ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2018 Sep 1;103(9):3420–3429.

This whole-exome study in 67 probands and 93 relatives from a large cohort of familial delayed puberty identifies a new heterozygous HS6ST1 mutation as a novel cause of delayed puberty.

The underlying pathophysiology of early and delayed puberty remains unexplained in most patients. As illustrated by this article, familial delayed puberty represents an invaluable resource to discover new regulators of the onset of puberty (1).

A whole-exome sequencing study in 67 informative families with self-limited delayed puberty identified 20 rare variants in 12 genes. After filtering for segregation with trait, HS6ST1 was retained as a candidate gene. One proband and his affected relatives carried a rare and likely damaging HS6ST1 variant that caused a non-conservative amino acid substitution in the coding sequence. This mutation reduced sulfotransferase activity in vitro. The authors showed that Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus and olfactory bulbs. GnRH neuron counts were similar in Hs6st1+/2 and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/2 mice despite normal postnatal growth.

Several lines of evidence support a role for heparan sulfate modification in the control of puberty. The C. elegans ortholog hst-6 is known to display genetic interactions with kal-1, and anosmin-1 requires heparin sulfate with specific 6-O-sulfate modifications to exert its function in vivo (2). HS6ST1 mutations have been previously identified in patients with idiopathic hypogonadotropic hypogonadism (3, 4) but this study is the first to identify a deleterious mutation as the likely causal factor for self-limited delayed puberty. This finding provides evidence that perturbations in a single allele of a gene regulating the hypothalamic-pituitary-gonadal axis is enough to cause self-limited delayed-puberty, while more deleterious alterations in the same gene, or in combination with additional genes, are required to cause more severe hypogonadotropic hypogonadism phenotypes.

This study helps us to better understand the genetic basis of self-limited delayed-puberty and brings us closer to the possibility of one day establishing a definitive diagnosis in adolescent patients presenting with delayed onset of puberty.

References: 1. Howard SR. 2018 Genes underlying delayed puberty. Mol Cell Endocrinol. 15:476:119–128.

2. Bülow HE, Berry KL, Topper LH, Peles E, Hobert O 2002 Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1. Proc Natl Acad Sci USA 99:6346–6351.

3. Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G, Van Uum S, Crowley WF, Habuchi H, Kimata K, Pitteloud N, Bulow HE. 2011 Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc. Natl. Acad. Sci. USA. 108(28):11524–11529.

4. Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. 2006 Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 254–255:60–69.