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Clinical Trial
. 2013 Oct 24;8(10):e77827.
doi: 10.1371/journal.pone.0077827. eCollection 2013.

Congenital hypogonadotropic hypogonadism during childhood: presentation and genetic analyses in 46 boys

Audrey Vizeneux  1 , Aude Hilfiger, Jérôme Bouligand, Monique Pouillot, Sylvie Brailly-Tabard, Anu Bashamboo, Ken McElreavey, Raja Brauner
Affiliations
Clinical Trial

Congenital hypogonadotropic hypogonadism during childhood: presentation and genetic analyses in 46 boys

Audrey Vizeneux et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Distribution of the plasma inhibin B concentrations in 27 boys with isolated hypogonadotropic hypogonadism.
Solid lines correspond to the median and broken lines to the 5th and 95th percentiles in infants and at each stage of puberty . Numbers (except 42) correspond to low concentrations (Tables 1 and 2): KS in cases 13,41 and 46, CHARGE syndrome in case 27, FGFR1 mutation in cases 14 and 36 and other HH in the others.
Figure 2
Figure 2. Distribution of the plasma AMH concentrations in 27 boys with isolated hypogonadotropic hypogonadism.
Broken lines to the 5th and 95th percentiles . Numbers correspond to low concentrations (Tables 1 and 2): KS in cases 13 and 46, CHARGE syndrome in case 27, FGFR1 mutation in cases 14 and 36 and other HH in the others.
See this image and copyright information in PMC

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