Weaver syndrome

2007-12-01   Maria Piccione , Giovanni Corsello 

Dipartimento Materno Infantile, University of Palermo, Italy



Weaver syndrome


The Weaver syndrome is characterized by macrocephaly, dysmorphic facial features, accelerated skeletal maturation, limb anomalies, development delay and a predisposition for tumors.


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.






3447 Weaver syndrome




Phenotype and clinics

  • 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.
  • Atlas Image
    Table 1: Characteristic clinical features of Weaver syndrome

    Differential diagnosis

    It is a clinical overlap with other overgrowth syndromes associated with tumors (tab.2)
    Atlas Image
    Table 2: Comparison of Perlman, Beckwith-Wiedemann, Sotos, Weaver and Simpson-Golabi-Behmel syndromes.


    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 is variable, most patients have normal life span and the clinical findings in adults with Weaver syndrome are subtle.


    Pubmed IDLast YearTitleAuthors
    24181891986Further delineation of Weaver syndrome.Ardinger HH et al
    105597621999Recognition and management of childhood cancer syndromes: a systems approach.Clericuzio CL et al
    15836611992Weaver syndrome.Cole TR et al
    105077381999A probable case of familial Weaver syndrome associated with neoplasia.Derry C et al
    124649972003NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes.Douglas J et al
    81313081993Twins and their mildly affected mother with Weaver syndrome.Dumić M et al
    39936811985Update on the Marshall-Smith-Weaver controversy.Fitch N et al
    104940981999Pachygyria in Weaver syndrome.Freeman BM et al
    91528411997Autosomal dominant inheritance of Weaver syndrome.Fryer A et al
    74414291980The Weaver-Smith syndrome.Gemme G et al
    40807341985Weaver syndrome: expanded natural history.Hall BD et al
    112414992001Weaver syndrome with neuroblastoma and cardiovascular anomalies.Huffman C et al
    111464722000Cervical spine anomalies and tumors in Weaver syndrome.Kelly TE et al
    73188391981The Weaver syndrome: a rare type of primordial overgrowth.Majewski F et al
    66417691983The Weaver syndrome in a girl.Meinecke P et al
    23194081990Weaver syndrome and instability of the upper cervical spine.Muhonen MG et al
    97819111998The syndromes of Sotos and Weaver: reports and review.Opitz JM et al
    97819121998Weaver syndrome: autosomal dominant inheritance of the disorder.Proud VK et al
    128079652003Spectrum of NSD1 mutations in Sotos and Weaver syndromes.Rio M et al
    104416971999A case with Weaver syndrome operated for congenital cardiac defect.Sarigül A et al
    87257891996Novel findings in a patient with Weaver or a Weaver-like syndrome.Scarano G et al
    23690501990[Weaver's syndrome. Apropos of a new case].Trabelsi M et al
    43661871974A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly.Weaver DD et al
    73188471981Accelerated bone maturation syndrome of the Weaver type.Weisswichert PH et al
    95987291998Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome.van Asperen CJ et al