Transforming growth factor, beta-2 gene mutation causes autosomal dominant Camurati-Engelmann disease, type 2 (OMIM % 606631)

Camurati-Engelmann disease, type 1 (CED1, OMIM # 131300) is the rare autosomal dominant skeletal dysplasia caused by select heterozygous loss-of-function defects within the gene TGFB1, which encodes transforming growth factor beta 1 (TGFB1). CED1 mutations are found in TGFB1 exons 1–4 that form the latency-associated peptide (LAP) of pro-TGFB1. Consequently, skeletal action of TGFB1 increases and thereby enhances bone formation manifest clinically as “progressive diaphyseal dysplasia”. Beginning 24 years ago negative TGFB1 analysis suggested rare genetic heterogeneity for CED, and Online Mendelian Inheritance In Man designated, of unknown etiology, “CED2” (OMIM % 606631). In 2024, three sporadic occurrences considered CED2 were reported to harbor either of two mutations of TGFB2, which encodes the LAP of transforming growth factor beta 2 (TGFB2).

Herein, three adults (father, son, daughter) having the CED2 phenotype in a Peruvian family revealed a novel missense variant (c.108G > T, p.R36S) within the TGFB2 LAP domain. Debilitating painful skeletal disease featuring hyperostosis of entire long bones, worse in the men, presented early in childhood. Aminobisphosphonate therapy seemed helpful. Their TGFB2 variant was within a highly conserved domain across species, absent in the gnomAD database, “possibly damaging” by Polyphen-2, not tolerated by SIFT, homologous with TGFB1 at the same amino acid position (R36) as one reported TGFB2 mutation, co-segregated as autosomal dominant, and “likely pathogenic” per ACMG guidelines.