RESUMO
Patients with Kallmann syndrome (KS; congenital hypogonadotropic hypogonadism and decreased/absent sense of smell), septo-optic dysplasia (SOD), or holoprosencephaly (HPE) reportedly have midline defects. In this study, we investigate a genetic overlap between KS, SOD, and HPE. Nineteen subjects (18 males, 1 female) with KS and without mutations in the known KS genes were screened for mutations in SOX2, SHH, SIX3,TGIF1,TDGF1,FOXH1,GLI2, and GLI3. One male carried 2 heterozygous missense changes, one in SIX3 (c.428G>A, p.G143D) and the other in GLI2 (c.2509G>A, p.E837K). Both of these genes have been implicated in the etiology of HPE and neither of these changes were present in 200 control subjects. Other variants found among the subjects were known polymorphisms. KS and HPE may display a genetic overlap. The involvement of genes implicated in the etiology of midline defects in patients with KS warrants further studies.
RESUMO
Patients with congenital hypogonadotropic hypogonadism (HH) may have reduced peak bone mass in early adulthood, and increased risk for osteoporosis despite long-term hormonal replacement therapy (HRT). To investigate the relationship between HRT history and measures of bone health in patients with HH, we recruited 33 subjects (24 men, nine women; mean age 39.8 years, range: 24.0-69.1) with congenital HH (Kallmann syndrome or normosmic HH). They underwent clinical examination, were interviewed and medical charts were reviewed. Twenty-six subjects underwent dual-energy X-ray absorptiometry for evaluation of BMD of lumbar spine, hip, femoral neck and whole body; body composition and vertebral morphology were evaluated in 22 and 23 subjects, respectively. Circulating PINP, ICTP and sex hormone levels were measured. HRT history clearly associated to bone health: BMDs of lumbar spine, femoral neck, hip and whole body were lower in subjects (n = 9) who had had long (≥5 years) treatment pauses or low dose testosterone (T) treatment as compared to subjects without such history (n = 17; all p-values < 0.05). In addition, fat mass and body mass index (BMI) were significantly higher in men with deficient treatment history (median fat mass: 37.5 vs. 23.1%, p = 0.005; BMI: 32.6 vs. 25.2 kg/m(2), p < 0.05). Serum PINP correlated with ICTP (r(s) = 0.61; p < 0.005) in men, but these markers correlated neither with circulating T, nor with serum estradiol levels in women. In conclusion, patients with congenital HH require life-long follow-up to avoid inadequate HRT, long treatment pauses and further morbidity.