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☆ The Pediatric Endocrinology Nursing Society (PENS) is committed to the development and advancement o fnurses in the art and science of pediatric endocrinology nursing and to improve the care of all children with endocrine disorders through the education of the pediatric healthcare community. To aid in achieving that goal, the purpose of the PENS department is to provide up-to-date reviews of topics relevant to the PENS membership and to the general readership of the Journal of Pediatric Nursing

Context Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous. Objective To determine the correlation between genotypic severity with pubertal and neuroendocrine phenotypes in IHH men. Design Retrospective study (1980-2020) examining olfaction (Kallmann syndrome [KS] vs. normosmic IHH [nIHH]), baseline testicular volume (absent vs. partial puberty), neuroendocrine profiling (pulsatile vs. apulsatile LH secretion), and genetic variants in 62 IHH-associated genes through exome sequencing (ES). Results In total, 242 men (KS: n = 131 [54%], nIHH: n = 111 [46%]) were included. Men with absent puberty had significantly lower gonadotropin levels (p < 0.001) and were more likely to have undetectable LH (p < 0.001). Logistic regression showed partial puberty as a significant predictor of pulsatile LH secretion (R2 = 0.71, p < 0.001, OR: 10.8 [95%CI: 3.6, 38.6]). Serum LH of 2.10 IU/L had a 95% true positive rate for predicting LH pulsatility. Genetic analyses in 204/242 IHH men with ES data available revealed 36/204 (18%) men carried protein truncating variants (PTVs) in 12 IHH genes. Men with absent puberty and apulsatile LH were enriched for oligogenic PTVs (p < 0.001), with variants in ANOS1 being the predominant PTV in this genotype-phenotype association. Men with absent puberty were enriched for ANOS1 PTVs compared to partial puberty counterparts (p = 0.002). PTVs in other IHH genes imparted more variable reproductive phenotypic severity. Conclusions Partial puberty and LH ≥ 2.10 IU/L are proxies for pulsatile LH secretion. ANOS1 PTVs confer severe reproductive phenotypes. Variable phenotypic severity in the face of severe genetic variants in other IHH genes point to significant neuroendocrine plasticity of the HPG axis in IHH men.