ESPE Abstracts

Introduction: Congenital multiple pituitary hormone deficiency (CMPHD) is a clinical condition that manifests in the early years of life. In most cases, pituitary stalk interruption syndrome (PSIS) can be detected by MR imaging. The current study presents a case with a novel candidate pathogenic gene Semaphorin 3A (SEMA3A) in CMPHD by whole-exome sequencing (WES).

Materials and Methods: Genomic DNA was extracted from the blood sample following the manufacturer's standard QIAamp DNA Blood Kit procedure. The WES results of 1 pediatric patient were analyzed with the "Integrative Genomics Viewer" and "Franklin by Genoox" data analysis programs.

Case presentation: A female patient was born with a weight of 3,010 grams and a height of 49 cm in the 36th week of pregnancy from a twenty-eight-year-old mother's first pregnancy by vaginal delivery. Postpartum nasal polyps and an incomplete cleft palate were noticed. In the abdominal ultrasonography, there was a situs inversus in the abdominal organs, and an atrial septal defect (ASD) was detected on echocardiography (no dextrocardia). Nasal polyp excision was performed at 11 months, cleft palate repair at 15 months, and atrial septal defect closure at 2.5 years old. Large anterior fontanelle and low free T4 hormone levels were noted at two years old. She was referred to the endocrine department because of short stature at 3 years-9 months. Central hypothyroidism was detected, and l-thyroxine treatment was started. A low dose (1 mcg) adrenocorticotrophic hormone stimulation test was normal during this period. A 5.5-year-old patient admitted to the emergency department with hypoglycemia was diagnosed with central adrenal insufficiency. Then growth hormone was started due to growth hormone deficiency. PSIS was detected on MRI. The prolactin value was within normal limits. The heterozygote missense variant (c.1450C>T, p.Arg484Trp) was detected in the SEMA3A gene by whole-exome sequencing. This variant (rs137871935) was classified as a variant of uncertain significance (VUS).

Discussion: Semaphorin protein (SEMA3) plays a role in developing the nervous system, including the hypothalamus. A deletion in this gene has been identified in a case with short stature, heart, and skeletal anomalies. In another case with PSIS, a pathogenic variant was found, while in yet another case with cardiac, skeletal, and genitourinary system anomalies, a different variant was identified. We predict that patients with incomplete cleft palate, partial situs inversus, cardiac anomaly, and PSIS could effectively explain the pathogenesis of the disease, and the SEMA3A gene is a novel candidate pathogenic gene in PSIS.