Combined pituitary hormone deficiency with a novel <scp> <i>GLI2</i> </scp> frameshift variant

Combined pituitary hormone deficiency (CPHD) is known to be caused by abnormalities in several transcription factors involved in pituitary differentiation. However, the genetic etiology of around 85% of CPHD cases remains unknown.1 GLI2 variants are detected relatively frequently among these cases2 with an autosomal dominant pattern of inheritance. Here, we present a case of CPHD with a novel GLI2 variant diagnosed after cardiopulmonary arrest on day age 1. The patient was born to a Panamanian father and a Canadian mother at 40 weeks of gestation via normal vaginal delivery after an uncomplicated pregnancy. His birth weight and length were 3.2 kg and 51 cm, respectively. The patient had no family history of sudden death, endocrine disorders, or short stature. He had no abnormal findings other than a micropenis; therefore, he stayed in the same room as his mother. On day 1, the patient experienced cardiopulmonary arrest. A pediatrician performed cardiopulmonary resuscitation, leading to the return of spontaneous circulation within 3 min. He developed a seizure with an undetectable low blood glucose level after 30 min of resuscitation. Due to persistent seizures, even after blood glucose was elevated by glucose supplementation, the patient was transferred to our hospital for hypothermia therapy. He had the micropenis (Figure 1a) and hypotelorism. Adrenal hypoplasia was suspected based on abdominal ultrasonography findings. The CPHD was suspected because of the presence of hypoglycemia, micropenis, and adrenal hypoplasia without pigmentation. Critical samples collected during hypoglycemia (41 mg/dL) showed low GH (2.64 ng/mL), ACTH (4.15 pg/mL), and cortisol (0.3 μg/dL). LH and FSH levels remained below detection limit during mini-puberty at 1 month old. Furthermore, TSH elevation was insufficient (1.50 ng/dL; reference range for early neonatal period, 1.0–8.4 μIU/mL) for the low FT4 (0.91 ng/dL; reference range for early neonatal period, 1.59–2.88 ng/dL) on day age 2 despite the timing of the TSH surge. IGF-1 was also below detection limit on day age 2. Magnetic resonance imaging (MRI) of the head showed a small anterior pituitary lobe, an interrupted pituitary stalk, and an ectopic posterior pituitary lobe, the classical triad of pituitary stalk interruption syndrome (Figure 1b). MRI of the abdomen showed adrenal hypoplasia with a length of 6.38 mm (normal range,3 17–35 mm) (Figure 1c). Based on these findings, the patient was diagnosed with congenital CPHD. The patient underwent therapeutic hypothermia for the first 3 days. Oral hydrocortisone replacement therapy, daily injection of recombinant human growth hormone, oral levothyroxine replacement therapy were initiated on day age 5, 20, 21 respectively. He was received 25 mg of intramuscular testosterone once a month from 1 to 3 months of age as a treatment for the micropenis. Although his growth and development were generally good, he experienced mild spasticity due to cerebral palsy. Fusion of maxillary central incisors was identified after eruption of deciduous tooth. Trio-based whole exome sequencing (WES) was performed and a novel heterozygous GLI2 variant was identified in the patient and the father: c.1989delC (p.Cys664Alafs*31) (NM_005270). This variant was confirmed using Sanger sequencing (Figure 1d). We re-interviewed the family and found the father, paternal grandfather, and paternal great-aunt had postaxial polydactyly (Figure 1e). The father also had hypotelorism. The novel GLI2 variant identified in this case was a truncating variant. Corder et al. reported that truncating variants of GLI2 are strongly associated with CPHD (Figure S1).4 According to the American College of Medical Genetics and Genomics classification, the variant is considered “pathogenic” because it is a frameshift variant (PVS1), is absent from controls (GnomAD) (PM2) and is also detected in the patient's father with polydactyly (PP1). In the present case, the patient had a severe CPHD phenotype, whereas his father, who had the same genotype, only exhibited polydactyly. The paternal grandfather and paternal great-aunt also had polydactyly and were suspected to have the same GLI2 variant. According to a previous report on nine families with a GLI2 gene deletion or variant,5 the phenotype with the same variant varies widely among family members, from holoprosencephaly to CPHD, midfacial malformations, polydactyly, and a normal phenotype, suggesting that the inheritance pattern is autosomal dominant with incomplete penetrance. Incomplete penetrance is believed to be caused by interactions with other genetic, epigenetic, or environmental factors. When the phenotype among family members is diverse, as in this case, it is difficult to assume that parents have the same variant as the patient. Therefore, early genetic testing is essential because it allows genetic counseling regarding risk to family members. In this case, the identification of the GLI2 variant by WES early after CPHD diagnosis allowed for genetic counseling regarding the risk to the next baby. As mentioned in the introduction, the number of CPHD candidate genes has increased recently; however, genetic abnormalities have only been identified in a few cases. WES can be used to analyze many candidate genes efficiently. WES is expected to be performed in many CPHD cases to accumulate knowledge of candidate genes and their pathophysiology. There is a limitation. Since WES is unable to detect intronic pathogenic variants or deletions in the causative genes for CPHD, including GLI2, it cannot be completely ruled out that other variants may be involved. In fact, various studies advocate the theory that CPHD has multigenic etiology.1 Y.M. and N.A. wrote the manuscript. N.A., T.M., and H.T. treated the patient. N.A., T.M., S.K., M.K., and H.T. gave technical support and conceptual advice. S.K. and M.K. conducted genetic analysis of the patient's family. H.T. supervised the study. All authors read and approved the final manuscript. This research was supported by AMED under Grant Number JP24ek0109760. The authors declare no conflict of interest. This study was approved by the Institutional Review Board of the University of Tokyo Hospital (2701-(6)). Informed consent was obtained from the parents of the children for genetic analysis and scientific publication of this report. Figure S1. 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