Commentary 2

Abstract

Now is the time to place your bets in the acne casino. Studies in molecular genetics determined the pathogenesis of many disorders, but even in Cockayne's (1) classic on genodermatology acne was not discussed. Present in many complex genetic syndromes, the keys to acne's pathogenesis may be discovered through genetic studies. Recent findings related to two genetic syndromes and a large twin study exemplify the potential of genetic studies in understanding acne. Apert syndrome (OMIM 101200) is a sporadic form of craniosynostosis, with premature sutural closure and cranial and facial malformations and limb changes, including mitten-type symmetrical syndactyly. Apert Syndrome is caused by a dominant mutation of paternal origin in fibroblast growth factor receptor 2 (FGFR2) (OMIM 176943). Over 30 years ago, nine Apert Syndrome patients were carefully studied and found to have extensive comedonal and cystic acne on their forearms, face, back, and chest (2). Extension of acne beyond its usual body sites is characteristic of this syndrome, confirmed by subsequent studies, as have frequent hyperhidrosis of the scalp and palms, wrinkling of the forehead, and interrupted eyebrows (related to boney defects) (3). The mutations of Apert Syndrome are frequently activating (gain of function) mutations which increase FGFR2 interactions and the receptor's affinity for fibroblast growth factors, including keratinocyte growth factor. Epidermal mosaicism for a comedonal nevus with a Blaschko line distribution in a patient without Apert syndrome was associated with a typical Apert ser252trp mutation in affected skin but not in normal skin (4,5). There were 508 potential SNPS (Single Nucleotide Polymorphisms) for FGFR2 in the NCBI database on December 28, 2004, that could be used for acre genotyping. The gain-of-function Apert mutation leads to FGF down-regulation of noggin with resulting interference with cranial suture formation (6). Noggin has a role in hair follicle formation as well (7,8). In a knockout model for one of the alternatively spliced forms of FGFR2 there was marked impairment of hair follicle development (9). The acne in Apert syndrome responds to isotretinoin, and the effect of retinoids on FGFR2 will be of interest as well (10). Thus FGFR2 is a candidate for extensive study in acne; focusing such studies on the follicle and sebaceous gland has a high probability of success. Pyogenic sterile arthritis, pyoderma gangrenosum, and severe cystic acne (beginning in infancy in some patients) are associated in a syndrome with mutations in a CD2-binding protein (CD2BP1). The syndrome is dominantly inherited and is associated with reduced binding between CD2BP1 and its effector proteins (11). Pyrin, the protein in Familial Mediterranean Fever, binds to this molecule as well (12). This inflammatory system and its control deserve more study in patients with acne and without the syndrome. The most complete article on nodulocystic acne as a feature of the XYY genotype is over 30 years old and even then ascertainment bias was recognized (13). Save your chips. A recent study of over 1500 pairs of monozygotic and dizygotic twins showed that 81% of the variance in acne was attributable to additive genetic factors (14). It will take a large grub stake – adding molecular genetic studies to well characterized family studies – but those studies may have a real long-term payoff.