 7, and mapping order was determined. Maternal meiosis I nondisjunction is the most likely mechanism in the cause of maternal disomy, presumably through a trisomic intermediate. Patients with either syndrome with a deletion tend to be hypopigmented, as are mice disomic for chromosome 7, suggesting that a gene involved in the pigment system is affected by gene dosage and not genomic imprinting. Wendy Robinson (University of &rich) presented her molecular studies of 36 patients with possible PWS. Distinction between patients on the basis of clinical criteria correlated with molecular testing in showing that all typical patients had either deletion or disomy. Disomy appeared to be for the entire chromosome 15, confirming other studies. Most strikingly, in disomy cases the parental age was advanced (about 8 years older than the deletion cases), pointing to maternal nondisjunction leading to trisomy with subsequent loss of the paternal chromosome as a mechanism in the disomic cases. The advanced maternal age in
Rader-Willi Conference Report disomy cases was confirmed by Nicholls from his studies. CYTOGENETICS AND CTJNICAL GENETICS Mosaicism for 15q deletion was initially thought to exist, then was later thought to result from variability of the proximal 15q region. Shiva Patil (University of Iowa) presented 3 sporadic patients and 2 familial cases in which chromosomal mosaicism for 15q was convincing. Of the sporadic cases, two had intellectual limitations and were small, but did not have evident PWS or AS. In the familial cases, the mothers had mosaicism for del 15q and the affected child had del 15q in all cells but did not have typical A S or PWS phenotype. The mosaicism could not be confirmed with molecular studies. Cytogenetic mosaicism must be carefully scrutinized. Dominique Smeets (University of Nijmegen) presented a family in which a balanced 6;15 translocation was present in two brothers, one of whom had a daughter with PWS and the other a daughter with AS. While the unaffected translocation carriers had normal molecular findings in 15q, the child with PWS had a molecular deletion in the translocation chromosome, and the cousin with AS had paternal disomy for 15 but no deletion. Thus, unequal crossing-over had likely occurred during meiosis in the PWS child. This suggests that the presence of translocations involving 15 may significantly increase the risk for deletion and disomy, adding further evidence to the study of Pembrey mentioned earlier. Looking at all the published data of approximately 800 PWS patients, including 7 fcmilies with recurrence, lngo Kennerknecht (University of Ulm) used sib and proband methods to study recurrence risks. None of the familial cases have had deletion or disomy. He proposed a mechanism in which maternal imprinting and paternal erasure of the imprint could account for the findings in PWS. In familial cases, he proposed that female transmitters would have normal children for a "dysfunctional" PWS genefregion, whereas male transmitters would have 50% affected children. He proposed
recurrence risks of 0.4% in an isolated case of PWS and 50% recurrence risk when more than one sib was affected. Arabella Smith (Children's Hospital, Camperdown, Australia) presented an Australian collaborative study looking for recurrence in 144 families with PWS. Among 266 living sibs there was no recurrence. There was only one familial recurrence, in third cousins, which could have been explained by coincidence. There were four sets of twins, all like-sex, all but one of which was discordant. There was no increase in fetal wastage. Many of the molecular findings were confirmed in presented as posters.
genetic studies
PHENOTYPE, NATURAL HISTORY, AND EPIDEMIOLOGY OF PWS Martin Ritzgn (Karolinska Institute) reviewed current knowledge about the endocrine findings in Pws. In addition to the well-described hypothalamic insufficiency leading to hypogonadotrophic hypogonadism, he noted that premature adrenarche but not gonadarche was common. His study of 8 PWS patients and 11 obese controls found differing FSH and LH response to GNRH, but no difference in melatonin or prolactin secretion, cortisol levels or thyroid hormones. There was no difference either in growth hormone response to stimulation, but those with PWS have lower spontaneous secretion of growth hormone following sleep. Insulin secretion following glucose load was prolonged in PWS. He recommended treatment of males with testosterone to increase muscle mass, independence, maturity and concentration. Tony Holland (Bethlem Royal Hospital, Kent) reviewed mechanisms of satiety in light of apparent absence of appropriate satiety in PWS. His studies in 13 obese adults with PWS indicated that they achieve satiety but only after three times more calories than controls (average: 1500 cal lunch), and their hunger returns much more quickly. Following a controlled meal, secretion of cholecystokinin (a satiety agent) is significantly higher in PWS versus controls, suggesting a possible
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alteration receptors.
in
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The d i f f i c u l t i e s o f d i a g n o s i n g PWS l e d a y r o u p o f 6 c l i n i c a l experts i n t h i s d i s o r d e r t o convene t o d e v e l o p c o n s e n s u s d i a g n o s t i c c r i t e r i a f o r PWS. The c r i t e r i a , p r e s e n t e d b y Vanja H o l m ( U n i v e r s i t y o f Washington), were based on a s c o r i n g s y s t e m which i n c l u d e d b o t h major and minor manifestations, s e p a r a t e d by t h e i r s p e c i f i c i t y and f r e q u e n c y . A s e p a r a t e s e t of c r i t e r i a was d e v e l o p e d f o r t h o s e below a g e 3 years, since t h e c l i n i c a l presentation i s so d i f f e r e n t a t t h a t t i m e . T e s t i n g of t h e s e c r i t e r i a on o v e r 100 p a t i e n t s r e f e r r e d f o r possible PWS i n d i c a t e d t h a t t h e t e s t s were e f f e c t i v e i n i n c l u d i n g t h e t y p i c a l PWS p a t i e n t s and e x c l u d i n g t h o s e f e l t n o t t o have t h i s c o n d i t i o n by the experienced testers. Christian Aashamar (Frambu H e a l t h C e n t e r , Norway) d e s c r i b e d t h e Norwegian s y s t e m of a t w o week r e s i d e n t i a l e d u c a t i o n a l and medical program f o r e n t i r e f a m i l i e s a f f e c t e d by conditions causing d i s a b i l i t y , including PWS. This provides support and i n f o r m a t i o n f o r p a r e n t s and siblings, a s s e s s m e n t and t e a c h i n g o f a f f e c t e d i n d i v i d u a l s , and a n i d e a l o p p o r t u n i t y f o r c l i n i c a l research. Bjqrn Lofterqd (Moss H o s p i t a l , Norway) t h e n p r e s e n t e d h i s p e r s o n a l and s u r v e y s t u d i e s on a l l c h i l d r e n w i t h PWS i n Norway known t o t h e Frambu C e n t e r . The i n c i d e n c e of PWS i n Norway i s 1/14,000, a f i g u r e v e r y close t o t h e only published epidemiologic s t u d y ( f r o m North D a k o t a ) . T h e r e w a s a h i g h f r e q u e n c y i n t h e Norwegian PWS p a t i e n t s of poor s h o r t term memory and h y p e r o p i a , and a lower f r e q u e n c y of s e i z u r e s and d i a b e t e s t h a n i n t h e published l i t e r a t u r e . A l e s s a n d r o S a l v a t o n i ( H o s p i t a l of Varese) pre se n t e d a m u l t i c e n t e r I t a l i a n s t u d y of 77 c h i l d r e n w i t h PWS. There were 4 p a t - i e n t s w i t h d i a b e t e s (two i n s u l i n d e p e n d e n t ) . Approximately 40% had an e l e v a t e d c h o l e s t e r o l and 14% an elevated triglyceride. I n t h e i r study, t h o s e w i t h o u t a 1Sq d e l e t i o n had a h i g h e r i n c i d e n c e of s h o r t s t a t u r e and less hypogonadism. Jeanne Hanchett ( R e h a b i l i t a t i o n I n s t i t u t e of P i t t s b u r g h ) p r e s e n t e d a c o m p a r a t i v e s t u d y between J a p a n e s e and American c h i l d r e n w i t h PWS. The f o r m e r had been o u t p a t i e n t s and t h e l a t t e r were i n p a t i e n t s a t h e r c e n t e r and
may have had more s e v e r e problems t h a n a v e r a g e . While many a b n o r m a l i t i e s were oE similar incidence in the two populations, obesity, skin picking, s p e e c h problems and b e h a v i o r problems occurred a t s t a t i s t i c a l l y significantly h i g h e r f r e q u e n c y among t h e Americans. C u l t u r a l and g e n e t i c d i f f e r e n c e s i n t h e t w o c o u n t r i e s are l i k e l y e x p l a n a t i o n s . Growth hormone deficiency and t r e a t m e n t were a major f o c u s of t h e c l i n i c a l p r e s e n t a t i o n s . Moris Angulo (Winthrop University, New York) p r e s e n t e d d a t a on 19 c h i l d r e n w i t h PWS (4 non-obese), all of whom had n e u r o s e c r e t o r y ( s p o n t a n e o u s 24 h o u r ) growth hormone d e f i c i e n c y . Treatment of 10 p a t i e n t s w i t h hGH r e s u l t e d in s i g n i f i c a n t i n c r e a s e i n growth, i n c r e a s e i n somatomedin-C and d e c r e a s e i n weight o v e r p e r i o d s up t o 4 y e a r s . Susanne B l i c h f e l d t ( R i g s h o s p i t a l e t , Copenhagen) d e s c r i b e d s t u d i e s of 24-hour u r i n a r y growth hormone e x c r e t i o n i n 12 c h i l d r e n and 9 a d u l t s w i t h PWS, compared w i t h 584 c o n t r o l c h i l d r e n and 110 a d u l t s . L e v e l s were below t h e mean i n o v e r 80% a t a l l a g e s , and below t h e 3 r d c e n t i l e i n 33% of c h i l d r e n , e s p e c i a l l y t h o s e under age 10. F r a n k Greenberg ( B a y l o r C o l l e g e of Medicine) u s e d t o t a l body e l e c t r i c a l c o n d u c t i v i t y (TOBEC) as a measure of f a t f r e e mass t o d e m o n s t r a t e t h a t PWS p a t i e n t s had s i g n i f i c a n t l y lower l e a n body mass t h a n obese c o n t r o l s w i t h similar p e r c e n t fat. Two p a t i e n t s t r e a t e d w i t h hGH showed s i g n i f i c a n t i n c r e a s e i n l e a n body mass o v e r t i m e . P e t e r D a v i e s (Dunn N u t r i t i o n U n i t , Cambridge) measured e n e r g y e x p e n d i t u r e i n 19 c h i l d r e n w i t h PWS b y i n d i r e c t c a l o r i m e t r y and found t h a t a l l were below t h e normal mean and a b o u t h a l f were less t h a n 2 s t a n d a r d d e v i a t i o n s below t h e mean compared with c o n t r o l s . T h i s i s d u e t o b o t h l o w basal metabolic rate and l o w p h y s i c a l a c t i v i t y . M e 1 J o n e s ( U n i v e r s i t y of L i v e r p o o l ) c o n d u c t e d an i n t e r n a t i o n a l s u r v e y of c o m p l i c a t i o n s of s c o l i o s i s s u r g e r y i n 33 PWS p a t i e n t s . H e found a h i g h rate of problems, i n c l u d i n g 55%e x c e s s b l e e d i n g , 27% s o f t b o n e s ( i n 4 cases too s o f t t o h o l d r o d s ) , 15% r e s p i r a t o r y problems, and 15% sepsis. Anticipation of p o t e n t i a l problems w a s recommended.
S e v e r a l posters i n d i c a t e d s i g n i f i c a n t
Prader-Willi Conference Report sleep disturbance in PWS, including hypoventilation, excessive daytime sleepiness, sleep-onset REM, and cataplexy. Cephalometric alterations were also described. PSYCHOLOGICAL AND BEHAVIORAL ASPECTS OF PWS Psychological characteristics and intervention strategies in PWS were reviewed by Paul Curfs (Pedological Institute DeHondsberg, Netherlands). Literature survey of data on 575 patients showed 5% severe mental retardation, 25% moderate, 33% mild, 20% borderline, and 5% with IQ in the normal range. Adults were not different from children, which speaks against reported decreased intelligence over time. A Be1,gian-Dutchcollaborative study did IQ subtesting on 55 patients. Neither performance or verbal scores were consistently higher, though many had more than 15 points difference between the two scores. Block design and other performance scores seemed to be particular strengths, but there was no specific pattern of weakness. Behavior problems were very common. Barbara Whitman (St. Louis University) presented data from a 144 patient survey o n medication usage in PWS. Of the 37% who took psychotropic or drugs for behavior, anxiety depression at some time, 40% lived at home and 60% in a residential setting. Those on medications tended to weigh less. Many of these were also taking medication for stomach distress. Martine Borghgraef (University of Leuven, Belgium) studied the psychological profile in 12 people with PWS. She documented that temper tantrums tended to develop at 3 to 5 years, and social problems at 6 to 9 years. Early diagnosis and education of families and patients was recommended to improve outcome for behavior and obesity. Agnes Wiegers (Pedological Institute DeHondsberg) presented behavioral studies on 27 patients living at home. Significant behavi.or and emotional problems were noted in all ages and sexes, particularly in externalizing and internalizing. Patients tended to be hyperactive and immature. LQ did not affect behavior problems.
Many of the presented emotional , behavioral and intelligence findings were emphasized in other studies presented as posters.
CLINICAL ASPECTS OF ANGELMAN SYNDROME Patrick Willems (University of Antwerp) presented data on 44 patients from the Belgian-Dutch collaborative Angehan syndrome project. Growth is normal in AS, though infantile feeding problems are common. Hyperlordosis, flexed arms, and wide-based jerky gait are common. Absent speech is found in 100%. Characteristic abnormal EEG and seizures occur in over 90%, the latter usually well controlled with medication and improving with age. Typical facial findings of prognathism and macrostomia are more evident after age 5 years. A low threshold for laughter occurs in 86%, and mild microcephaly in 77%. Recurrence risk was 4%, and 60% of the patients in 4 studies had a 15q deletion. There were no clinical differences between deletion and familial cases. The absence of an autosomal recessive gene on chromosome 15 for AS in familial cases is supported by data indicating that parental alleles are not always the same. Jill Clayton-Smith (Institute of Child Health, London) presented data on 17 patients ages 10-24 years. Scoliosis was found in 23%, and 3 patients became nonambulatory with time. Most had up to 5 words and even more could use some sign language. Seizures ceased in a third during the second decade. Puberty appeared normal. Retching was particularly noted in girls, as was some obesity developing with age. Early sleep problems later improve. Many developed some self-help skills. Roberto Zori (University of Florida) sought clinical differences between patients without deletion or disomy and those with these anomalies. The only differences among 5 such patients compared with 21 with deletion was that 2 did not have seizures, and 2 were tall and had normal head circumference. Jill Hendrickson (University of Florida) presented genetic studies among 46 patients with AS and 15q deletion in
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llorida and Oregon. Ten had no siblings. There were Gl siblings among the other 36, as well as 9 maternal and 6 paternal half-sibs, and none had AS. One girl had a mother with some changes of AS (ataxia,brachycephaly, motor delay) who did not have a deletion. There were affected first cousins (different sexes) who both had maternal del 15, though in one case it was inherited through the father. They conclude that sibling recurrence is below 5% in deletion cases. Poster presentations on AS provided morphometric analysis of the facial abnormaliti.es, and added some findings including recurrent upper airway infections, hypopigmentation, and orset of seizures between 10 and 31 months.
PANEL DISCUSSION The panel discussion focused on summarizing the molecular findings in PWS and AS and determining appropriate sibling recurrence risks based on these findings. The general consensus was that in PWS 77% have a paternal 15q deletion or some other chromosome anomaly involving 15, and 23% have maternal disomy. No typical patient has neither. Recurrence risk is below 1% in deletion cases (none reported), and unknown in disomy cases, but still probably below 2%. In AS, 60% have maternal 15q deletion, 4% have paternal disomy, and the remainder have neither. Recurrence risk is below 2% in & nova deletion cases and empirically 18% in nondeletion cases with disomy excluded. Guesses at appropriate recurrence risks in other situations include 5-10% in deletion or disomy cases in which there is a rearranged parental chromosome 15, 2% in the few disomy cases, and 50% once a recurrence has already occurred in siblings. Theories for the cause in familial non-deletion cases include maternally derived mutation, which may be dominant, or a submicroscopic deletion.
ACKNOWLEDGEMENTS Many people contributed to make this workshop successful. I want to thank the members of the Scientific Advisory Committee for their assistance in identifying speakers and selecting abstracts (Nicholas Barnes, Tim Donlon, Jean-Pierre Fryns, VanLja Holm, Martin Ritzen, Martinus Niermeijer and Evelyn Wesby-van Swaay). Particular gratitude is due to Henk Moezelaar, head of the Dutch PWS association, for the local arrangements, and to Jean PhillipsMartinsson, head of the Swedish PWS association, for using international contacts to identify people with interest in PWS. The PWSA (US) provided a grant to assist in planning of the conference, and contributions were made by the March of Dimes/Birth Defects Foundation (Grant No. 4-237) and by Vivigen. Major support for this workshop was provided by an Advanced Research Workshop Award from NATO. I am grateful to Maryann Wagner for her invaluable administrative and secretarial assistance.
