Subscribe to RSS
DOI: 10.1055/s-2001-15857
Georg Thieme Verlag Stuttgart ·New York
Klinik und Genetik des Prader-Willi-Syndroms
Clinical features and genetic analysis of Prader-Willi SyndromePublication History
Publication Date:
31 December 2001 (online)
![](https://www.thieme-connect.de/media/klinpaed/200103/lookinside/thumbnails/10.1055-s-2001-15857-1.jpg)
Zusammenfassung.
Das Prader-Willi-Syndrom (PWS) zählt zu den seltenen neurogenetischen Funktionsstörungen und stellt andererseits die häufigste Form des syndromatischen Übergewichts dar. Klinische Hauptmerkmale sind eine im Neugeborenenalter ausgeprägte Hypotonie mit anfänglich erheblicher Trinkschwäche und dadurch bedingter Gedeihstörung, ab dem 2. Lebensjahr Entwicklung einer Hyperphagie mit stammbetonter, unbehandelt bisweilen morbider Adipositas. Neben einer verzögert ablaufenden motorischen Entwicklung ist auch der Spracherwerb verlangsamt und bleibt oft eingeschränkt, die intellektuelle Entwicklung ist durch eine Lernbehinderung mit Beeinträchtigung besonders des Kurzzeitgedächtnisses und abstrakter Denkvorgänge gekennzeichnet. Der genetische Hintergrund aller bisher bekannter Genotypen ist ein Funktionsverlust eines väterlich vererbten Genclusters am Chromosom 15 (q11.2). Die elternspezifische Prägung (genomic imprinting) stellt ein epigenetisches Phänomen dar, wodurch identische Basensequenzen homologer elterlicher Gene ein- und ausgeschaltet werden können. Das PWS wie auch das molekulargenetisch eng benachbarte, klinisch allerdings völlig andersartige Angelman-Syndrom (AS) zählen zu den ersten Krankheitsbildern, bei denen ein Funktionsausfall eines Imprint-Gens als Krankheitsursache nachgewiesen wurde. Bei unterschiedlichen Genotypen ist der Phänotyp vergleichsweise sehr ähnlich und zeigt beim PWS nur diskrete statistische Differenzen, z. B. bezüglich der Pigmentierung. Eine frühe klinische Diagnose ist in Kenntnis des neuromuskulären Defizits anzustreben, weil eine frühzeitig einsetzende gut strukturierte kalorienreduzierte Ernährung dem sonst ungehemmten Gewichtszuwachs mit nachfolgenden Komplikationen entgegenwirken kann. Die Diagnose über die Morphologie allein ist in der Neugeborenenperiode schwierig und wird oft erst durch die Kombination mit der erheblichen Hypotonie in Betracht gezogen. Die Verfügbarkeit verlässlicher, mittlerweile bevorzugt nicht-radioaktiver molekulargenetischer Nachweismethoden lässt die Diagnose zweifelsfrei feststellen und ein tragfähiges Konzept für eine sinnvolle symptomatische Therapie erarbeiten. Zu diesen Maßnahmen zählt auch der Einsatz von rekombinantem Wachstumshormon, das nach den Ergebnissen zahlreicher klinischer Studien bei gegebenem funktionellen Wachstumshormonmangel einen zweifelsfreien auxologischen Nutzen und auch eine günstige Veränderung der Fett: Muskelmasse und eine Verbesserung der motorischen Aktivität und der respiratorischen Funktion bewirkt. Fazit: Eine frühzeitige Diagnose des PWS durch DNA-Analyse verhilft zu einer klaren Auskunft hinsichtlich der Genetischen Beratung, erspart dem Kind unnötige zusätzliche Untersuchungen wie CT und Muskelbiopsie und bereitet den Weg zu einer gezielten symptomatischen Therapie, zu der im Hinblick auf den funktionellen HGH-Mangel bei PWS auch eine Wachstumshormontherapie empfehlenswert erscheint. Wegen der im Verlauf der Entwicklung vielfachen möglichen Komplikationen erscheint ein multidisziplinäres Betreuungskonzept an einem Zentrum empfehlenswert.
Prader-Willi syndrome (PWS) is considered to be a rare neurogenetic disorder, nevertheless it represents the most common syndromatic obesity. Main features are severe hypotonia in the newborn period with feeding difficulty and failure to thrive in the first few months, and improvement in later infancy. Between 1 and 6 years the development of a marked truncal obesity is observed, sometimes later on reaching a life-threatening degree. Apart from retarded motor development speech ability is also hampered due to dysfunction of oropharyngeal muscles. Moreover, intellectual impairment is observed that leads to mostly moderate learning difficulty due to deficits in short term memory and abstract thinking. The genetic background of PWS is loss of function of a paternally inherited gene cluster on chromosome 15q11.2, therefore representing a paradigm of an epigenetic phenomenon with silencing and activating of genes depending on their parental origin. Together with the Angelman-Syndrome (AS), genetically located in the same region but clinically different PWS was identified as one of the first human disorders to be caused by the mechanism of genomic imprinting. There are some different genotypes in PWS leading to a quite similar phenotype with small differences eg. In the pigment expression. An early diagnosis is important because the neuromuscular dysfunction improves with appropriate physiotherapy. Even more, dietary programs with periodical calory restricted meals can counteract development of morbid obesity with subsequent complications of cardiovascular disorders and diabetes. Clinical diagnosis remains difficult especially in the newborn period and is considered mostly because of the marked hypotonia. Today, the availability of molecular testing of loss of function in the paternal inherited PWS canditate gene makes a defintitive diagnosis possible as a prerequisite of symptomatic therapy. One of the most recommended therapeutic interventions is the application of recombinant human growth hormone (rhGH) which has been shown to be useful for improvement of length, physical ability and favourable influence on respiratory problems by a lot of clinical studies. Summary: Early diagnosis by means of molecular methods is helpful for comprehensive genetic counseling. It may avoid unnecessary investigations like computed tomography of the brain and muscle biopsy and it enables parents and professionals to start a purposeful therapy. Although it remains a symptomatic tool, GH therapy appears to be useful for most of the patients. Considering the multimorbidity in PWS a multidisciplinary approach seems appropriate for this still mystical condition.
Schlüsselwörter:
Prader-Willi-Syndrom - Epigenetik - hypothalamische Dysfunktion
Key words:
Prader-Willi syndrome - epigenetics - hypothalamic obesity
Literatur
- 01 Akefeldt A, Törnhage C J, Gillberg C. A woman with Prader-Willi syndrome gives birth to a healthy baby girl (letter). Dev Med Child Neur. 1999;; 41 789-790
- 02 Angulo M, Castro-Magana M, Uy J. Pituitary evaluation and growth hormone treatment in Prader-Willi syndrome. J Pediatr Endocrinol. 1991;; 4 167-173
- 03 Angulo M, Castro-Magana M, Mazur B, Canas J A, Vitollo P M, Sarrantonio M. Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi syndrome. J Pediatr Endocrinol Metabol. 1996;; 9 393-400
- 04 Behrens M JW, Hordijk R, Scheffer H, Oosterwjik J C, Halley D JJ, Sorgedraeger N. Two cases of maternal uniparental disomy 14 with a phenotype overlapping with the Prader-Willi phenotype. Am J Med Genet. 1999;; 84 76-79 (letter)
- 05 Bueno G, Moreno L A, Pineda I, Campos J, Ruibal J L, Juste M G, Casado E, Bueno M. Serum Leptin concentrations in children with Prader-Willi syndrome and non-syndromal obesity. J Pediatr Endocrinol Metabol. 2000;; 13 425-430
- 06 Buiting K, Färber C, Kroisel P, Wagner K, Brueton L, Robertson M E, Lich C, Horsthemke B. Imprinting center deletions in two PWS families: implications for diagnostic testing and genetic counseling. Clin Genet. 2000; 58 284-290
- 07 Butler M G, Palmer C G. Parental origin of chromosome 15 deletion in Prader-Willi syndrome. Lancet. 1983; 1 1285-1286
- 08 Butler M G, Meaney F J. Standards of selected anthropometric measurements in Prader-Willi syndrome. Pediatrics. 1991;; 88 853-860
- 09 Butler M G, Moore J, Morawiecki A, Nicolson M. Comparison of Leptin Protein levels in Prader-Willi syndrome and control individuals. Am J Med Genet. 1998a;; 75 7-12
- 10 Butler M G et al. Photoanthropometric study of craniofacial traits in individuals with Prader-Willi syndrome on short term growth therapy. Clin Genet. 1998b;; 53 268-275
- 11 Butler M G, Meaney F J. Standards of selected anthropometric measurements in Prader-Willi syndrome. Pediatrics. 1991;; 88 853-860
- 12 Butler M G. A 68-year old white female with Prader-Willi Syndrome. Clin Dysmorphol. 2000;; 9 65-67 (letter)
- 13 Carrel A L, Myers S E, Whitman B Y, Allen D B. Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: a controlled study. J Pediatr. 1999;; 134 215-221
- 14 Cassidy S B, Forsythe M, Heeger S, Nicholls R D, Schork N, Benn P, Schwarzt S. Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15. Am J Med Genet. 1997a;; 68 433-440
- 15 Cassidy S B. Prader-Willi Syndrome. J Med Genet. 1997b;; 34 917-923
- 16 Davies P SW, Evans S, Broomhead S, Clough H, Day J ME, Laidlaw A, Barnes N D. Effect of growth hormone on height, weight, and body composition in Prader-Willi syndrome. Arch Dis Child. 1998;; 78 474-476
- 17 Descheemaeker M J, Vogels A, Borghgraef M, Plissart L, Willekens D, Govers V, Roelants M, Swillen A, Fryns J P. Physical characteristics and behavioural phenotype in Prader-Willi syndrome: 15 years of experience. 3rd PWS International Scientific Workshop, Jesolo, Italy,; May 1998:
- 18 Eiholzer U, Stutz K, Weinmann C, Blum W F, Molinari L, Prader A. Body composition and leptin levels in obese and non-obese PWS-children. 3rd PWS International Scientific Workshop, Jesolo, Italy,; May 1998a:
- 19 Eiholzer U, Gisin R, Weinmann C, Kriemler S, Steinert H, Torresani T, Zachmann M, Prader A. Treatment with human growth hormone in patients with Prader-Willi syndrome reduces body fat and increases muscle mass and physical performance. Eur J Pediatr. 1998b;; 157 368-377
- 20 Eiholzer U, Blum W F, Molinari L. Body fat determined by skinfold measurements is elevated despite underweight in infants with Prader-Labhart-Willi Syndrome. J Pediatr. 1999;; 134 (2) 222-225
- 21 Engel E. A new genetic concept: uniparental disomy and ist potential effect, isodisomy. Am J Med Genet. 1980;; 6 137-143
- 22 Gillessen-Kaesbach G, Horsthemke B. Clinical and molecular studies in fragile X patients with a Prader-Willi like phenotype [letter; comment] [see comments]. J Med Genet. 1994;; 31 260-261
- 23 Gillessen-Kaesbach G, Gross S, Kaya-Westerloh S, Passarge E, Horsthemke B. DNA methylation based testing of 450 patients suspected of having Prader-Willi syndrome. J Med Genet. 1995;; 32 88-92
- 24 Gimelli G, Stein S C, Zuffardi O. A second locus for Prader-Willi syndrome in chromosome 6q. Eur J Hum Genet. 2000;; Suppl 1(A) 84 (A)
- 25 Golden W L, Sudduth K W, Burnett S H, Kelly T E. Mosaicism in Prader-Willi Syndrome: detection using Fluorescence In Situ Hybridisation. Am J Med Genet. 1999;; 85 424-425
- 26 Hauffa B P. One year results of growth hormone treatment of short stature in Prader-Willi syndrome. Acta Paediatr. 1997;; Suppl 423 63-65
- 27 Hauffa B P. Spontaneous growth in German children and adolescents with genetically confirmed Prader-Willi Syndrome. Acta Paediatr. 2000;; 89 1302 ff
- 28 Holm V A, Laurnen E L. Prader-Willi Syndrome and Scoliosis. Dev Med Child Neurol. 1981;; 92 201
- 29 Holm V A, Cassidy S B, Butler M G, Hanchett J M, Greenswag L R, Whitman B Y, Greenberg F. Prader-Willi syndrome: Consensus diagnostic criteria. Pediatrics. 1993;; 91 398-402
- 30 Kiess W, Siebler T, Englaro P, Kratsch J, Deutscher J, Meyer K, Gallaher B, Blum W F. Leptin as a Metabolic regulator during fetal life and in childhood and adolescence. J Pediatr Endocrinol Metab. 1998;; 11 483-496
- 31 Lämmer C, Pankau R. Die Behandlung der Adipositas bei PWS. Monatsschr Kinderheilkd. 1999;; 147 1066 A
- 32 Ledbetter D H, Riccardi V M, Airhart S D, Strobel R J, Keenan B S, Crawford J D. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med. 1981;; 304 325-329
- 33 Lee P DK, Wilson D M, Rountree L, Hintz R L, Rosenfeld R G. Linear growth response to exogenous growth hormone in Prader-Willi syndrome. Prader-Willi und Angelman Syndrom. Molekulargenetische Diagnostik mittels MS-PCR. Am J Med Genet. 1987;; 28 865-871
- 34 Lerch N, Bösch N, Müller Hj, Malik N H. Prader-Willi- und Angelman-Syndrom. Monatschr Kinderheilkd. 2000;; 148 691-695
- 35 Lindgren A C, Hagenäs L, Müller J, Blichfeldt S, Rosenborg M, Brismar T, Ritzen E M. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth ad body composition favourable. Acta Paediatr. 1998;; 87 28-31
- 36 Lindgren A C, Hagenäs L, Ritzen E M. Growth hormone treatment of children with Prader-Willi syndrome: effects on glucose and insulin homeostasis. Horm Res. 1998a;; 51 (4) 157-161
- 37 Lindgren A C, Hellström L G, Ritzen E M, Milerad J. Growth hormone treatment increases CO2-response, vntilation and central inspiratory drive in children with Prader-Willi syndrome. Eur J Pediatr. 1999;; 158 936-940
- 38 Lindgren A C, Barkeling B, Hägg A, Ritzen E M, Marcus C, Rössner S. Eating behaviour in Prader-Willi syndrome, normal weight and obese control group. J Pediatr. 2000;; 137 50-55
- 39 Linnemann K, Schröder C, Mix M, Krüger G, Fusch C. Prader-Labhart-Willi syndrome with central precocious puberty and empty sella syndrome. Acta Paediatr. 1999;; 88 1295-1297
- 40 Maier-Brandt B, Ries M, Lang T, Rauch R, Naehrlich L, Harms D, Wenzel D. Prader-Willi Syndrom. Monatsschr Kinderheilkd. 1997;; 145 515-518
- 41 Mascari M J, Gottlieb W, Rogan P K, Butler M G, Waller D A, Armour J AL, Jeffreys A J, Ladda R L, Nicholls R D. The frequency of uniparental disomy in Prader-Willi syndrome. N Eng J Med. 1992;; 326 1599-1607
- 42 Miller S P, Riley P, Shevell M I. The neonatal presentation of Prader-Willi syndrome revisited. J Pediatr. 1999;; 134 (2) 226-228
- 43 Myers S E, Carrel A L, Whitman B Y, Allen D B. Physical effects of growth hormone treatment in children with PWS. Acta Paediatr Suppl. 1999;; 433 112-114
- 44 Myers S E, Carrel A L, Whitman B Y, Allen D B. Substained benefit after two years of growth hormone on body composition, fat utilisation, physical strength and agility, and growth in Prader-Willi syndrome. J Pediatr. 2000;; 137 42-49
- 45 Nicholls R D, Knoll J HM, Butler M G, Karam S, Lalande M. Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature. 1989;; 342 281-285
-
46 Nicholls R D. Prader-Willi and Angelman syndromes. In: Jamesson JL (Ed).
Principles of Molecular Medicine. Humana Press Inc., Totawa, NJ; 1998: - 47 Park J P, Moeschler J B, Hani V H, Hawk A B, Belloni D R, Noll W W, Mohandas T K. Maternal Disomy and Prader-Willi syndrome consistent with geamete complementation in a case of familial translocation (3; 15)(p25; q11.2). Am J Med Genet. 1998;; 78 134-139
- 48 Prader A, Labhard A, Willi H. Ein Syndrom von Adipositas, Kleinwuchs, Kryptochismus und Oligophrenie nach myatonieartigem Zustand im Neugeborenenalter …. Schweiz Med Wochenschr. 1956;; 86 1260
- 49 Ritzen E M, Lindgren A C, Hagenäs L, Marcus C, Müller J, Blichfeldt S in collaboration with the Swedish Growth Hormone Advisory Group. Growth hormone treatment of patients with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 1999;; 12 345-349
- 50 Rost I, Schuffenhauer S, Tcherepnine P. PWS im Säuglingsalter. Monatsschr Kinderheilkd. 1995;; 143 617
- 51 Saitoh S, Wada T. Parent-of-Origin Specific Histone Acetylation and Reactivation of a Key Imprinted Gene Locus in Prader-Willi Syndrome. Am J Hum Genet. 2000;; 66 1958-1962
- 52 Schrander-Stumpel C, Gerver W J, Meyer H, Engelen J, Mulder H, Fryns J P. Prader-Willi-like phenotype in fragile X syndrome. Clin Genet. 1994;; 45 175-180
- 53 Schulze A, Hansen C, Baekgaard P, Blichfeldt S, Petersen M B, Tommerup N, Brondum-Nielsen K. Clinical features and molecular genetic analysis of a boy with Prader-Willi Syndrome caused by an imprinting effect. Acta Paediatr. 1997;; 86 906-910
- 54 Schulze A, Mogensen H, Hamborg-Peterseh B, Grem N, Oestergaard J, Brondum-Nielsen K. Titel A woman with Prader-Willi syndrome gave birth to a child with Angelman syndrome. Eur J Hum Genet. 2000;; Suppl 1 77-78 (A)
- 55 Sills I N, Rapaport R. Non-Insulin dependent diabetesmellitrus in a prepubertal child with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 1998;; 11 281-282
- 56 Swaab D F. Prader-Willi Syndrome and the hypothalamus. Acta Paediatr. 1997;; Suppl 423 50-54
- 57 Toth-Fejel S, Olson S, Gunter K, Quan F, Wolford J, Popovich B W, Magenis R E. The impact of imprinting: Prader-Willi Syndrome resulting from chromosome translocation, recombination and non-disjunction. Am J Hum Genet. 1996;; 58 1008-1016
- 58 Vettor R, Chierichetti F, Grugni G, Bettio D, Cargniel S, Ferlin G, Morabito F, Federspil G. Evidence for a reduction of regional brain glucose uptake in obese Prader-Willi patients. 3rd PWS International Scientific Workshop, Jesolo, Italy,; May 1998:
- 59 Wevrick R, Francke U. Diagnostic test for the Prader-Willi syndrome by SNRPN expression in blood. Lancet. 1996;; 348 1068-1069
- 60 Zeschnigk M, Lich C, Buiting K, Doerfler W, Horsthemke B. A single-tube PCR test for the diagnosis of Angelman and Prader-Willi syndrome based on allelic methylation differences at the SNRPN locus. Eur J Hum Genet. 1997;; 5 94-98
- 61 Zipf W B. Glucose homeostasis in PWS and potential implications of growth hormone therapy. Acta Paediatr Suppl. 1999;; 433 115-117
Dr. med. Olaf Rittinger
St.-Johanns-Spital
Klinische Genetik am
Kinderspital
Müllner Hauptstr. 48
5020 Salzburg
Österreich