Other molecular mechanisms involve the sonic hedgehog signaling pathway ( GLI3, KIF7 and PTCH1) and cell cycle checkpoints ( CCND2, CDKN1C, CUL4B, DIS3L2, HUWE1, OFD1, PPP2R5B, PPP2R5C, PPP2R5D, and STRADA) to name a few.ĭue to the diverse functions of the genes involved, all varieties of pathogenic variants have been reported including, missense, nonsense, frameshift, gross deletions, and structural rearrangements (Human Genome Mutation Database). Many of the overgrowth syndromes are caused by activation (often loss of inhibition) of the PI3K/AKT/mTOR tyrosine receptor kinase pathway ( AKT1, AKT2, AKT3, MTOR, PIK3CA, PIK3R2, PTEN, and TBC1D7), which plays a central role in cell growth and proliferation, angiogenesis, metabolism, and cell survival (Mester and Eng. The majority of overgrowth- and macrocephaly-related disorders are inherited in an autosomal dominant manner however, recessive and X-linked inheritance is also observed. However, molecular diagnosis can provide valuable prognostic information for guiding clinical management particularly related to cancer surveillance (Mester and Eng. There are currently no treatments for constitutional overgrowth syndromes. This panel targets over 40 disorders that include excess growth as a prominent and early symptom of the disease. However, in some conditions growth excess may not be appreciated until childhood. In many of the overgrowth disorders, these defects occur early in development resulting in prenatal or neonatal onset. The physiological mechanisms of overgrowth are diverse, involving an increase in cell number, cell volume, or tissue proliferation. Frequently, overgrowth disorders are associated with developmental delay, intellectual disability, and seizures, and may predispose patients to certain cancers (Olney et al.

Excess growth can occur as an isolated feature or as part of a multiple malformation syndrome. This panel is designed to aid the molecular diagnosis of disorders with features of macrocephaly (occipitofrontal circumference >98 percentile) and/or overgrowth that may be generalized, segmental, symmetric, or asymmetric. The majority of the disorders in this group are extremely rare. Overgrowth and macrocephaly syndromes constitute a heterogeneous group of developmental disorders that share growth excess as a predominant clinical feature.

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