A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

Abstract

The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of individuals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical "handles" to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.

Keywords: Large stature; Macrocephaly; Macrosomia; Obesity; Overgrowth; Tall stature.

Fig. 1

Flow chart showing a diagnostic approach to generalized overgrowth. A, B Facial findings in a patient with Sotos syndrome showing prominent forehead, frontotemporal hair sparsity, and prominent and narrow jaw. C, D A patient with BWS who has infraorbital creases, a small midface, macroglossia, and anterior linear earlobe creases. E, F Facial findings in a patient with SGB syndrome demonstrating wide-spaced eyes, epicanthic folds, downslanting palpebral fissures, low-set ears, and macroglossia. G Facial features of a patient with Weaver syndrome (EZH2 mutation) demonstrating almond-shaped and downslanting palpebral fissures. H, I A patient with Weaver syndrome due to an EED mutation showing almond-shaped and downslanting palpebral fissures as well as retrognathia. J A patient with possible Luscan-Lumish syndrome with a variant of unknown significance [SETD2 (NM_014159.6): c.3229A>G, p.(Thr1077Ala)] but probably pathogenic. He has a prominent forehead and a high frontal hairline. Facial features resemble patients with Sotos syndrome. K A patient with a PPR2R5B pathogenic mutation with a prominent forehead, high frontal hairline, strabismus, wide-spaced eyes, and open-mouthed expression. L Facial findings in a patient with a small chromosomal microdeletion including the NFIX gene with a high forehead and downslanting palpebral fissures. M, N A patient with Cantu syndrome showing a low anterior hairline, wide-spaced eyes, and a flat nasal bridge. BWS, Beckwith-Wiedemann syndrome; SGB, Simpson-Golabi-Behmel syndrome; WES, whole exome sequencing.