ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This case series describes the effect of recombinant human IGF-1 (rhIGF-1) administration on growth of three siblings with STAT5B homozygous recessive mutations.

The peripheral effects of GH are primarily mediated by IGF-I through the activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling. Patients carrying STAT5B mutations have severe postnatal growth failure and IGF-I deficiency associated with immunodeficiency and increased risk of autoimmune and pulmonary disease (1). GH resistance makes rhGH treatment ineffective in stimulating growth (2).

The three siblings harboring a homozygous inactivating mutation in STA5B were evaluated for severe short stature (height at baseline: -6.5; -4.9, -5.3 SDS). All had reduced IGF-I (< -2.5 SDS) and IGFBP-3 (< -3 SDS) levels and received rhIGF-1 treatment under FDA guidelines for severe primary IGF-I deficiency, at an early age (4.9, 2.8, and 2.1 years). The duration of follow-up was up to 6 years. The starting dose was 40 μg/kg/dose twice daily subcutaneously and progressively increased up to 110-120 μg/kg/dose twice daily and then was modulated according to side effects. Height velocity (cm/year) and height gain (SDS) were the main outcome measures. Patient 1 had baseline height velocity of 3 cm/year, thereafter 5.7 cm/year, 6 cm/year, 5.2 cm/year and 4.7 cm/year in the first, second, third and sixth year of treatment, respectively. The overall height gain was +2.21 SDS after 6 years of treatment (height from -6.87 to -4,66 SDS). Patient 2 had pretreatment height velocity of 3 cm/year, and 7.1 cm/year, 4.9 cm/year, 4.8 cm/year and 3.8 cm/year in the first, second, third and sixth year of treatment, respectively. The overall height gain was +0.93 SDS SDS after 6 years of treatment (height from -5.87 to -4.94 SDS). Patient 3 had pretreatment height velocity of 5.2 cm/year, and 7.4 cm/year, 5.5 cm/year and 4.3 cm/year in the first, second and fifth year of treatment, respectively. The overall height change was – 0.62 SDS after 5 years of treatment (height from -5.86 to -6.48 SDS). No major side effects were observed during treatment in all patients.

Available data on the efficacy of rhIGF-I for increasing growth in patients with STAT5B inactivating mutations are scant and inconclusive (3). These results show that rhIGF-I therapy may be effective in stimulating growth and partial catch-up growth, especially in the first year of treatment and may represent a therapeutic option to avoid worsening of growth failure in subjects with inactivating STAT5B mutations.

References: 1. Hwa V. STAT5B deficiency: Impacts on human growth and immunity. Growth Horm IGF Res. 2016:28:16-20.2. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003 18;349(12):1139-47.3. Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz D, Rockstroh D, Colombo R, Sanchez MA, Vokurkova D, Kowalczyk J, Metherell L, Rosenfeld R, Pfäffle R, Dattani M, Dauber A, Hwa V. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun. 2018 29;9(1):2105.