title: A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy.
abstract: OBJECTIVE
  Homozygous mutations in HPGD gene, encoding 15-hydroxyprostaglandin dehydrogenase, have recently been associated with primary hypertrophic osteoarthropathy (PHO). So far, only 7 HPGD alterations are known. In order to expand this mutational spectrum and better delineate the HPGD-related phenotype, we report the clinical and molecular characterisation of a 13-year-old boy and compare his features to known mutated patients.
  
  
  METHODS
  The HPGD gene exons 1-7 and exon-intron junctions were analysed by direct sequencing. Previously published HPGD-mutated patients were systematically reviewed based on the original clinical description.
  
  
  RESULTS
  A novel homozygous c.217+1G>A mutation affecting the obligatory donor splice site of HPGD exon 2 was identified in our proband who showed a mild form of PHO. Review of HPGD-mutated patients outlined all patients manifested digital clubbing, periostosis and acro-osteolysis. Hyperhidrosis (92%), arthralgia (65%) and eczema (33%) were variably associated features. Pachydermia (54%) was mild and mostly limited to palms and sole; cutis vertigis gyrata, blepharoptosis and severe skin thickening were never observed. Besides digital clubbing, PHO infants often presented patent ductus arteriosus (PDA) (32%) and delayed cranial sutures closure (55%).
  
  
  CONCLUSIONS
  The present findings broaden the allelic spectrum of HPGD gene to include a novel c.217+1G>A mutation. Mutated patients display a homogeneous phenotype mainly consisting in digital clubbing, periostosis, acro-osteolysis, hyperhidrosis and mild pachydermia. Earliest manifestations include delayed closure of the cranial sutures and PDA. In conclusion, the information reported herein would facilitate the diagnosis of PHO due to HPGD mutations.
authors.affiliation: CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Sinibaldi
authors.forename: G
authors.initials: G
authors.lastname: Harifi
authors.forename: I
authors.initials: I
authors.lastname: Bottillo
authors.forename: M
authors.initials: M
authors.lastname: Iannicelli
authors.forename: S
authors.initials: S
authors.lastname: El Hassani
authors.forename: F
authors.initials: F
authors.lastname: Brancati
authors.forename: B
authors.initials: B
authors.lastname: Dallapiccola
mesh_terms: D000293:Adolescent; D006720:Homozygote; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008297:Male; D010004:Osteoarthropathy, Primary Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics*; D010005:Osteoarthropathy, Secondary Hypertrophic / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D011859:Radiography; D012720:Severity of Illness Index
chemical_list: D022821:RNA Splice Sites; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase