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Weaver syndrome

Written2007-12Maria Piccione, Giovanni Corsello
Dipartimento Materno Infantile, University of Palermo, Italy

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Identity

Atlas_Id 10141
Genes implicated inEED  EZH2  NSD  
Note The Weaver syndrome is characterized by macrocephaly, dysmorphic facial features, accelerated skeletal maturation, limb anomalies, development delay and a predisposition for tumors.
Inheritance Inheritance is an autosomal dominant nature.
Etiology: Intragenic mutations in the NSD1 gene (nuclear receptor binding SET domain protein 1), that have been associated with Sotos syndrome, have been found in patients with Weaver syndrome.The majority of known NSD1 functional domains are in exons 11-23 and all mutations identified were clustered in these domains. The NSD1 mutations in patients with Weaver syndrome are in exons 5, 16, 19, 22 and 23. The identification of NSD1 mutation in patients with Weaver and Sotos syndrome demonstrates that the two conditions are allelic, but it remains possible that separate, second Weaver syndrome gene exists.
The pathophysiology and the etiology of the other cases remain unknown.
Although both sexes are affected, the sex ratio is 2M:1F.

Clinics

Phenotype and clinics Abnormalities
  • Growth: persistent overgrowth of prenatal onset and accelerated growth and markedly advanced skeletal maturation during infancy.
  • Craniofacial: macrocephaly, flat occiput, redundant nuchal skin folds, broad forehead with frontal bossing, thin scalp hair, hypertelorism, upslanting or downslanting palpebral fissures, small palpebral fissures, strabismus, ptosis, broad nasal root, long philtrum, large and dysmorphic ears, micrognathia and highly arched palate.
  • Skeletal findings: advanced bone age, abnormal or assent femur, splayed metaphyses and mottled epiphyses, broad iliac wings and restricted joint mobility.
  • Limb anomalies: campotodactyly, prominent finger pads, clinodactyly of fifth finger and toes, broad thumbs, foot deformities (talipes equinovarus, talipes calcaneovalgus, metatarsus adductus, pes adductus and pes cavus), broad iliac wings, cervical kyphosis, cervical spine anomalies and underdevelopment of the mid cervical vertebral bodies.
  • Performance and Central Nervous System: hypotonia or hypertonia, hoarse voice and development delay.
  • Tumors: neuroblastoma, malignant ovarian endodermal sinus tumor, sacrococcigeal teratoma and lymphoma.

    Occasional abnormalities:

  • Central nervous System abnormalities: dilation of the ventricles, basal cisterns, sylvian cistern and interhemispheric fissure, cystis of the septum pellucidum, enlarged vessels and hypervascularization in the areas of the middle and left posterior cerebral arterias and pachygiria.
  • Difficulty in swallowing or breathing is frequent but voracius appetite is present in infant period.
  • Cardiovascular anomaly: mitral valve prolapse, ventricular septal defect, patent arteriosus ductus and congestive cardiomyopathy.
  • Umbelical hernia
  • Inguinal hernia
  • Cryptorchidism
  • NF1 associated with café-au-lait spots, Lish nodules, axillary freckling and numerous neurofibromas.
  • Skeletal anomalies: demineralisation of the bones of the hands and feet.
  •  
      Table 1: Characteristic clinical features of Weaver syndrome
    Differential diagnosis It is a clinical overlap with other overgrowth syndromes associated with tumors (tab.2)
     
      Table 2: Comparison of Perlman, Beckwith-Wiedemann, Sotos, Weaver and Simpson-Golabi-Behmel syndromes.
    Evolution Multidisciplinary management (pediatric, orthopaedic, neurological, Cardiological care etc. ) is necessary. X-ray cervical spine is necessary. Cervical spine anomalies represent a consistent radiographic finding in Weaver syndrome. The brain abnormalities reported in some cases suggest that MRI should be considered as part of the follow-up. The tumors occur in Weaver syndrome more commonly than expected ( 5 patients described). Since two patients have had neuroblastoma, retroperitoneal ultrosonography is suggested every 3 month from 0-3 years, every 6 month from 3-6 years and 1 once a year up to the age of 12.
    Prognosis Prognosis is variable, most patients have normal life span and the clinical findings in adults with Weaver syndrome are subtle.

    Bibliography

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    NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes.
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    Cervical spine anomalies and tumors in Weaver syndrome.
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    The Weaver syndrome in a girl.
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    Opitz JM, Weaver DW, Reynolds JF Jr
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    Weaver syndrome: autosomal dominant inheritance of the disorder.
    Proud VK, Braddock SR, Cook L, Weaver DD
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    Spectrum of NSD1 mutations in Sotos and Weaver syndromes.
    Rio M, Clech L, Amiel J, Faivre L, Lyonnet S, Le Merrer M, Odent S, Lacombe D, Edery P, Brauner R, Raoul O, Gosset P, Prieur M, Vekemans M, Munnich A, Colleaux L, Cormier-Daire V
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    A case with Weaver syndrome operated for congenital cardiac defect.
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    Novel findings in a patient with Weaver or a Weaver-like syndrome.
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    [Weaver's syndrome. Apropos of a new case]
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    A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly.
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    Accelerated bone maturation syndrome of the Weaver type.
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    Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome.
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    Citation

    This paper should be referenced as such :
    Piccione, M ; Corsello, G
    Weaver syndrome
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):93-95.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/WeaverID10141.html


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