Jee Youn Hee, Gangat Mariam, Yeliosof Olga, Temnycky Adrian G, Vanapruks Selena, Whalen Philip, Gourgari Evgenia, Bleach Cortney, Yu Christine H, Marshall Ian, Yanovski Jack A, Link Kathleen, Ten Svetlana, Baron Jeffrey, Radovick Sally
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States.
Front Genet. 2021 Aug 11;12:697549. doi: 10.3389/fgene.2021.697549. eCollection 2021.
Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown.
We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) ( = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups.
First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology ( mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, = 0.01).
Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.
先天性垂体功能减退通常为散发性。大多数患者的病因尚不清楚。
我们研究了13例散发性先天性垂体功能减退患儿。将非内分泌、非家族性特发性身材矮小（NFSS）患儿（n = 19）作为对照组。对先证者及其未受影响的双亲进行外显子组测序。采用负荷测试方法比较两组候选变异的数量。
首先，我们评估了先前报道的与垂体发育相关的42个基因中罕见的、预测致病的变异频率。先天性垂体功能减退先证者中每个个体的变异平均数高于NFSS患者（1.1 对 0.21，平均变异数/先证者，P = 0.03）。先天性垂体功能减退患者中至少有1个垂体相关基因突变的先证者数量多于NFSS患者（62% 对 21%，P = 0.03）。其次，我们评估了外显子组中罕见的、预测致病的变异频率（以发现未被发现的病因），这些变异以一种能够解释先证者单基因病因（突变、常染色体隐性或X连锁隐性）散发性发病且完全外显的方式遗传。先天性垂体功能减退先证者中的单基因候选变异少于NFSS患者（1.3对2.5个候选变异/先证者，P = 0.024）。与NFSS（19例先证者中有8例，P = 0.01）不同，我们在先前报道的可解释先天性垂体功能减退表型的基因中未发现任何候选变异（13例先证者中有0例）。
我们的研究结果提供了证据，表明散发性先天性垂体功能减退的病因有主要的遗传成分，但可能很少是完全外显的单基因病因，提示病因更为复杂。
