Case Report: A Detailed Phenotypic Description of Patients and Relatives with Combined Central Hypothyroidism and Growth Hormone Deficiency Carrying IGSF1 Mutations

Abstract

In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants.

Keywords: IGSF1; genetic variation; growth hormone; hypothyroidism; pituitary hormones.

Figure 1

Schematic representation of IGSF1 protein domain structure and the relative locations of the mutations identified in this study and previously reported pathogenic mutations. The two novel variants (p.L570I and c.1765+37C>A) are framed in black. The pathogenic variant is labeled with (★). Region screened in this study (grey).

Figure 2

Family pedigree of the two brothers with the p.C947R variant showing affected and carrier family members. Numbers I, II and III indicate the first, second and third generation. Closed figures = hemizygous p.C947R variant; half open figures = carrier.

Figure 3

TRH stimulation tests results of patient III-4 and III5 with the p.C947R variant. Y-axis shows TSH (mIU/L) (in grey) and prolactine (ug/L) hormone concentrations (in black).