ESPE Abstracts

Background: Central hypothyroidism is rare in children. It is often part of multiple pituitary hormone deficiency but can occur in isolation. Isolated central hypothyroidism may be due to mutations in TSHB, TRHR or IGSF1, involved in TRH signalling. We present an adolescent with a novel truncating variant of IGSF1, resulting in delayed puberty, central hypothyroidism and macroorchidism.

Case presentation: A 15-year-old male was referred for pubertal delay, obesity and abnormal thyroid function tests (FT4 (6.5pmol/L [8.4-19.1], TSH 3.23mU/L [0.3-5.0]). He was born breech, birth weight 3.7kg (+0.32 SDS). At age 2, weight was 11kg (-1.38 SDS), height 85cm (-0.75 SDS), head circumference 52cm (+2.30 SDS). His medical history included raised ALT and liver steatosis. At presentation, his height was 166cm (-0.52 SDS), BMI 38.5kg/m2. On examination, Tanner staging was P1G1A1, 8ml testes. Initial investigations revealed LH 0.7IU/L, FSH 4.1IU/L, Testosterone 7.6nmol/L, IGF1 11.2ng/ml (13.5-66), prolactin 136 IU/L (90-300), AMH 28.1 (5.5-103). An LHRH-test showed a peak LH 11.2, FSH 12.8. Bone-age delayed 1 year. MRI showed a small pituitary gland. Levothyroxine was commenced and increased. Primed glucagon test showed undetectable GH but with suboptimal FT4 (7.3pmol/L). Later, primed insulin tolerance test (ITT) showed a low GH peak (4.21mcg/L). His growth and puberty progressed with quickly enlarging testes to 30ml. Sequencing of IGSF1 revealed a previously undescribed de novo hemizygous pathogenic variant c.3343C>T p.(Gln1115*) causing frameshift and premature stop codon. The identified IGSF1 variant is not described in GnomAD. It locates to the 12th Ig-like loop, clustering with other frameshift mutations. The mutation likely leads to abnormal glycosylation and retention of shortened IGSF1 in the ER, resulting in ER-stress response and apoptosis in the pituitary contributing to pituitary hormone deficiency. 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 his normalising height and IGF1.

Conclusion: We describe a novel frameshift IGSF1 variant, resulting in most previously described features associated with IGSF1 deficiency, including 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 for clinicians, highlights the importance of careful assessment for timely genetic diagnosis.