Weaver syndrome is an autosomal dominant rare overgrowth syndrome distinguished by accelerated osseous maturation correlated with craniofacial, limb, neurological, skeletal and further abnormalities. Craniofacial symptoms include macrocephaly, broad forehead, hypertelorism, telecanthus, large and low-set ears, long and prominent philtrum, and relative micrognathia. Limb abnormalities consist of prominent finger pads, thin and deeply-set nails, camptodactyly, wide distal long bones, foot deformities, and broad thumbs. Further associated anomalies include psychomotor retardation, hoarse and low-pitched voice, hypertonia, umbilical and inguinal hernia, and excess loose skin. To this point, 30 cases have been reported, most of them being sporadic, however, two families were portrayed as having an autosomal dominant transmission. Prognosis varies with every case as some patients retain a normal life span and with an ordinary adult height. Curative treatments are not available, though every case must be adapted to a multidisciplinary (e.g., neurological, pediatric, orthopedic, genetic counseling, and psychomotor care) management. Though both sexes are affected with Weaver syndrome, the sex ratio was established as 2M:1F.
Amongst Weaver syndrome patients tested, some revealed intragenic mutations in the NSD1 gene (nuclear receptor binding SET domain protein 1), which was also associated with Sotos syndrome. The majority of identified NSD1 functional domains are located in exons 11-23 and the entire recognized mutations were clustered in these mutations. The mutations that are associated with Weaver syndrome are positioned in a minor specific fraction of the gene in exons 5, 16, 19, 22, and 23. The detection of NSD1 mutation in Weaver and Sotos syndrome patients reveals that both disorders are allelic, nevertheless, the possibility of a second separate Weaver syndrome gene exists. The precise pathophysiology and the etiology of the residual cases remain vague.
NSD1 gene consists of 2,696 amino acids and has a molecular weight of 296,652 kDa. The NSD1 gene provides directions for creating a protein with unknown function. This protein is active in numerous organs and tissues, comprising the brain, the kidney, skeletal muscle, spleen, thymus, and lungs. Investigators presumed that the NSD1 protein controls the activity of specific genes engaged in normal growth and development, and have the ability of turning genes on or off as required.
Teebi et al. (1989) described two sibs, a brother and a sister, born to consanguineous Bedouin parents, who demonstrated features similar to Weaver syndrome. The two sibs suffered from accelerated growth of prenatal onset, hypotonia, psychomotor retardation, excess loose skin, peculiar craniofacial and acral abnormalities, dental dysplasia and/or serrated gums, joint laxity, and hoarse low-pitched cry. One sibling experienced accelerated harmonic skeletal maturation. The arcal anomalies comprised of a short fifth digit with clinodactyly V. The younger sibling did not present accelerated growth and experienced delayed bone maturation at the age of 13 months. Teebi et al. (1989) proposed an autosomal recessive inheritance and discussed the distinguished symptoms from Weaver syndrome.
Al-Salem et al., (2013) described a 15-month-old boy with Weaver Syndrome who presented with remarkably accelerated growth pattern; his growth parameters were: weight 18.2 kg, length 89 cm, and OFC 49 cm. He had a flat occiput, downslanting palpebral fissures, round face, retrognathia, and hypertelorism with mild degree of exophthalmos. His physical examination showed umbilical hernia and discrepancy in the size of the lower extremities with the left side being smaller. His left side of the body also showed exaggerated reflexes, increased tone, and reduction of power. A de novo c.2233G>A missense mutation in exon 20 of the EZH2 gene was identified in the affected patient, resulting in a Glu745Lys amino acid substitution. This mutation was not found in 200 Saudi Exomes and the Exome Variants Server (ESV) and this de novo mutation is likely to be disease causing.
Trabelsi et al. (1990) reported the case of a male infant with Weaver syndrome with the unusual presence of respiratory disorders, a feature often seen in Marshall-Smith syndrome but occurring rarely in Weaver syndrome. The infant also had a congestive cardiomyopathy, which has apparently never been described in this syndrome, and major macrocrania.
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