ABSTRACT
Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm. The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E(2) levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.
Subject(s)
Chromosomes, Human, Pair 4/genetics , Frameshift Mutation/genetics , Hydroxyprostaglandin Dehydrogenases/genetics , Osteoarthropathy, Primary Hypertrophic/etiology , Adolescent , Adult , Amino Acid Sequence , Child , Consanguinity , Dinoprostone/urine , Female , Genome, Human , Heterozygote , Homozygote , Humans , Hydroxyprostaglandin Dehydrogenases/chemistry , Hydroxyprostaglandin Dehydrogenases/metabolism , Male , Middle Aged , Models, Molecular , Molecular Sequence Data , Osteoarthropathy, Primary Hypertrophic/enzymology , Osteoarthropathy, Primary Hypertrophic/pathology , Pedigree , Protein Conformation , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Sequence Homology, Amino AcidABSTRACT
OBJECTIVE: Psoriatic arthritis (PsA) is characterized by inflammatory arthritis in the presence of psoriasis. Certain clinical features help characterize this disorder, one of which is dactylitis. Hitherto an instrument for quantifying dactylitis has not been developed. METHODS: A dactylitis score sheet was developed. The score is a function of finger circumference and tenderness, assessed and summed across all dactylitic digits. Initial results were obtained on a small sample of patients attending clinics. Inter and intraobserver agreement on the presence of dactylitis using kappa agreement statistics, and the validity and reliability of the instrument, using intraclass correlation coefficients (ICC), were assessed in a further group of 7 patients with PsA. RESULTS: Tender dactylitis was deemed present in 74 digits out of a total of 280 (140 digits on each occasion). Kappa agreement scores for the presence of tender dactylitis were poor to good, both within and between observers (0.25 to 0.89 between observers and 0.29 to 0.91 within observers). Agreement scores for non-tender dactylitis were poor (0.01 to 0.66 between observers and 0.01 to 0.59 within-observer agreement). The new dactylitis instrument was simple and easy to administer and was found to measure appropriate scores in patients with different severity of dactylitis. Inter and intraobserver agreement was good (interobserver ICC 0.90, 95% CI 0.74-0.98; intraobserver ICC 0.84, 95% CI 0.71-0.92). Intraobserver ICC improved but interobserver ICC deteriorated by rating simply presence or absence, rather than a 4 point grade, of tenderness. CONCLUSION: A new method for quantifying dactylitis based on digital circumference and tenderness has been described. This instrument has shown good inter and intraobserver reliability. Further studies of responsiveness are now required.
