Sotos syndrome, also known as cerebral gigantism, was first described in 1964 (109). Since then, several hundred cases have been reported. Cardinal features of the disorder include early onset overgrowth, a characteristic facial configuration and stereotypical behavioral profile. The overgrowth in Sotos syndrome is of prenatal onset, with length being the most significantly affected parameter. After birth, acceleration of all growth parameters ensues, with OFC measuring above the 97th percentile in nearly all affected infants by 12 months of age (110). Although the growth velocity slows by age 3 or 4, height invariably remains above the normal range throughout childhood, typically in association with somewhat lower weight percentiles. In contrast, adult stature in Sotos syndrome is usually within the normal range for the general population (111), which has been attributed to the combination of an advanced bone age and a relatively early onset of puberty. Classic facial features include macrocephaly with dolichocephaly, hypertelorism, prominent forehead and a pointed chin (112). Developmental delay is ubiquitous, particularly in the area of speech and language acquisition (113). Children with Sotos syndrome are often described as being clumsy, with a tendency toward aggressive behavior (114). A minority have seizures, as well as structural abnormalities of the brain such as enlarged ventricles and absence of the corpus callosum.

Sotos syndrome is typically sporadic, although a few familial occurrences have been reported. Isolated cases of identical twin pairs who are concordant as well as discordant for the condition have also been described (115). Historically, the diagnosis was based entirely on clinical criteria. However, it is now known that Sotos syndrome is caused by intragenic mutations or microdeletions resulting in haploinsufficiency of the nuclear receptor-binding SET domain-containing protein 1 (NSD1) gene at 5q35 (116;117). The NSD1 gene encodes for a nuclear protein believed to function as a basic transcription factor and transcriptional regulator. While genotype-phenotype correlations have been suggested(118;119), this needs to be confirmed by additional studies of affected patients.

Two physicians independently reported the first recognized cases of BWS in the 1960’s(120;121). Since that time, tremendous progress has been made in unraveling several aspects of this complex disorder. BWS is typified by the combination of prenatal and postnatal overgrowth, congenital malformations and a predisposition to embryonal tumors. Characteristic features noted in the neonatal period include macroglossia, abdominal wall defects such as umbilical hernia, ear creases, visceromegaly and hyperinsulinemic hypoglycemia (122). A variety of additional abnormalities are found in a subset of patients, including hemihypertrophy (123). While intelligence may be normal, mild to moderate developmental delay may also be present. Although usually sporadic, several families manifesting heterogeneous inheritance patterns have been reported in whom there are several generations of affected individuals (124). The reported incidence of malignancy in children with BWS varied between 4-21% (125), with the majority consisting of Wilms tumor. Therefore, frequent screening via abdominal ultrasonography during infancy and early childhood is essential, especially in patients with hemihypertrophy, which is known to be associated with an increased risk of cancer (126). Insights into the pathophysiology of the abnormal growth in this condition emerged with the discovery of abnormalities in imprinting of a number of growth regulatory genes within three regions of chromosome 11p15, including IGF-2 and H19. The molecular genetic defects resulting in BWS are extremely heterogenous, and include maternal hypomethylation of 11p15, paternal uniparental disomy of this region, and unbalanced translocations leading to trisomy of the 11p15 locus(127;128). Enhanced understanding of the relationship between tumor risk and the molecular subtype in BWS will result in improvements in targeted screening (129). Interestingly, an association has been noted between assisted reproduction and risk of imprinting disorders such as BWS (130). Figure 6 demonstrates several classic clinical features in a child with BWS.

Figure 6. 

SGBS is a complex X-linked overgrowth disorder sharing many features with BWS. It is characterized by prenatal and postnatal overgrowth, coarse facial features and congenital anomalies. Some of the most commonly reported abnormalities include skeletal/hand defects, supernumerary nipples, macroglossia and visceromegaly (131). However, a wide spectrum in severity has been noted, ranging from mild features in carrier females to a lethal form of the disorder in affected males. Similarly, cognitive abilities vary from within the normal range to severe developmental delays. Approximately 36% of patients have a cardiac abnormality, the most common of which is a cardiovascular malformation (132). As is the case in BWS, an increased incidence of embryonal tumors during early life is present. Delineation of the molecular genetic cause of SGBS has provided significant insight as to the reason for the striking similarities between this disorder and BWS. Inactivating mutations of the glypican-3 (GPC3) gene at Xq26 have been demonstrated in the majority of individuals with SGBS (133). GPC3 is a member of a multigene family known to have critical roles in growth and development through the modulation of cellular responses to growth factors, including IGF-2 (134). Exactly how abnormal levels of GPC3 promote tumorigenesis is poorly understood, but it may be through a disruption of the normal GPC3/IGF-2 complex, which is believed to be involved in IGF-2 modulation (135). Paradoxically, evidence derived from different types of cancers has suggested both a role for GPC3 in tumor suppression and in tumor growth promotion, as well as tissue-specific actions(136). Application of GPC3 mutational analysis in patients with unspecified overgrowth conditions has resulted in an extension of the SGBS phenotype (137), and the establishment of an international registry will be invaluable in providing information regarding the natural history and pathophysiology of this interesting condition.

Weaver syndrome is a rare condition of unknown etiology that is similar to Sotos syndrome and was first reported in 1974 (138). Major features include prenatal or postnatal overgrowth, characteristic facies and advanced skeletal maturation. The typical appearance includes macrocephaly, hypertelorism, large ears and micrognathia. A subset of patients have been reported to have cervical spine abnormalities (139), and the occasional development of neoplasia has also been noted in this population. The majority of individuals with Weaver syndrome have developmental delay, which is typically mild. Initially believed to be sporadic, multiple instances of familial occurrence have pointed strongly toward an autosomal dominant form of transmission (140). Although a molecular genetic cause has yet to be identified in the majority of patients, mutations in NSDI (the same gene implicated in Sotos syndrome) have been detected in a subset of individuals with Weaver syndrome (141).