Klinefelter’s syndrome and juvenile chronic arthritis

Abstract

Klinefelter’s syndrome (KS) is the most common disorder of sexual differentiation in males and the most common disorder of sex chromosomes in humans. In KS, primary male hypogonadism is caused by developmental testicular defects due to the presence of two or more X-chromosomes. The classic karyotype for KS is 47XXY, but the mosaic form, 46XY/47XXY occurs in about 10% of cases. Other extreme variants such as 48XXYY, 48XXXY, and 49XXXXY also exist. It is estimated that the frequency of KS is about 1/500 at conception and 1/1000 at birth due to in utero fetal loss. First described in full by Dr. Harry Klinefelter in 1942 [1], the full syndrome begins to manifest in adolescence and its characteristics include gynecomastia, testicular atrophy, azoospermia and sparse facial and body hair. Increased leg length and armspan are also typical of the syndrome. The phenotypic expression is variable, however, and some individuals are not diagnosed until adulthood. Decreased secretion of androgens, an increased estradiol/testosterone ratio (a relative increase in estrogen effect) and elevated gonadotropin levels are noted in KS. The patients evaluated and described by Dr. Klinefelter demonstrated normal to moderately reduced function of the Leydig cells, increased excretion of follicle-stimulating hormone, and reduced excretion of 17-ketosteroids. As a result of the hormonal abnormalities, clinical findings of hypogonadism, azoospermia, and gynecomastia are noted. Small testes, measuring less than 2–3 cm are the most consistent physical finding. Additional physical features are small phallus and decreased upper to lower body ratio [2]. Laboratory evaluation generally demonstrates elevated FSH and LH and a decreased testosterone levels. KS patients generally need to be started on testosterone replacement therapy at about 12 years of age, with increasing dosages over time that simulate age-appropriate concentrations. Klinefelter’s syndrome has been noted to have an association with several autoimmune diseases including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), autoimmune diseases of the thyroid, and ankylosing spondylitis (AS). It has been speculated that some of these diseases, which normally show a female predominance, are seen concomitant with KS due to a relative excess of estrogens and lack of androgens in these patients. An association between KS and SLE is well described [3]. It has been suggested that the peripheral venous and arterial vascular abnormalities seen in KS (such as commonly seen leg ulcers) may be related to immune mechanisms involving anticardiolipin antibodies in KS patients [3]. Many reports of KS in association with autoimmune disease reflect a continuing interest in the complex relationship between sex hormones and autoimmune processes. Complicating this question, however, is the ‘‘Take home message’’: Pediatric patients with Klinefelter’s syndrome, a genetic condition characterized by primary male hypogonadism, should be considered at potential risk for the development of autoimmune diseases, including juvenile chronic arthritis.