Endocrine Abstracts

Background: Central hypothyroidism (CeHT) is uncommon in children. CeHT is often part of multiple pituitary hormone deficiency but can occur in isolation, and may occasionally be due to mutations in TSHB, TRHR or IGSF1, involved in TRH signalling. We present an adolescent with a novel truncating mutation of IGSF1.

Case presentation: A 15-year-old male was referred for pubertal delay, obesity and abnormal TFTs (FT4 (6.5 pmol/l [8.4–19.1], TSH 3.23 mU/l [0.3–5.0]). He was born breech, birth weight 3.7 kg (+0.32 SDS). At age 2, weight was 11 kg (−1.38 SDS), height 85 cm (−0.75 SDS), head circumference 52 cm (+2.30 SDS). Medical history: raised ALT and liver steatosis. Examination: Height 166 cm (−0.52 SDS), BMI 38.5 kg/m². Tanner staging P1G1A1, 8 ml testes. Investigations: LH 0.7 IU/l, FSH 4.1 IU/l, Testosterone 7.6 nmol/l, IGF1 11.2 ng/ml (13.5–66), prolactin 136 IU/l (90–300), AMH 28.1 (5.5–103). LHRH-test: peak LH 11.2, FSH 12.8. Bone-age was 1 year delayed. MRI showed a small pituitary gland. Levothyroxine was started and increased gradually. Primed glucagon test showed undetectable GH but with suboptimal FT4 (7.3 pmol/l). Later, a primed insulin tolerance test (ITT) showed a low GH peak (4.21 mcg/l). His growth and puberty progressed with quickly enlarging testes to 30 ml. Sequencing of IGSF1 revealed a previously undescribed hemizygous pathogenic variant c.3343C>T p.(Gln1115*) causing frameshift and premature stop codon. The identified IGSF1-mutation is not described in GnomAD. It locates to the 12th Ig-like loop in the C-terminal domain, clustering with other frameshift mutations. The mutation likely leads to abnormal glycosylation and retention of shortened IGSF1 in the ER and may result in ER-stress response and cell death in the pituitary contributing to pituitary hormone deficiency, as previously described for GH1 mutations. Growth hormone deficiency (GHD) was evident on glucagon test and ITT, although difficult to interpret due to hypothyroidism and obesity. GHD may be transient given normalising height and IGF1, as seen previously.

Conclusion: We describe a novel frameshift IGSF1 mutation, resulting in most previously described features: central hypothyroidism, macroorchidism, macrocephaly, delayed adrenarche and puberty, GHD, obesity, fatty liver disease and higher than average birth weight. This case adds to genotype-phenotype correlations and highlights the importance of careful assessment for a timely genetic diagnosis.