Novel mutations causing pachydermoperiostosis - hormonal and phenotypic alterations

Maria Stelmachowska-Banaś; Sayka Barry; Ishita Angurala; Tom Rice; Kesson Magid; Ana Carreira; Ashutosh Rai; Amy Evans; Mark Bollington; Vaishali Kaur; Silaghi Cristina Alina; Alan McGregor; Kudakwashe Mandisodza; Jayaprakash Sahoo; Rahul Gupta; Kishore Behera; Ayan Roy; Ian Carr; Paul Loughrey; Pinaki Dutta; Marta Korbonits

doi:10.1530/endoabs.99.P513

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Endocrine Abstracts (2024) 99 P513 | DOI: 10.1530/endoabs.99.P513

ECE2024 Poster Presentations Pituitary and Neuroendocrinology (120 abstracts)

Novel mutations causing pachydermoperiostosis - hormonal and phenotypic alterations

Maria Stelmachowska-Banaś ¹ , Sayka Barry ² , Ishita Angurala ² , Tom Rice ² , Kesson Magid ² , Ana Carreira ² , Ashutosh Rai ² , Amy Evans ² , Mark Bollington ² , Vaishali Kaur ³ , Cristina Alina Silaghi ⁴ , Alan McGregor ⁵ , Kudakwashe Mandisodza ⁵ , Jayaprakash Sahoo ⁶ , Rahul Gupta ⁷ , Kishore Behera ⁸ , Ayan Roy ⁹ , Ian Carr ¹⁰ , Paul Loughrey ¹¹ , Pinaki Dutta ³ & Márta Korbonits ²

Err

Author affiliations

¹Centre of Postgraduate Medical Education, Department of Endocrinology, Warsaw, Poland; ²Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; ³Postgraduate Institute of Medical Education and Research, Department of Endocrinology, Chandigarh, India; ⁴Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Department of Endocrinology, Cluj-Napoca, Romania; ⁵College of Health Sciences, Parirenyatwa Group of Hospitals Harare, University of Zimbabwe, Department of Medicine, Harare, Zimbabwe; ⁶Jawaharlal Institute of Postgraduate Medical Education & Research, Department of Endocrinology, Puducherry, India; ⁷All India Institute of Medical Sciences, Department of Endocrinology and Metabolism, Bhopal, India; ⁸All India Institute of Medical Sciences, Department of Endocrinology, Bhubaneswar, India; ⁹All India Institute of Medical Sciences, Department of Endocrinology, Kalyani, India; ¹⁰University of Leeds, Molecular Medicine Unit, Leeds, United Kingdom; ¹¹Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, United Kingdom

Background: Pachydermoperiostosis (primary hypertrophic osteoarthropathy, PHO) is a rare genetic disease characterised by clinical signs and symptoms which may overlap with acromegaly (pachydermia, hyperhidrosis and enlargement of hands and feet). In the majority of cases, the disease is due to biallelic loss-of-function variants in either of two genes, SLCO2A1 and HPGD playing an important role in prostaglandin metabolism. Although PHO patients are often referred to endocrinologists, a detailed hormonal assessment is not available for these patients.

Patients and methods: Patients (n=16, all males), referred to endocrinology centres with a possible diagnosis of acromegaly and eventually diagnosed with PHO, were assessed for biochemical and hormonal abnormalities. Acromegaly was excluded based on normal IGF-1 concentration and/or GH suppression during an oral glucose tolerance test (OGTT). Sanger sequencing for HPGD and SLCO2A1 variants on peripheral blood DNA was performed. The identified variants on both genes were classified using the American College of Medical Genetics classification guidelines.

Results: The mean (± standard deviation) age at PHO diagnosis was 27.8 years ±11.3 (range 9-43 years). Digital clubbing and periostosis were present in all patients. Arthralgia of large joints was present in 15/16 patients (94%), periarticular oedema in 13/16 (81%), pachydermia in 14/16 (88%) and facial features suggesting acromegaly in 12/16 (75%). Further characteristic features included eyelash trichomegaly (10/16 patients), blepharoptosis (9/16), high-arched palate (9/15), gastrointestinal symptoms (7/16), gingival hypertrophy (1/16) and marfanoid habitus (2/16). All tested patients (n=13) suppressed GH on OGTT<1.0 µg/l, but 4 (31%) did not supress GH<0.4 µg/l. Nine patients (57%) had abnormally low serum IGF-1 level and the other three patients (19%) had IGF-1 levels in the lower quartile of the reference range. While testosterone and prolactin levels were normal, oestradiol concentration was increased above the normal range in eight patients (62%). Two families harboured homozygous HPGD changes (one of these is a novel variant). Ten families had 12 different pathogenic/likely pathogenic variants in SLCO2A1 (eight novel variants). Eight kindreds had homozygous change while two kindreds had compound heterozygous mutation. Two patients from two different kindreds had no identifiable pathogenic/likely pathogenic variant in HPGD or SLCO2A1. Their phenotype was not different from the other patients.

Conclusion: Low IGF-1 and elevated oestradiol levels are typical features for patients with both HPGD or SLCO2A1 mutations while analysing the data of 14 kindreds with PHO carrying nine novel and five known pathogenic/likely pathogenic genetic variants.