ESPE Yearbook of Paediatric Endocrinology

Eur J Endocrinol. 2021 Oct 8;185(5):617-627. doi: 10.1530/EJE-21-0387. PMID: 34403359. https://eje.bioscientifica.com/view/journals/eje/185/5/EJE-21-0387.xml

Brief Summary: This study investigates the role of Whole Exome Sequencing in the differential diagnosis of delayed puberty, evaluating a genotype-phenotype correlation.

Delayed puberty (DP) comprises a spectrum of disorders ranging from isolated hypogonadotropic hypogonadism (IHH) to self-limiting delayed puberty (SLDP). The differential diagnosis between these conditions is difficult and no available investigation can reliably distinguish between them [2,3].

This study investigated the impact of genetic analysis on the diagnosis of DP in a cohort of 46 patients (40 males and 6 females). After clinical diagnosis of SLDP or IHH, subjects were followed until 18 years of age to confirm diagnosis. 25 patients were diagnosed as having SLDP, while 21 had IHH. Whole-Exome-Sequencing was performed in these patients and 35 controls, and results were filtered using a virtual panel of 47 known genes. Genotypic diagnosis was defined as SLDP, IHH or inconclusive. Potentially deleterious variants of 12 genes were found in 15 patients and a genetic diagnosis was possible for 1 SLDP and 7 IHH. In all cases, the genetic diagnosis fully corresponded to final clinical diagnosis. Three patients with initial SLDP diagnosis received a genetic diagnosis of IHH that was clinically confirmed at the end of follow-up. Clinical presentations for known pathogenic mutations corresponded to literature data (homozygous TAC3 or GNRHR)[4,5]. Authors identified heterozygous variants in IHH causative genes (DMXL2, OTUD4, SEMA3E) in 3 patients with a final clinical diagnosis of SLDP. This indicates the potential overlap of pathophysiological mechanisms between SLDP and IHH. In this study, genetic analysis showed a 100% specificity and positive predictive value for the diagnosis of IHH. However, its sensitivity (33.3%) and negative predictive value (64.1%), were lower than other biochemical profilings, such as basal and stimulated gonadotropins, or basal inhibin B [3][6][7]. Further studies will be necessary to enrich these virtual panels and improve knowledge regarding these conditions.

References: 1. Palmert MR, Dunkel L. (2012) “Clinical practice. Delayed puberty.” N Engl J Med; 366(5):443–53. 2. Howard SR. (2018) “Genes underlying delayed puberty.” Mol Cell Endocrinol; 476:119–128. 3. Harrington J, Palmert MR. (2012) “Clinical review: Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests.” J Clin Endocrinol Metab; 97(9):3056–67. 4. Young J, Bouligand J, Francou B, Raffin-Sanson ML, Gaillez S, Jeanpierre M, Grynberg M, Kamenicky P, Chanson P, Brailly-Tabard S, Guiochon-Mantel A. (2010) “TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans.” J Clin Endocrinol Metab; 95(5):2287–95. 5. Lin L, Conway GS, Hill NR, Dattani MT, Hindmarsh PC, Achermann JC. (2006) "A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia," J Clin Endocrinol Metab; 91(12):5117–21. 6. Brown DC, Stirling HF, Butler GE, Kelnar CJH, Wu FCM. (1996) "Differentiation of normal male prepuberty and hypogonadotrophic hypogonadism using an ultrasensitive luteinizing hormone assay," Horm Res; 46(2),83–7. 7. Gao Y, Du Q, Liu L, Liao Z. (2021) "Serum inhibin B for differentiating between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty: a systematic review and meta-analysis," Endocrine; 72(3):633–643.