Focal dermal hypoplasia: a probable underrecognized low bone mass disorder secondary to aberrant Wnt signaling

A 29-year-old Spanish Caucasian man, without relevant family history, was attended in our unit due to an undiagnosed skeletal dysplasia associated with low bone mass and several fragility fractures throughout his childhood and adolescence. DXA exams throughout his life showed very low BMD values; currently, his spinal and femoral neck T-scores were - 4.3 and - 3.5, respectively. Blood and urinary tests were normal. Other relevant features included right hand and foot syndactyly, aplasia cutis, right hemibody hypoplasia, vertebral malformations, abnormal-looking humerii, and Asperger's syndrome among others. Whole exome sequencing retrieved a highly probable pathogenic variant in the PORCN gene p.(Arg296Pro) in mosaicism. PORCN mutations cause focal dermal hypoplasia (FDH), an X-linked ultra-rare ecto-mesodermal disorder characterized by several of the findings the patient presented. However, low BMD has not been classically associated with the disease. Noteworthy, PORCN is key for canonical Wnt signaling. Literature scrutiny has yielded other cases of FDH with skeletal fragility during childhood. In addition, preclinical studies with PORCN inhibitors, currently under development as an antitumoral therapy, have shown rapid detrimental effects on bone mass. Collectively, these findings indicate that FDH is probably an underrecognized monogenic cause of low bone mass due to defective Wnt signaling.