Endocrine Alterations in Patients With Pachydermoperiostosis

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 is often referred to endocrinologists. A detailed endocrine assessment is not available for these patients.

Objective To assess the genetic and endocrine characteristics of patients with PHO referred to endocrine centers with a possible diagnosis of acromegaly.

Methods Seventeen patients from 14 families in which acromegaly was excluded based on lack of elevated insulin-like growth factor (IGF)-1 levels and/or growth hormone 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 ± SD, range 9-43). Digital clubbing was present in all patients. Periostosis (94%), arthralgia (88%), periarticular edema (77%), pachydermia (82%), and coarsened facial features resembling acromegaly (71%) were present in the vast majority of the patients, while eyelash trichomegaly, blepharoptosis, high-arched palate, gingival hypertrophy, gastrointestinal symptoms, and marfanoid habitus were 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. Estradiol concentration was increased above the normal range in 8 male patients (62%) with normal testosterone and prolactin levels. Biallelic HPGD (2/14 kindreds) or SLCO2A1 (8 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.

Conclusion We establish that low IGF-1 and elevated estradiol levels are frequent features of PHO. Nine novel and 5 known pathogenic/likely pathogenic genetic variants were identified.