Hypertrophic osteoarthropathy: estrogens, prostaglandinE2, prostaglandin A2, and the inflammatory reflex.

It has been claimed that hyperestrogenism occurs in hypertrophic osteoarthropathy (HOA), but not in simple clubbing. However, one of our patients had simple clubbing and hyperestrogenism. We therefore measured estrogens, androgens, sex hormone-binding globulin (SHBG), and gonadotropins in five patients with HOA and in 18 patients with simple clubbing. Of the patients with HOA, 80% had a high urinary estriol concentration. In their serum, 80% had high estrone, 0% high estradiol, and 40% high SHBG. Of the patients with simple clubbing, 89% had a high urinary estriol concentration. In their serum, 76% had high estrone, 6% high estradiol, and 31% high SHBG. In all patients, urinary estriol concentration correlated positively with the degree of clubbing. Serum concentration of androstenedione, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was mostly normal, but androstenedione concentration correlated positively with the degree of clubbing. Spider angiomas were present in 74%, palmar erythema in 39%, and gynecomastia in 9%. Urinary creatinine concentration was low in 48% and correlated positively with the degree of clubbing. We reject the claim that hyperestrogenism occurs in HOA, but not in simple clubbing. Hyperestrogenism occurs both in HOA and in simple clubbing. Our results also support earlier reports that clubbing and HOA are associated with spider angiomas, palmar erythema, gynecomastia, adrenal cortical hyperfunction, muscle atrophy, and water retention. These results led to a new hypothesis on the pathogenesis of HOA, involving estrogens, prostaglandin E2, prostaglandin A2, and the inflammatory reflex.

Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing.

Digital clubbing is usually secondary to different acquired diseases. Primary hypertrophic osteoarthropathy (PHO) is a rare hereditary disorder with variable digital clubbing as the most prominent feature, subperiosteal new bone formation, and arthropathy. Recently, mutations in the 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) encoding gene HPGD were found to cause PHO. Here, we identified three unrelated families with different mutations in the prostaglandin transporter (PGT) encoding gene SLCO2A1 which presumably result in reduced metabolic clearance by 15-PGDH due to diminished cellular uptake of prostaglandin E(2) (PGE(2)) by mutant PGT. In two consanguineous families, homozygous mutations, an intragenic deletion that results in frameshift and a missense mutation, are associated with a severe PHO phenotype. In a third family, a heterozygous carrier of a stop mutation presents with isolated digital clubbing. Thus, our study further supports the importance of PGE(2) metabolism in the pathogenesis of digital clubbing and PHO.

An XX male with the sex-determining region Y gene inserted in the long arm of chromosome 16.

OBJECTIVE: To report a case of a 46,XX male with an insertion of the sex-determining region Y (SRY) region in the terminal end of the long arm of chromosome 16. DESIGN: Case report. SETTING: Molecular and cytogenetic units in a university hospital. PATIENT(S): An infertile male, with normal masculinization of the external genitalia, who was referred for chromosomal analysis as an unaffected member of a family with idiopathic hypertrophic osteoarthropathy. INTERVENTION(S): Cytogenetic investigation, physical examination, and hormonal assays. MAIN OUTCOME MEASURE(S): Chromosomal analysis using GTG banding and fluorescence in situ hybridization (FISH). RESULT(S): Conventional chromosome analysis revealed a normal 46,XX karyotype. The FISH with bacterial artificial chromosomes (BACs) of the SRY region indicated the presence of this region on the terminal end of the long arm of chromosome 16. CONCLUSION(S): This is the first case of a 46,XX male with the SRY gene present on an autosome-here chromosome 16. The size of the inserted region containing SRY, inserted in 16qter, is approximately 600 kb.