Whole-exome sequencing expands congenital hypopituitarism aetiology understanding

medwireNews: A whole-exome sequencing study has identified novel genes involved in the development of spontaneous congenital hypopituitarism (CH) in a large group of unrelated children from Argentina.

Maria Ines Perez-Millan, from the Universidad de Buenos Aires in Argentina, and co-workers say their findings, published in the Journal of Clinical Endocrinology & Metabolism, “provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.”

They report findings for 131 children with sporadic CH and six children with familial CH, 89 of whom were boys. The majority (68.6%) had combined pituitary hormone deficiency (CPHD), 30.0% had isolated growth hormone (GH) deficiency and 1.4% had isolated central congenital hypothyroidism.

Sixty percent of the patients had at least one other organ system, other than the gonads, affected by a pituitary axis defect, such as abnormalities in brain morphology or function (37.6%), visual system defects (27.8%) or craniofacial anomalies (25.4%). Septo-optic dysplasia was more common in children with CPHD than those with isolated GH deficiency (21.2 vs 2.4%).

Whole-exome sequencing identified pathogenic genetic variants in 5.3% of the 137 children, likely pathogenic variants in 32.8% and variants of uncertain significance in 25.2%. No clinically relevant alterations were detected in 36.6% of the cohort.

The researchers note that while 43% of the patients with a confirmed genetic finding had an alteration in a gene traditionally associated with CH, the remainder had alterations in genes associated with complex syndromes, such as CHD7, KDM6A, PTPN11, ALG1 or MORC2, or in ROBO1 or PIBF1, which have only recently been linked to CH.

“Many of the [pathogenic/likely pathogenic] variants found are in new candidates and novel genes (16%), and 3% of them are found in heterozygous fashion for a recessive disorder”, report Perez-Millan and co-authors.

The researchers say the candidate genes are for “diverse protein families and function”, such as the cilia, cell signalling, RNA processing and DNA methylation.

Perez-Millan et al also note that although PROP1 and POU1F1 are the most commonly reported genetic alterations in CH, there was only one case of the former and none of the latter in the current study, “highlighting the importance of genetic testing in understudied populations.”

The team identified two children from different families who had similar presentations of CPHD with partial GH deficiency and hypogonadism that were traced to missense mutations in FGFR1. The researchers note that a sibling with short stature responsive to GH therapy also carried the FGFR1 variant and had brachymesophalangy, which has previously been linked to Pfeiffer syndrome caused by alterations in the same gene.

Moreover, eight affected children from seven families had mutations in ROBO1, including monozygotic twins with the same de novo genetic mutation but differing phenotypes. One twin had CPHD and severe short stature, pituitary stalk interruption syndrome including anterior pituitary hypoplasia, ectopic posterior pituitary and absent stalk; the second twin had IGHD, an intrasellar arachnoidocele, anterior pituitary hypoplasia and thin stalk but a eutopic posterior pituitary.

“This case highlights the variable expressivity of ROBO1 mutations and the possible existence of modified alleles,” the investigators comment.

Mutations were also identified in three genes from the PTPN family including PTPN11, which is associated with Noonan syndrome, and also genes associated with cilia (PIBF1, TBC1D32), transition zone complex (CC2D2A), ion channels and regulators (RIMBP2) and transcription and epigenetics (ARID1A, ARID5B, TIPARP).

Three children with CHARGE syndrome (coloboma, heart defects, choanal atresia, growth retardation, genital and ear abnormalities) had nonsense mutations in CHD7. A fourth patient with IGHD, PSIS intraventricular communication, syringomyelia, tethered spinal cord and dysplastic sacrum had a missense mutation in CHD7 of unknown significance, which the researchers believe “adds to the evidence that missense mutations in CHD7 can give a spectrum of phenotypes with CH, result in milder or no features of CHARGE syndrome.”

The team also describes chromosomal deletions in 3.8% of the 131 children with sporadic CH, affecting multiple genes associated with CPHD including SOX2, LHX4 and TGIF1, and copy number variation (5–10%), leading the researchers to recommend karyotyping and copy number variation techniques in children with syndromic presentations before considering whole-exome sequencing.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metab 2024; doi:10.1210/clinem/dgae320
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