Prader Willi syndrome

2008-04-01   Maria Piccione  , Giovanni Corsello  

Dipartimento Materno Infantile, University of Palermo, Italy

Identity

Name

Prader Willi syndrome

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.

Omim

176270

Mesh

D011218

Orphanet

739 Prader-Willi syndrome

Umls

C0032897

Clinics

Phenotype and clinics

Abnormalities
  • Growth: Intrauterine growth retardation, short stature due to a growth hormone deficiency.
    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.
  • Congenital and acquired hypothyroidism.
    • Atlas Image
    Fig 1: Dysmorphic facial features: high prominent forehead, narrow bifrontal diameter, downturned corners of the mouth, micrognathia.
    Atlas Image
    Fig 2: Obesity in a 5-year-old patient.

    Evolution

    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.

    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.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    180590832008Early diagnosis and multidisciplinary care reduce the hospitalization time and duration of tube feeding and prevent early obesity in PWS infants.Bacheré N et al
    175625872007Prader-Willi syndrome: medical prevention and behavioral challenges.Benarroch F et al
    105562981999The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region.Boccaccio I et al
    117393332001Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH.Burman P et al
    155066762004Plasma peptide YY and ghrelin levels in infants and children with Prader-Willi syndrome.Butler MG et al
    182662482008Array comparative genomic hybridization (aCGH) analysis in Prader-Willi syndrome.Butler MG et al
    173045462007Thyroid function studies in Prader-Willi syndrome.Butler MG et al
    163740182006Postprandial adiponectin levels are unlikely to contribute to the pathogenesis of obesity in Prader-Willi syndrome.Caixàs A et al
    178036682007Quality of life assessment in a sample of patients affected by Prader-Willi syndrome.Caliandro P et al
    155801942004Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome.Carrel AL et al
    93918861997Prader-Willi syndrome.Cassidy SB et al
    168869572006Growth hormone treatment and adverse events in Prader-Willi syndrome: data from KIGS (the Pfizer International Growth Database).Craig ME et al
    126927142003Hypogonadism and pubertal development in Prader-Willi syndrome.Crinò A et al
    120918832002Elevated plasma ghrelin levels in Prader Willi syndrome.Cummings DE et al
    125845402003Myeloid leukemia in Prader-Willi syndrome.Davies HD et al
    124663372002High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome.DelParigi A et al
    163526912006Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart- Willi syndrome.Eiholzer U et al
    112301842001Association of acetylated histones with paternally expressed genes in the Prader--Willi deletion region.Fulmer-Smentek SB et al
    172239882007A lesser postprandial suppression of plasma ghrelin in Prader-Willi syndrome is associated with low fasting and a blunted postprandial PYY response.Giménez-Palop O et al
    146934212004Prader-Willi syndrome: advances in genetics, pathophysiology and treatment.Goldstone AP et al
    182031982008The Italian National Survey for Prader-Willi syndrome: an epidemiologic study.Grugni G et al
    116946762001The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria.Gunay-Aygun M et al
    129156382003Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome.Haqq AM et al
    111060402000Spontaneous growth in German children and adolescents with genetically confirmed Prader-Willi syndrome.Hauffa BP et al
    121614802002Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity.Höybye C et al
    159104632005Acute lymphoblastic leukemia in a patient with Prader-Willi syndrome under growth hormone therapy.Kato M et al
    163572272006The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C.Kishore S et al
    169321102006Prader-Willi Syndrome: clinical concerns for the orthopaedic surgeon.Kroonen LT et al
    107122012000Identification of novel imprinted transcripts in the Prader-Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control.Lee S et al
    172641852007Conditional cardiovascular response to growth hormone therapy in adult patients with Prader-Willi syndrome.Marzullo P et al
    111578012001Large-scale evaluation of imprinting status in the Prader-Willi syndrome region: an imprinted direct repeat cluster resembling small nucleolar RNA genes.Meguro M et al
    163170592006Short-term effects of growth hormone on sleep abnormalities in Prader-Willi syndrome.Miller J et al
    171034382007Intracranial abnormalities detected by three-dimensional magnetic resonance imaging in Prader-Willi syndrome.Miller JL et al
    107974182000Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting.Ming JE et al
    171034372007Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits.Myers SE et al
    166425082006The neonatal phenotype of Prader-Willi syndrome.Oiglane-Shlik E et al
    109253852000Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15.Olander E et al
    169412272007Behavioral and emotional symptoms of children and adolescents with Prader-Willi Syndrome.Reddy LA et al
    179937762007Hypothyroidism in Prader-Willi syndrome: a case report and review of the literature.Savopoulos C et al
    147355792004Prader-Willi syndrome: causes of death in an international series of 27 cases.Schrander-Stumpel CT et al
    125983992003Birth prevalence of Prader-Willi syndrome in Australia.Smith A et al
    111463682000Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children.Tauber M et al
    183246852008Review of 64 cases of death in children with Prader-Willi syndrome (PWS).Tauber M et al
    151507732004Psychotic disorders in Prader-Willi syndrome.Vogels A et al
    146793972004Minimum prevalence, birth incidence and cause of death for Prader-Willi syndrome in Flanders.Vogels A et al
    183246892008In search of the psychosis gene in people with Prader-Willi syndrome.Webb T et al
    147236592004Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome.Whittington J et al
    111599382001A translocation breakpoint cluster disrupts the newly defined 3' end of the SNURF-SNRPN transcription unit on chromosome 15.Wirth J et al
    168827852006Brain developmental abnormalities in Prader-Willi syndrome detected by diffusion tensor imaging.Yamada K et al
    174821192007Scoliosis associated with Prader-Willi syndrome.Yamada K et al
    183030772008High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome.de Lind van Wijngaarden RF et al