In affected members of 2 consanguineous Pakistani families with autosomal recessive cranioosteoarthropathy (see 259100), Uppal et al. (2008) identified a homozygous 418G-C transversion in exon 4 of the HPGD gene, resulting in an ala140-to-pro (A140P) substitution. Clinical features included infantile onset of swelling of the joints, digital clubbing, hyperhidrosis, delayed closure of the fontanels, periostosis, and variable patent ductus arteriosus. Pachydermia was not a prominent feature. In vitro functional analysis showed that the mutant protein had no detectable activity. Modeling suggested that the mutation disrupts the binding of the substrate prostaglandin E. The mutation was not identified in 100 control individuals of Pakistani origin. One of the families had been reported by Sinha et al. (1997) and the other by Dabir et al. (2007).
In 3 affected individuals from 2 unrelated Turkish families with primary hypertrophic osteoarthropathy (PHOAR1; 259100), Yuksel-Konuk et al. (2009) identified homozygosity for the A140P mutation in the HPGD gene. The mutation segregated with disease in both families and was not found in 100 controls. The 2 families originated from different cities and denied any relationship; haplotype information was unavailable.
In a 3-year-old boy (patient 2), born to consanguineous Indian parents, with PHOAR1, Radhakrishnan et al. (2020) identified homozygosity for the A140P mutation in the HPGD gene. The mother was a carrier for the mutation, but the father was not tested. Functional studies were not performed.
