Objectives: Patients with homozygous 6Ψ mutations have GH insensitivity (GHI). We previously described spectrum of clinical and biochemical phenotypes of 11 6Ψ patients (David et al. JCEM 2007;92:655) and now report 9 additional patients. Response to rhIGF-I therapy has not previously been assessed.
Methods: 20 6Ψ patients (12 M, 11 families, mean age 4.0±2.2 year) were diagnosed genetically in our centre. Continuous parametric variables were compared using student t-test or ANOVA with Bonferroni correction for multiple comparisons.
Results: 10/20(50%) patients had facial features of GHI, 19/20(95%) from consanguineous families and 18/20(90%) of Pakistani origin. At diagnosis, mean height SDS −4.1±0.95 (−5.9 to −1.7), mean IGF-1SDS −2.8±1.4 (−6.8 to −1.0), IGFBP-3 SDS −3.0±2.1(−8.9 to −0.6), mean basal and peak GH levels 11.9 and 32.9 mcg/l respectively. 12/20 had IGF-1 generation test (IGFGT), 11/12(92%) showed no response (IGF-1 rise <15 ng/ml), 1 responded (132 to 255 ng/ml). 17/20 (85%; 11M) received rhIGF-I. Complete data was available for 15/17. Mean age at rhIGF-I initiation was 9.0±2.7 years (3 pubertal at rhIGF-1 initiation and received GnRH analogue concomitantly). Mean duration of rhIGF-1 was 5.3±2.5 years. Mean baseline HV 4.6±1.1 cm/yr increased to 7.4±1.8 cm/yr (P=0.001) during Year1 of treatment. There was no correlation between year1 HV and sex, age at rhIGF-1 initiation, baseline height SDS or baseline IGF-1SDS. Mean cumulative change in height SDS at end of treatment was 1.4±0.8 (0.4 to 2.0). 11/15 patients (10 naive to rhIGF-1) completed linear growth; mean final height (FH) was −4.0±1.5 SDS (−5.7 to −1.8). In 4/15 (all naïve to rhIGF-1), height SDS at latest assessment (LH) was −2.9±0.3 SDS(−3.2 to −2.6) compared to pre-treatment −4.1±0.5 SDS (−4.6 to −3.6) (P=0.02). In 3 untreated patients, FH was −3.5 and −5.0 and LH was −4.4 SDS. Difference between target height (TH) SDS and FH/LH SDS was less than that of TH SDS and pretreatment height SDS (2.3±0.3 vs 3.2±0.8; P=0.001).
Conclusion: The homozygous pseudoexon GHR mutation caused both classical and mild GHI phenotypes, even within the same family. The majority of patients did not increase IGF-1 during an IGFGT. RhIGF-1 treatment improved height outcomes and responses are comparable to those seen in patients with other homozygous GHR mutations.
22 - 24 Nov 2017
British Society for Paediatric Endocrinology and Diabetes