New multisystemic disorder involving heart valves, skin, bones, and joints in two brothers

Abstract

We report on 2 brothers with a severe progressive disorder characterized by thick skin, acne conglobata, "coarse" face, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. The youngest brother died at age 24 years because of heart failure. Biochemical and pathological studies excluded known metabolic diseases. We think that this is a new genetic disorder inherited in autosomal recessive or X-linked recessive manner.

Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling

“…Subsequent genetic analysis of these two individuals identified a homozygous MMP14 missense mutation (MIM #600754; Evans et al, ). In 2007, we reported two patients with a phenotype similar to that of the patients described by Borrone et al (Borrone et al, ; Van Steensel, Ceulen, Delhaas, & De Die‐Smulders, ; Vanagt, Daenen, & Delhaas, ). However, we did not identify deleterious changes of SH3PXD2B or its homolog SH3PXD2A .…”

“…Most examined individuals with an SH3PXD2B or MMP14 mutation had a broad mouth, as well as one third of examined patients with an MMP2 mutation. Finally, thick lips and either a small or heavy mandible have been reported in most examined patients with an SH3PXD2B , MMP14 , or MMP2 mutation (Al Aqeel et al, ; Al Kaissi et al, ; Azzollini et al, ; Bader‐Meunier et al, ; Bendon et al, ; Bhavani et al, ; Borrone et al, ; Castberg et al, ; Chang et al, ; Eisenstein et al, ; Ekbote et al, ; Gok et al, ; Hamel et al, ; Iqbal et al, ; Jeong et al, ; Maas et al, ; Martignetti et al, ; Mégarbané et al, ; Phadke & Dalal, ; Pichler et al, ; Prapanpoch et al, ; Rouzier et al, ; Temtamy et al, ; Ter Haar et al, ; Tuysuz et al, ; Vanatka et al, ; Van Steensel et al, ; Wilson et al, ; Winchester et al, ; Zankl et al, ; Zankl et al, ; Zrhidri et al, ).…”

“…Based on the resemblance with the individuals described by Frank et al and Ter Haar et al, Maas and colleagues suggested that all of these patients represent a novel entity that they named Frank‐Ter Haar syndrome (FTHS, MIM #249420; Maas, Kayserili, Lam, Apak, & Hennekam, ). Borrone, Di Rocco, Crovato, Camera, & Gambini () described two brothers with similar features. In these two patients, as well as in individuals previously diagnosed with FTHS, we identified homozygous mutations in SH3PXD2B (MIM #613293; Wilson et al, ).…”

What does acne genetics teach us about disease pathogenesis?

“…Frank–ter Haar syndrome (FTHS) causes a wide range of developmental abnormalities such as brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, megalocornea with or without glaucoma, full cheeks and multiple skeletal anomalies, including osteolysis, contractures and short stature . Adult patients with this syndrome have been characterized as having acne conglobata with hypertrophic scarring and thickened skin . FTHS is inherited as an autosomal recessive trait and is caused by loss‐of‐function mutations and deletions in SH3PXD2B on chromosome 5q35·1 .…”

“…67 Adult patients with this syndrome have been characterized as having acne conglobata with hypertrophic scarring and thickened skin. 68 FTHS is inherited as an autosomal recessive trait and is caused by loss-of-function mutations and deletions in SH3PXD2B on chromosome 5q35Á1. [69][70][71][72] SH3PXD2B codes for TKS4, a tyrosine kinase substrate adaptor protein required for podosome maturation.…”