Endocrine alterations in patients with pachydermoperiostosis

Abstract Context Pachydermoperiostosis (primary hypertrophic osteoarthropathy, PHO) usually due to biallelic loss-of-function variants in HPGD and SLCO2A1, has some features overlapping with acromegaly and often referred to endocrinologists. A detailed endocrine assessment is not available for these patients. Objective To assess the genetic and endocrine characteristics of PHO patients referred to endocrine centres with a possible diagnosis of acromegaly. Methods Seventeen patients from 14 families in which acromegaly was excluded based on lack of elevated IGF-1 levels and/or GH suppression on an oral glucose tolerance test were assessed for HPGD and SLCO2A1 variants. Results Age at diagnosis was 26.2±9.0 years (mean±standard deviation, range 9-43). Digital clubbing was present in all patients. Periostosis (94%), arthralgia (88%), periarticular oedema (77%), pachydermia (82%) and coarsened facial features resembling acromegaly (71%) was present in the vast majority of the patients, while eyelash trichomegaly, blepharoptosis, high-arched palate, gingival hypertrophy, gastrointestinal symptoms and marfanoid habitus was seen in some. Nine patients (53%) had low IGF-1 levels, the rest of the patients had IGF-1 levels in the lowest quartile of the reference range. Oestradiol concentration was increased above the normal range in eight male patients (62%) with normal testosterone and prolactin levels. Biallelic HPGD (2/14 kindreds) or SLCO2A1 (eight novel) variants (12/14 kindreds) were found. Two patients had no identifiable pathogenic/likely pathogenic variant in HPGD or SLCO2A1. Their phenotype was not different from the other patients. Conclusions We establish that low IGF-1 and elevated oestradiol levels are frequent features of PHO. Nine novel and five known pathogenic/likely pathogenic genetic variants were identified.