The child with overgrowth between clinical variability and genetic heterogeneity

Key words: Segmental overgrowth syndrome, Next generation sequencing, Oncological surveillance, Genotype-phenotype correlation

Either in the newborn or in the child overgrowth can be generalized or localized if it is limited to one or more body regions. When overgrowth depends on a metabolic imbalance, or it is constitutional, the excessive growth can be the only clinical sign. In most cases genomic or epigenetic alterations, which affect factors involved in cell proliferation and/or regulation of gene expression (observed also in tumours), are related to overgrowth syndromes, in which excess growth may be associated with dysmorphic features, neuromotor/intellectual disabilities and behavioural disorders. These rare conditions are characterized by clinical and molecular overlap. The paper describes the cases of three patients with localized overgrowth, in which a detailed evaluation of the phenotype, appropriately integrated by next generation sequencing (NGS) techniques, led to the genetic diagnosis of segmental overgrowth syndrome. Many patients with a previous clinical diagnosis of overgrowth syndrome are now framed in the context of segmental overgrowth syndromes associated with PIK3CA, whose identification may be obtained by extending molecular analyses to somatic cells. The paediatrician has to take into consideration these syndromes to guarantee an early genetic diagnosis and the appropriate clinical management to these patients (including reproductive counselling to the family, follow-up and oncological surveillance). NGS techniques improved the understanding of the molecular basis of some of these conditions, as well as the identification of the role of new genes and mechanisms, whose study may help to reduce the number of patients for which a genetic diagnosis related with the phenotype is not yet possible.