Pachydermoperiostosis Due to a Novel HPGD Splicing Site Mutation Masquerading as Acromegaly

Abstract

Hypertrophic osteoarthropathy (HOA: MIM 167100)) is classified into primary and secondary types. Primary HOA, also known as pachydermoperiostosis (PDP), is a rare genetic condition with distinct clinical features including digital clubbing, skin thickening, and periostosis. Secondary HOA often occurs as a paraneoplastic syndrome or is associated with systemic diseases. In this report, we present a 17-year-old male patient who initially presented with significant digital clubbing, enlarged hands and feet, and excessive sweating. Although the initial suspected diagnosis was acromegaly, the patient's plasma level of insulin-like growth factor 1 was normal and growth hormone levels suppressed to <1 ng/dL following oral glucose tolerance test. Whole exome sequencing followed by Sanger sequencing of leukocyte deoxyribonucleic acid revealed a novel splicing variant in the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene (NM_000860.6: c.662 + 5_662 + 8del). Reverse transcription polymerase chain reaction confirmed that this variant led to defective splicing with skipping of exon 6, a frameshift, and truncation at codon 13 of exon 7 downstream. His symptoms did not respond well to nonsteroidal anti-inflammatory drugs but showed excellent response to a trial of lanreotide autogel that has been used for about 1 year.

Keywords: HPGD; acromegaly; pachydermoperiostosis; pseudoacromegaly; somatostatin analogues.

Figure 1.

Family pedigree showing the index case with 4 unaffected full siblings and 2 affected and 1 unaffected half sibling from another mother. Parents are first-degree cousins.

Figure 2.

Radiological assessment (left upper panel) showed acro-osteolysis, with more pronounced severity detected in the feet. The patient had mild dextroconvex thoracic scoliosis. There is no evidence of periosteal reaction or bone enlargement. The cranial radiograph revealed no abnormalities. The other pictures are of the feet and hands (dorsal and plantar aspects) showing a bulky appearance with pseudo clubbing.

Figure 3.

A chromatogram of 3′ end of exon 6 and part of intron 6 showing a novel homozygous 4-nucleotide deletion variant (NM_000860.6; c.662 + 5_662 + 8del) in the HPGD gene, located 5 nucleotides downstream of the last nucleotide of exon 6 (A). This deletion led to the failure of splicing at this position with an alternative splicing between exons 5 and 7 and skipping of exon 6. The frameshift that resulted from this alternative splicing led to the creation of a stop codon and truncation at 13 codons downstream in exon 7 (B).