Download Cancer Prone Disease Section Prader Willi syndrome Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Review
Prader Willi syndrome
Maria Piccione, Giovanni Corsello
Dipartimento Materno Infantile, University of Palermo, Italy (MP, GC)
Published in Atlas Database: April 2008
Online updated version : http://AtlasGeneticsOncology.org/Kprones/PraderWilliID10114.html
DOI: 10.4267/2042/44461
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
At 1-3 years hyperphagia appears with rapid weight
gain and obesity. The leptine levels are normal and
ghrelin levels are significantly elevated, 3-4 fold higher
in children with PWS than in general population.
Craniofacial characteristics: High prominent
forehead, narrow bifrontal diameter, telecanthus,
downlated fissures, downturned corners of the mouth,
micrognathia, dysplasic ears and diminished mimic
activity due to muscular hypotonia (fig.1).
Dermatological anomalies: Hypopigmentation-fair
skin and severe skin-picking.
Limbs and skeletal anomalies: Small hands and feet
(acromicria), bracydactyly, clynodactyly of fifth finger,
delayed bone age especially in the limbs, related to
growth hormone function and diminished bone mineral
density.
Hypothalamic
dysfunction:
Hypogonadropic
hypogonadism with cryptorchidism and micropenis,
delayed or incomplete gonadal maturation with delayed
pubertal findings, short stature secondary to growth
hormone deficiency, hyperphagia with absence of
satiety and obesity (fig.2), temperature instability,
central adrenal insufficiency.
Performance and behavioural problems: Hypotonia,
sleep disorders, obsessive compulsive behaviour,
possessiveness, stubbornness and mild to moderate
mental retardation.
Tumors: Myeloid leukaemia cases are 40 fold higher
in PWS patients than in the general population. There
have also been cases of lymphoblastic leukaemia,
seminoma, adult ovarian teratoma, hepatic tumours,
Hodgkin lymphoma and type 1 multiple endocrine
neoplasia.
Occasional abnormalities
Skeletal findings: Scoliosis, kyphosis and hip
dysplasia.
Central nervous system: Ventriculomegaly, decreased
volume of the parietal-occipital lobe, sylvian fissure
polymicrogyria and incomplete insular closure.
Identity
Note
The Prader Willi syndrome (PWS) is characterized by
diminished fetal activity, dysmorphic facial features,
small hands and feet, marked hypotonia, neonatal
feeding problems, thick saliva, hyperphagia and weight
gain between the ages of 1 and 6, poor linear growth,
short stature, hypothalamic dysfunction (obesity,
absence of satiety, hypogonadism with cryptorchidism,
abnormal temperature control and GH deficiency),
cognitive difficulties and characteristic behavioural
traits.
Inheritance
It is sporadic and familial cases are rare. The incidence
is 1:10.000-15.000 births.
Etiology
PWS is genetically heterogeneous. The absent
expression of the paternal activity in the critical region
on chromosome 15 has been found in patients with
PWS. In 70-75% of patients there is a deletion of the
paternal 15q11-q13 chromosome (del15) and in about
25% there is a maternal uniparental disomy 15
(UDP15), and a small percentage of patients may have
an imprinting center mutation or translocations
involving chromosome15. In the 15q11-q13 region a
lot of candidate genes are present. The C/D box small
nucleolar RNA (snoRNA) gene cluster HBII-85, IPW,
PAR1, MAGEL2 and SNRPN genes is not expressed in
patients with PWS and may be involved in the
phenotype.
Clinics
Phenotype and clinics
Abnormalities
Growth: Intrauterine growth retardation, short stature
due to a growth hormone deficiency.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(4)
319
Prader Willi syndrome
Piccione M, Corsello G
Congenital and acquired hypothyroidism.
References
Cassidy
SB.
Prader-Willi
syndrome.
Characteristics,
management, and etiology. Ala J Med Sci. 1987 Apr;24(2):16975
Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997
Nov;34(11):917-23
Boccaccio I, Glatt-Deeley H, Watrin F, Roëckel N, Lalande M,
Muscatelli F. The human MAGEL2 gene and its mouse
homologue are paternally expressed and mapped to the
Prader-Willi region. Hum Mol Genet. 1999 Dec;8(13):2497-505
Carrel AL, Myers SE, Whitman BY, Allen DB. Growth hormone
improves body composition, fat utilization, physical strength
and agility, and growth in Prader-Willi syndrome: A controlled
study. J Pediatr. 1999 Feb;134(2):215-21
Hauffa BP, Schlippe G, Roos M, Gillessen-Kaesbach G,
Gasser T. Spontaneous growth in German children and
adolescents with genetically confirmed Prader-Willi syndrome.
Acta Paediatr. 2000 Nov;89(11):1302-11
Fig 1: Dysmorphic facial features: high prominent forehead,
narrow bifrontal diameter, downturned corners of the mouth,
micrognathia.
Lee S, Wevrick R. Identification of novel imprinted transcripts
in the Prader-Willi syndrome and Angelman syndrome deletion
region: further evidence for regional imprinting control. Am J
Hum Genet. 2000 Mar;66(3):848-58
Ming JE, Blagowidow N, Knoll JH, Rollings L, Fortina P,
McDonald-McGinn
DM,
Spinner
NB,
Zackai
EH.
Submicroscopic deletion in cousins with Prader-Willi syndrome
causes a grandmatrilineal inheritance pattern: effects of
imprinting. Am J Med Genet. 2000 May 1;92(1):19-24
Olander E, Stamberg J, Steinberg L, Wulfsberg EA. Third
Prader-Willi syndrome phenotype due to maternal uniparental
disomy 15 with mosaic trisomy 15. Am J Med Genet. 2000 Jul
31;93(3):215-8
Tauber M, Barbeau C, Jouret B, Pienkowski C, Malzac P,
Moncla A, Rochiccioli P. Auxological and endocrine evolution
of 28 children with Prader-Willi syndrome: effect of GH therapy
in 14 children. Horm Res. 2000;53(6):279-87
Burman P, Ritzén EM, Lindgren AC. Endocrine dysfunction in
Prader-Willi syndrome: a review with special reference to GH.
Endocr Rev. 2001 Dec;22(6):787-99
Fulmer-Smentek SB, Francke U. Association of acetylated
histones with paternally expressed genes in the Prader--Willi
deletion region. Hum Mol Genet. 2001 Mar 15;10(6):645-52
Fig 2: Obesity in a 5-year-old patient.
Evolution
Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan MA,
Cassidy SB. The changing purpose of Prader-Willi syndrome
clinical diagnostic criteria and proposed revised criteria.
Pediatrics. 2001 Nov;108(5):E92
Multidisciplinary
management
(paediatrician,
endocrinologist, orthopaedic specialist, dietologist,
cardiologist, psychiatrist etc.) is necessary.
Growth hormone treatment and strict diet control have
been reported to significantly modify the life of
children with PWS.
Testosterone therapy has resulted in the enlargement of
the micropenis to normal size for age and hormonal
substitutive therapy with testosterone or estrogens
allows a complete pubertal development.
Meguro M, Mitsuya K, Nomura N, Kohda M, Kashiwagi A,
Nishigaki R, Yoshioka H, Nakao M, Oishi M, Oshimura M.
Large-scale evaluation of imprinting status in the Prader-Willi
syndrome region: an imprinted direct repeat cluster resembling
small nucleolar RNA genes. Hum Mol Genet. 2001 Feb
15;10(4):383-94
Wirth J, Back E, Hüttenhofer A, Nothwang HG, Lich C, Gross
S, Menzel C, Schinzel A, Kioschis P, Tommerup N, Ropers
HH, Horsthemke B, Buiting K. A translocation breakpoint
cluster disrupts the newly defined 3' end of the SNURFSNRPN transcription unit on chromosome 15. Hum Mol Genet.
2001 Feb 1;10(3):201-10
Prognosis
The patients have an increased mortality of 3% across
all age groups but, if strict weight control is achieved,
survival is improved. Diabetes and its complications,
cardiac failure and respiratory disorders (respiratory
insufficiency or infections) are major causes of
morbidity and mortality in PSW patients.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(4)
Carrel AL, Myers SE, Whitman BY, Allen DB. Benefits of longterm GH therapy in Prader-Willi syndrome: a 4-year study. J
Clin Endocrinol Metab. 2002 Apr;87(4):1581-5
Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE,
Frayo RS, Schwartz MW, Basdevant A, Weigle DS. Elevated
320
Prader Willi syndrome
Piccione M, Corsello G
plasma ghrelin levels in Prader Willi syndrome. Nat Med. 2002
Jul;8(7):643-4
treatment and adverse events in Prader-Willi syndrome: data
from KIGS (the Pfizer International Growth Database). Clin
Endocrinol (Oxf). 2006 Aug;65(2):178-85
DelParigi A, Tschöp M, Heiman ML, Salbe AD, Vozarova B,
Sell SM, Bunt JC, Tataranni PA. High circulating ghrelin: a
potential cause for hyperphagia and obesity in prader-willi
syndrome. J Clin Endocrinol Metab. 2002 Dec;87(12):5461-4
Eiholzer U, l'Allemand D, Rousson V, Schlumpf M, Gasser T,
Girard J, Grüters A, Simoni M. Hypothalamic and gonadal
components of hypogonadism in boys with Prader-LabhartWilli syndrome. J Clin Endocrinol Metab. 2006 Mar;91(3):892-8
Höybye C, Hilding A, Jacobsson H, Thorén M. Metabolic profile
and body composition in adults with Prader-Willi syndrome and
severe obesity. J Clin Endocrinol Metab. 2002 Aug;87(8):35907
Kishore S, Stamm S. The snoRNA HBII-52 regulates
alternative splicing of the serotonin receptor 2C. Science. 2006
Jan 13;311(5758):230-2
Crinò A, Schiaffini R, Ciampalini P, Spera S, Beccaria L, Benzi
F, Bosio L, Corrias A, Gargantini L, Salvatoni A, Tonini G,
Trifirò G, Livieri C. Hypogonadism and pubertal development in
Prader-Willi syndrome. Eur J Pediatr. 2003 May;162(5):327-33
Kroonen LT, Herman M, Pizzutillo PD, Macewen GD. PraderWilli Syndrome: clinical concerns for the orthopaedic surgeon.
J Pediatr Orthop. 2006 Sep-Oct;26(5):673-9
Miller J, Silverstein J, Shuster J, Driscoll DJ, Wagner M. Shortterm effects of growth hormone on sleep abnormalities in
Prader-Willi syndrome. J Clin Endocrinol Metab. 2006
Feb;91(2):413-7
Davies HD, Leusink GL, McConnell A, Deyell M, Cassidy SB,
Fick GH, Coppes MJ. Myeloid leukemia in Prader-Willi
syndrome. J Pediatr. 2003 Feb;142(2):174-8
Haqq AM, Stadler DD, Rosenfeld RG, Pratt KL, Weigle DS,
Frayo RS, LaFranchi SH, Cummings DE, Purnell JQ.
Circulating ghrelin levels are suppressed by meals and
octreotide therapy in children with Prader-Willi syndrome. J
Clin Endocrinol Metab. 2003 Aug;88(8):3573-6
Oiglane-Shlik E, Zordania R, Varendi H, Antson A, Mägi ML,
Tasa G, Bartsch O, Talvik T, Ounap K. The neonatal
phenotype of Prader-Willi syndrome. Am J Med Genet A. 2006
Jun 1;140(11):1241-4
Smith A, Egan J, Ridley G, Haan E, Montgomery P, Williams
K, Elliott E. Birth prevalence of Prader-Willi syndrome in
Australia. Arch Dis Child. 2003 Mar;88(3):263-4
Yamada K, Matsuzawa H, Uchiyama M, Kwee IL, Nakada T.
Brain developmental abnormalities in Prader-Willi syndrome
detected by diffusion tensor imaging. Pediatrics. 2006
Aug;118(2):e442-8
Butler MG, Bittel DC, Talebizadeh Z. Plasma peptide YY and
ghrelin levels in infants and children with Prader-Willi
syndrome. J Pediatr Endocrinol Metab. 2004 Sep;17(9):117784
Benarroch F, Hirsch HJ, Genstil L, Landau YE, Gross-Tsur V.
Prader-Willi syndrome: medical prevention and behavioral
challenges. Child Adolesc Psychiatr Clin N Am. 2007
Jul;16(3):695-708
Carrel AL, Moerchen V, Myers SE, Bekx MT, Whitman BY,
Allen DB. Growth hormone improves mobility and body
composition in infants and toddlers with Prader-Willi syndrome.
J Pediatr. 2004 Dec;145(6):744-9
Butler MG, Theodoro M, Skouse JD. Thyroid function studies
in Prader-Willi syndrome. Am J Med Genet A. 2007 Mar
1;143(5):488-92
Caliandro P, Grugni G, Padua L, Kodra Y, Tonali P, Gargantini
L, Ragusa L, Crinò A, Taruscio D. Quality of life assessment in
a sample of patients affected by Prader-Willi syndrome. J
Paediatr Child Health. 2007 Dec;43(12):826-30
Goldstone AP. Prader-Willi syndrome: advances in genetics,
pathophysiology and treatment. Trends Endocrinol Metab.
2004 Jan-Feb;15(1):12-20
Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, Cassidy SB,
Schrander JJ, Fryns JP. Prader-Willi syndrome: causes of
death in an international series of 27 cases. Am J Med Genet
A. 2004 Feb 1;124A(4):333-8
Giménez-Palop O, Giménez-Pérez G, Mauricio D, GonzálezClemente JM, Potau N, Berlanga E, Trallero R, Laferrère B,
Caixàs A. A lesser postprandial suppression of plasma ghrelin
in Prader-Willi syndrome is associated with low fasting and a
blunted postprandial PYY response. Clin Endocrinol (Oxf).
2007 Feb;66(2):198-204
Vogels A, De Hert M, Descheemaeker MJ, Govers V,
Devriendt K, Legius E, Prinzie P, Fryns JP. Psychotic disorders
in Prader-Willi syndrome. Am J Med Genet A. 2004 Jun
15;127A(3):238-43
Marzullo P, Marcassa C, Campini R, Eleuteri E, Minocci A,
Sartorio A, Vettor R, Liuzzi A, Grugni G. Conditional
cardiovascular response to growth hormone therapy in adult
patients with Prader-Willi syndrome. J Clin Endocrinol Metab.
2007 Apr;92(4):1364-71
Vogels A, Van Den Ende J, Keymolen K, Mortier G, Devriendt
K, Legius E, Fryns JP. Minimum prevalence, birth incidence
and cause of death for Prader-Willi syndrome in Flanders. Eur
J Hum Genet. 2004 Mar;12(3):238-40
Miller JL, Couch JA, Schmalfuss I, He G, Liu Y, Driscoll DJ.
Intracranial abnormalities detected by three-dimensional
magnetic resonance imaging in Prader-Willi syndrome. Am J
Med Genet A. 2007 Mar 1;143(5):476-83
Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H.
Cognitive abilities and genotype in a population-based sample
of people with Prader-Willi syndrome. J Intellect Disabil Res.
2004 Feb;48(Pt 2):172-87
Myers SE, Whitman BY, Carrel AL, Moerchen V, Bekx MT,
Allen DB. Two years of growth hormone therapy in young
children
with
Prader-Willi syndrome:
physical
and
neurodevelopmental benefits. Am J Med Genet A. 2007 Mar
1;143(5):443-8
Kato M, Mugishima H, Chin M, Urakami T, Harada K. Acute
lymphoblastic leukemia in a patient with Prader-Willi syndrome
under growth hormone therapy. Pediatr Int. 2005
Jun;47(3):336-7
Reddy LA, Pfeiffer SI. Behavioral and emotional symptoms of
children and adolescents with Prader-Willi Syndrome. J Autism
Dev Disord. 2007 May;37(5):830-9
Caixàs A, Giménez-Palop O, Giménez-Pérez G, Potau N,
Berlanga E, González-Glemente JM, Arroyo J, Laferrère B,
Mauricio D. Postprandial adiponectin levels are unlikely to
contribute to the pathogenesis of obesity in Prader-Willi
syndrome. Horm Res. 2006;65(1):39-45
Savopoulos C, Hatzitolios A, Panagopoulou P, Kosmidou M,
Tsirogianni E, Konstantinou V. Hypothyroidism in Prader-Willi
syndrome: a case report and review of the literature. J
Endocrinol Invest. 2007 Oct;30(9):804-5
Craig ME, Cowell CT, Larsson P, Zipf WB, Reiter EO,
Albertsson Wikland K, Ranke MB, Price DA. Growth hormone
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(4)
321
Prader Willi syndrome
Piccione M, Corsello G
Yamada K, Miyamoto K, Hosoe H, Mizutani M, Shimizu K.
Scoliosis associated with Prader-Willi syndrome. Spine J. 2007
May-Jun;7(3):345-8
Cappa M, Caselli G, Cerioni V, Delvecchio M, Giardino D,
Iannì F, Memo L, Pilotta A, Pomara C, Radetti G, Sacco M,
Sanzari A, Sartorio A, Tonini G, Vettor R, Zaglia F, Chiumello
G. The Italian National Survey for Prader-Willi syndrome: an
epidemiologic study. Am J Med Genet A. 2008 Apr
1;146(7):861-72
Bacheré N, Diene G, Delagnes V, Molinas C, Moulin P, Tauber
M. Early diagnosis and multidisciplinary care reduce the
hospitalization time and duration of tube feeding and prevent
early obesity in PWS infants. Horm Res. 2008;69(1):45-52
Tauber M, Diene G, Molinas C, Hébert M. Review of 64 cases
of death in children with Prader-Willi syndrome (PWS). Am J
Med Genet A. 2008 Apr 1;146(7):881-7
Butler MG, Fischer W, Kibiryeva N, Bittel DC. Array
comparative genomic hybridization (aCGH) analysis in PraderWilli syndrome. Am J Med Genet A. 2008 Apr 1;146(7):854-60
Webb T, Maina EN, Soni S, Whittington J, Boer H, Clarke D,
Holland A. In search of the psychosis gene in people with
Prader-Willi syndrome. Am J Med Genet A. 2008 Apr
1;146(7):843-53
de Lind van Wijngaarden RF, Otten BJ, Festen DA, Joosten
KF, de Jong FH, Sweep FC, Hokken-Koelega AC. High
prevalence of central adrenal insufficiency in patients with
Prader-Willi syndrome. J Clin Endocrinol Metab. 2008
May;93(5):1649-54
This article should be referenced as such:
Piccione M, Corsello G. Prader Willi syndrome. Atlas Genet
Cytogenet Oncol Haematol. 2009; 13(4):319-322.
Grugni G, Crinò A, Bosio L, Corrias A, Cuttini M, De Toni T, Di
Battista E, Franzese A, Gargantini L, Greggio N, Iughetti L,
Livieri C, Naselli A, Pagano C, Pozzan G, Ragusa L, Salvatoni
A, Trifirò G, Beccaria L, Bellizzi M, Bellone J, Brunani A,
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(4)
322