Endocrine Abstracts

The index case, born to non-consanguineous British parents, was born with a normal birth weight. He grew along the −2.9 S.D. centile from the age of 2 years. Eczema was diagnosed at the age of 2 weeks. Investigations at 3–4 years of age showed: IGF1<25 ng/ml, IGFBP3 1.29 (N 0.8–3.9), prolactin 265–653 mU/l (N 59–271), GH peak (glucagon test) 17.3 ug/l, normal GH peaks on overnight sampling, and an IGF1<25 ng/ml on a standard IGF1generation test. His younger brother had short stature (−2.9 S.D.) with poor height velocity, eczema and mild speech delay, undetectable IGF1, and a GH peak of 13.9 ug/l.

Heights of his mother, maternal aunt and maternal grandmother are ~155 cm (−1.2 S.D.). Mother and maternal aunt were previously investigated for transient hyperprolactinaemia. The mother had low normal IGF1 (113 ng/ml (69–268)) and a detectable random GH (0.3 ug/l).

An extended three step IGF1-generation test (2 weeks GH S.C. at 0.7, 1.4 and 2.4 mg/m² per day, with wash-out periods) showed little response; index case: step1 IGF1 56 ng/ml, IGFBP3 2.62 mg/l, step 2 IGF1 61 ng/ml, igfbp3 2.87 ng/ml, step 3 IGF1 83 ng/ml (N 57–316), IGFBP3 3.33 (N 1.4–6.1) and brother: step1 and step 2: IGF1<25 ng/ml, step3, IGF1 32 ng/ml, IGFBP3 2.37 mg/l.

Exons and intron–exon boundaries of STAT5B were sequenced. A heterozygous variant c.1433C>T (p.A478V) was found in the index case. The brother and mother but not the father, had the same variant, suggestive of a dominant negative effect or haplo-insufficiency. STAT5B sequencing in maternal aunt and grandmother is underway. The variant occurred in a highly conserved residue and is predicted to alter helix 6, at the end of the DNA-binding domain, and would potentially disrupt function. We hypothesise that this variant has a dominant negative effect on STAT5B function, given the requirement for dimerization of the protein, resulting in moderate short stature with a poor growth rate.