Genetic disorders associated with macrocephaly

Abstract

Macrocephaly is associated with many genetic disorders and is a frequent cause of referral to the clinical geneticist. In this review we classify the commonly encountered macrocephaly disorders into useful categories and summarize recent genetic advances. Conditions where macrocephaly is a predominant aspect of the clinical presentation are discussed and a diagnostic approach to the common macrocephaly disorders is provided. Some emphasis is placed on familial macrocephaly (sometimes referred to as benign external hydrocephalus) and on the macrocephaly associated with autism spectrum disorders. The more recent conditions associated with the leukodystrophies and the organic acidurias are reviewed, but the well known conditions involving storage disorders and bone dysplasias are mentioned but not discussed. The genetic macrocephaly conditions cover a broad spectrum of gene disorders and their related proteins have diverse biological functions. As of yet it is not clear what precise biological pathways lead to generalized brain overgrowth. ß

Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly

“…Several genetic and non-genetic conditions are associated with macrocephaly and include benign familial macrocephaly, cancer predisposition syndromes, and metabolic disorders. 11 Germline PTEN mutations are positively associated with the occurrence and degree of macrocephaly both in humans and in Pten knock-in mice. 19 Germline PTEN mutations molecularly define PTEN hamartoma tumor syndrome (PHTS), a cancer predisposition syndrome, and are associated with an elevated risk of female breast, epithelial thyroid, renal, and endometrial cancers.…”

“…7 In addition, germline PTEN (OMIM #601728) mutations have been identified in a subset of individuals having both ASDs and macrocephaly. [8][9][10][11] We recently identified a biochemical alteration (elevated plasma succinate) in PTEN and SDH mutation-positive individuals meeting full or partial criteria for Cowden Syndrome (CS, OMIM #158350), in which macrocephaly is one major diagnostic criterion. 12 Therefore, we hypothesized that a biochemical marker(s) may exist that can be used to identify individuals within similar phenotypic (and in some cases genetic) subgroups.…”

Head Circumference in Canadian Male Adults: Development of a Normalized Chart

“…114 syndromes associated with macrocephaly are listed (Winter & Baraitser, 1996). In some of them, macrocephaly persist into adulthood: Cowden disease, neurofibromatosis type 1, tuberous sclerosis; overgrowth syndromes such as Sotos syndrome (cerebral gigantism), Weaver syndrome, Simpson-Golabi-Behmel syndrome, and macrocephaly-capillary malformation (M-CM) syndrome; neuron-cardio-facial-cutaneous syndromes such as Noonan syndrome, Costello syndrome, and cardiofaciocutaneous syndrome and Fragile X syndrome (Williams et al, 2008). 94% of individuals with a PTEN (a tumor suppressor gene) hamartoma tumor syndrome (such as Cowden syndrome) present with a macrocephaly (Mester et al, 2011).…”

Диференціальна Діагностика Макроцефалій (Мегаленцефалій) У дітей

“…Деякі авто-ри пропонують вважати макроцефалією збільшення окружності голови більше ніж на 2,5 SD (більше 99,6-го перцентиля) [1,2].…”

“…Уперше класифікація макроцефалій у дітей була роз-роблена в 1986 р. DeMyer [3] та доповнена у подальшому Bodensteiner et Chung в 1993 [4] та Williams у 2008 [1]. Класифікація базується на етіології розладу, а також наяв-ності супутніх вад розвитку, порушень метаболізму та змін головного мозку при нейровізуалізації.…”