Background: The majority of the patients reported with mutations in isolated hypogonadotropic hypogonadism (HH) are adults. We analysed the presentation and the plasma inhibin B and anti-müllerian hormone (AMH) concentrations during childhood and adolescence, and compared them to the genetic results.
Methods: This was a retrospective, single-center study of 46 boys with HH.
Results: Fourteen (30.4%) had Kallmann syndrome (KS), 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had HH without olfaction deficit nor olfactive bulb hypoplasia. Eighteen (39%) had an associated malformation or syndromes. At diagnosis, 22 (47.8%) boys were aged <one year, 9 (19%) 1-11 and 15 (32.6%) 11-17.6 years. They presented with micropenis (n = 32, 69.6%, including all those <one year), cryptorchidism (n = 32, 69.6%, unilateral in 8, bilateral in 24), and/or pubertal delay (n = 11). The plasma inhibin B concentrations were normal in 8 (3 KS including one CHARGE and 5 other HH), at the lower limit of the normal in 6 and decreased in 13 (48%) boys. The AMH concentrations were normal in 15 (6 KS including one CHARGE and 9 other HH) and decreased in 12 (44%) boys. In addition to the CHD7 gene mutations in 4 patients with CHARGE, mutations were found in 5/26 other boys analysed including one in KAL1 gene with STS, 2 in FGFR1 gene, one in PROKR2 gene and one in GnRHR gene.
Conclusions: The presence of micropenis in neonate, particularly if associated with cryptorchidism, is an indication to look for gonadotropin deficiency isolated or associated with other hypothalamic-pituitary deficiencies. Inhibin B and AMH concentrations are suggestive if low, but they may be normal. Despite the high frequency of the associated malformations and excluding the patients with CHARGE or ichtyosis, the 4 patients with mutations had no family history or malformation. This suggests that many other genes are involved.