Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

Abstract

Background: Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism. Methods: We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, +3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency. Result: We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0). Conclusion: This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation.

Hypoprolactinemia as a Clue to Diagnosis of Mild Central Hypothyroidism due to <i>IGSF1</i> Deficiency

“…Increased birth weight or length is observed in a substantial number of patients (12). 67% of IGSF1-deficient male children were classified as overweight and 21% as obese (4), being in accord with the phenotype of our patient.…”

Analysis of large versus small dogs reveals three genes on the canine X chromosome associated with body weight, muscling and back fat thickness

“…At locus 2, 20 protein-coding genes are annotated, including a cluster of olfactory receptor genes, and seven noncoding RNAs including microRNA, noncoding RNA and pseudogenes (S2 Fig). From these 20 genes, we identified one striking candidate, Immunoglobulin Superfamily member 1 (IGSF1 ), that encodes an immunoglobulin in the thyroid hormone pathway, and which was previously associated with obesity in IGSF1-deficient humans [50–52]. …”

“…Since the IGSF1 gene is a strong candidate for body size [50–52], we examined it further, noting three variants in the canine sequence (S2 Fig). The first is a single nucleotide change in the 3’UTR (chrX.g.102360204G>A; rs24856221), but the distribution of the genotype in the dog population suggests that it was not associated with SBW (S4 Table).…”

“…In large dog breeds, we identified two mutations, one single codon deletion and one missense mutation, both of which are located in a highly conserved immunoglobulin-like domain of IGSF1 protein. In humans, mutations in the same IGSF1 protein domain are associated with the X-linked IGSF1 deficiency syndrome [50–52,67–69]. Some patients show growth hormone (GH) deficiency during childhood, and 67% of male children are reportedly overweight while 21% are obese (Review in [70]).…”

“…We show that both of the previously identified loci are strongly associated with large breeds, and we perform fine mapping at each locus using WGS data from 163 breeds. Together, these data reveal associations with three excellent positional candidate genes: Insulin Receptor Substrate 4 ( IRS4 ) which interacts with multiple growth factor receptors such as IGF1R [49], Immunoglobulin superfamily member 1 ( IGSF1) which is involved in the biosynthesis of thyroid hormones [50–52] and Acyl-CoA Synthetase Long-chain family member 4 ( ACSL4 ) which plays a role in lipid biosynthesis and fatty acid degradation [53]. …”