Childhood Overgrowth Syndromes

Genetic Susceptibility Team

Section: Section of Cancer Genetics

Childhood overgrowth syndromes affect at least 1 in 10,000 children and are characterised by advanced height and head circumference, together with a variety of medical and developmental problems. Childhood overgrowth conditions are associated with an increased risk of cancer, particularly embryonal tumours. Through collaboration with Clinical Genetics departments we are collecting cases to evaluate the phenotypic spectrum of overgrowth conditions; to produce guidelines for management, particularly with regard to cancer screening; to identify the molecular causes of the overgrowth conditions; and to evaluate any genes we identify for somatic alterations in cancers. We are particularly focussing on the following areas.

Sotos syndrome

Sotos syndrome is characterised by height and head circumference >97th centile, facial dysmorphism, developmental delay and a broad range of associated medical problems. We demonstrated that intragenic NSD1 (Nuclear Receptor Set-domain containing protein-1) mutations are the major cause of Sotos syndrome. We also showed that 5q35 microdeletions encompassing NSD1 cause approximately 10% of cases and that multiple mechanisms generate the microdeletions, including non-allelic homologous recombination between low copy repeats. We developed an assay to detect deletions or duplications encompassing one or more NSD1 exons and demonstrated that exonic deletions cause 5% of Sotos syndrome. We performed a genotype-phenotype analysis of 266 NSD1+ve Sotos syndrome cases, which showed that pathogenic missense mutations are restricted to functional domains and that the phenotype of microdeletion cases and intragenic mutations cases are broadly similar. We have used these clinical and molecular data to produce diagnostic and management guidelines for Sotos syndrome.

NSD1 is a histone methyltransferase and acts as a bifunctional transcriptional regulator that can activate or repress transcription according to the cellular context. NSD1 is implicated in neoplasia as Sotos cases have an small increased risk of some cancers, such as neuroblastoma and NSD1 is a fusion partner in the recurrent t(5;11)(q35;p15.5) translocation found in childhood AML. We are examining tumours from Sotos cases for loss of heterozygosity or mutational events that inactivate the wild-type allele. We are also screening a large panel of cancers for somatic NSD1 mutations to evaluate the potential role of NSD1 in malignancy.

Asymmetric overgrowth (hemihypertrophy) syndromes

Asymmetric overgrowth (also known as hemihypertrophy or hemihyperplasia) results in one region of the body being larger than its counterpart on the other side of the body. Hemihypertrophy is associated with >20 syndromes, several of which have an increased risk of cancer. However, the great majority of hemihypertrophy cases occur in children without a recognised genetic condition. The cause of most hemihypertrophy cases is unknown and the condition is likely to be heterogeneous. We are collecting clinical data and samples from hemihypertrophy cases with, and without, cancer. All cases are analysed for uniparental disomy and epigenetic abnormalities at 11p15, but these only account for a small proportion of cases. We aim to use the clinical and molecular data to define the clinical and cancer phenotypes associated with hemihypertrophy and to identify the genes and molecular pathways involved in the pathogenesis of hemihypertrophy.

PTEN-associated syndromes

Somatic PTEN mutations are present in a broad range of malignancies and constitutional mutations cause Cowden syndrome, a disorder associated with malignant and benign tumours, particularly breast cancer and thyroid cancer. Macrocephaly (increased head circumference) and childhood overgrowth can also occur and a variety of childhood overgrowth syndromes including Bannayan-Riley-Ruvulcaba syndrome and some cases of Proteus syndrome have been associated with constitutional PTEN mutations. We are investigating the prevalence, phenotype and cancer risks of PTEN mutations in our series of non-NSD1 overgrowth cases.

Ehlers-Danlos VIII syndrome

Ehlers-Danlos VIII (EDS-VIII) is an autosomal dominant disorder characterised by severe early-onset periodontal disease in conjunction with features of Ehlers Danlos syndrome and tall stature. We localised a predisposition gene for EDS-VIII to chromosome 12p13 and demonstrated that the condition is genetically heterogeneous. We are undertaking analyses to identify the causative genes.

Unexplained overgrowth phenotypes

The majority of overgrowth cases do not fit into any of the recognised syndromes and their cause(s) are unknown. We have collected >500 overgrowth cases without a specific diagnosis or molecular cause and in whom we have excluded NSD1 and PTEN mutations. We are reviewing the clinical features of these cases to define the phenotype of new syndromes and are using a variety of strategies including DNA SNP analysis, candidate gene screening and CGH array analysis to identify new overgrowth genes.