Genetic testing can contribute to clinical diagnosis of delayed puberty

medwireNews: Genetic analysis can confirm or challenge initial clinical diagnoses, helping doctors refine treatment for adolescents with delayed puberty, report researchers.

“Use of early genetic diagnosis in this condition has the potential for significant cost savings as it can prevent unnecessary investigations and lead to improved health and fertility outcomes for patients”, they say.

Their conclusions are based on analysis of 46 adolescents (median age 16 years, 87% male) without chronic illness but with delayed puberty who underwent whole-exome sequencing as part of a research study between 2015 and 2020.

The final clinical diagnosis was self-limited delayed puberty (SLDP) in 54.3% of these patients and idiopathic hypogonadotropic hypogonadism (IHH) in 45.7%, with a respective 72.0% and 47.6% of these groups having a family history of pubertal delay.

All patients had normal basal pituitary function, and just two, both with IHH, had micropenis with bilateral cryptorchidism, one of whom also had synkinesis. Five patients, all in the IHH group, had anosmia.

“Thus, most patients in this cohort presented with isolated delayed puberty without clear clinical signs of IHH”, say Gary Butler (University College London Hospitals NHS Foundation Trust, UK) and study co-authors.

They add that such patients represent those “in whom the distinction between SLDP and IHH is considered most difficult.”

Genetic testing revealed that 15 (32.6%) patients had potentially deleterious mutations in 12 genes with a previously reported association with IHH or SLDP (of a total of 47 such genes assessed).

All of the variants were rare and the majority (73.3%) were heterozygous; all homozygous mutations were found in patients with IHH. Variants were found in six genes previously associated only with IHH, one with only SLDP, and five associated with both conditions.

Based on genotype alone, seven patients were diagnosed with IHH and one with SLDP, but in the remaining seven patients the diagnosis was inconclusive.

The researchers stress that three patients given an initial clinical diagnosis of SLDP had their diagnoses revised to IHH based on the genetic testing, with this confirmed by longer-term clinical follow-up.

“These 3 cases are in keeping with the published literature of these known pathogenic mutations, where cases with IHH can present initially with simple delayed puberty”, they write in the European Journal of Endocrinology.

They add that “early diagnosis of IHH can facilitate the use of optimal therapeutic modalities for pubertal induction, such as the use of gonadotropins in males with IHH and commencement of therapy at an earlier age than the standard sex steroid therapy indicated for SLDP patients.

“Our clinical data highlight this issue, as the mean age of development of secondary sexual characteristics, following hormonal induction, in the patients with a final diagnosis of IHH was over 16 years.”

Another three patients had a final clinical diagnosis of SLDP, despite harbouring deleterious variants expected to contribute to IHH.

But the researchers caution: “Although these patients had clinical characteristics of SLDP, they may have a more significant defect in their GnRH [gonadotrophin-releasing hormone] neuroendocrine system, including impact on fertility or timing of menopause/andropause, which may need monitoring into adulthood.

“Moreover, it suggests that in a subset of patients with pubertal delay there may be some overlap of genetic and pathophysiological mechanisms between SLDP and IHH, or lie along a spectrum of GnRH deficiency.”

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

Eur J Endocrinol 2021; doi:10.1530/EJE-21-0387
Martin Savage
Programme Director
Sign up for eAlerts
Be the first to hear about new resources and content by signing up to receive our eAlerts.

We'd love your feedback!

Please complete this short 5-question survey to help improve the content offered on this website.
Please rank the following aspects of the program from best [1] to worst [4].