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Weaver syndrome

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

(Note : for Links provided by Atlas : click)


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.


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.


    Further delineation of Weaver syndrome.
    Ardinger HH, Hanson JW, Harrod MJ, Cohen MM Jr, Tibbles JA, Welch JP, Young-Wee T, Sommer A, Goldberg R, Shprintzen RJ
    The Journal of pediatrics. 1986 ; 108 (2) : 228-235.
    PMID 2418189
    Recognition and management of childhood cancer syndromes: a systems approach.
    Clericuzio CL
    American journal of medical genetics. 1999 ; 89 (2) : 81-90.
    PMID 10559762
    Overgrowth syndromes.
    Cohen MMJr, Neri G, Weksberg R
    Oxford University press. 2002.
    Weaver syndrome.
    Cole TR, Dennis NR, Hughes HE
    Journal of medical genetics. 1992 ; 29 (5) : 332-337.
    PMID 1583661
    A probable case of familial Weaver syndrome associated with neoplasia.
    Derry C, Temple IK, Venkat-Raman K
    Journal of medical genetics. 1999 ; 36 (9) : 725-728.
    PMID 10507738
    NSD1 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, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S, Hughes HE, Cole TR, Rahman N
    American journal of human genetics. 2003 ; 72 (1) : 132-143.
    PMID 12464997
    Twins and their mildly affected mother with Weaver syndrome.
    Dumić M, Vuković J, Cvitkovic M, Medica I
    Clinical genetics. 1993 ; 44 (6) : 338-340.
    PMID 8131308
    Update on the Marshall-Smith-Weaver controversy.
    Fitch N
    American journal of medical genetics. 1985 ; 20 (3) : 559-562.
    PMID 3993681
    Pachygyria in Weaver syndrome.
    Freeman BM, Hoon AH Jr, Breiter SN, Hamosh A
    American journal of medical genetics. 1999 ; 86 (4) : 395-397.
    PMID 10494098
    Autosomal dominant inheritance of Weaver syndrome.
    Fryer A, Smith C, Rosenbloom L, Cole T
    Journal of medical genetics. 1997 ; 34 (5) : 418-419.
    PMID 9152841
    The Weaver-Smith syndrome.
    Gemme G, Bonioli E, Ruffa G, Lagorio V
    The Journal of pediatrics. 1980 ; 97 (6) : 962-964.
    PMID 7441429
    Weaver syndrome: expanded natural history.
    Hall BD
    Progress in clinical and biological research. 1985 ; 200 : 123-144.
    PMID 4080734
    Weaver syndrome with neuroblastoma and cardiovascular anomalies.
    Huffman C, McCandless D, Jasty R, Matloub J, Robinson HB, Weaver DD, Cohen MM Jr
    American journal of medical genetics. 2001 ; 99 (3) : 252-255.
    PMID 11241499
    Cervical spine anomalies and tumors in Weaver syndrome.
    Kelly TE, Alford BA, Abel M
    American journal of medical genetics. 2000 ; 95 (5) : 492-495.
    PMID 11146472
    The Weaver syndrome: a rare type of primordial overgrowth.
    Majewski F, Ranke M, Kemperdick H, Schmidt E
    European journal of pediatrics. 1981 ; 137 (3) : 277-282.
    PMID 7318839
    The Weaver syndrome in a girl.
    Meinecke P, Schaefer E, Engelbrecht R
    European journal of pediatrics. 1983 ; 141 (1) : 58-59.
    PMID 6641769
    Weaver syndrome and instability of the upper cervical spine.
    Muhonen MG, Menezes AH
    The Journal of pediatrics. 1990 ; 116 (4) : 596-599.
    PMID 2319408
    The syndromes of Sotos and Weaver: reports and review.
    Opitz JM, Weaver DW, Reynolds JF Jr
    American journal of medical genetics. 1998 ; 79 (4) : 294-304.
    PMID 9781911
    Weaver syndrome: autosomal dominant inheritance of the disorder.
    Proud VK, Braddock SR, Cook L, Weaver DD
    American journal of medical genetics. 1998 ; 79 (4) : 305-310.
    PMID 9781912
    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
    Journal of medical genetics. 2003 ; 40 (6) : 436-440.
    PMID 12807965
    A case with Weaver syndrome operated for congenital cardiac defect.
    Sarigül A, Yilmaz M, Ateu S, Yurdakul Y
    Pediatric cardiology. 1999 ; 20 (5) : 375-376.
    PMID 10441697
    Novel findings in a patient with Weaver or a Weaver-like syndrome.
    Scarano G, Della Monica M, Lonardo F, Neri G
    American journal of medical genetics. 1996 ; 63 (2) : 378-381.
    PMID 8725789
    [Weaver's syndrome. Apropos of a new case]
    Trabelsi M, Ben Hariz M, Monastiri K, Taktak M, Bennaceur B
    Annales de pediatrie. 1990 ; 37 (5) : 327-330.
    PMID 2369050
    A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly.
    Weaver DD, Graham CB, Thomas IT, Smith DW
    The Journal of pediatrics. 1974 ; 84 (4) : 547-552.
    PMID 4366187
    Accelerated bone maturation syndrome of the Weaver type.
    Weisswichert PH, Knapp G, Willich E
    European journal of pediatrics. 1981 ; 137 (3) : 329-333.
    PMID 7318847
    Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome.
    van Asperen CJ, Overweg-Plandsoen WC, Cnossen MH, van Tijn DA, Hennekam RC
    Journal of medical genetics. 1998 ; 35 (4) : 323-327.
    PMID 9598729


    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 :

    Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

    Genes EZH2

    External links

    OrphanetWeaver syndrome
    Other databaseWeaver syndrome (GARD)
    Genes implicated inEED   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inEZH2   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inNSD   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

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