Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report

In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene. So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein.The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations.Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb [1]. In most cases BDE is syndromic and occurs within the clinical spectrum of Turner syndrome, Albright hereditary osteodystrophy (AHO; MIM#103580) or 2q37 deletion [1]. Isolated BDE is rare and in the majority of cases has unknown genetic background. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene [2]. Some patients from these families presented not only with BDE, but also with overlapping features of brachydactyly type D (BDD), defined as shortening and broadening of the thumbs [2].Missense variants affecting other residues of the C-terminal HOXD13 homeodomain may also give rise to different and more severe limb phenotypes such as synpolydactyly (SPD; MIM#186000) or syndactyly type 5 (MIM#186300), whereas expansion or contraction of the N-terminal HOXD13 polyalanine tract usually results