ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2017) 51 OC5.6 | DOI: 10.1530/endoabs.51.OC5.6

Phenotypic spectrum and response to recombinant human IGF1(rhIGF1) therapy in patients with homozygous intronic pseudoexon (6Ψ)GH receptor mutations

Sumana Chatterjee1, Stephen Rose2, Talat Mushtaq3, Peter Clayton4, Svetlana Ten5, Amrit Bhangoo6, Uma Kumbattae7, Renuka Dias8, Lucy Shapiro1, Louise Metherell1, Martin Savage1 & Helen Storr1

1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University London, London, UK; 2Birmingham Heartland Hospital, Birmingham, UK; 3Leeds Teaching Hospital, Leeds, UK; 4Royal Manchester Children’s Hospital, Manchester, UK; 5Maimonides Paediatric Speciality Centre, Brooklyn, New York, USA; 6CHOC Children’s Clinic, Orange, California, USA; 7Royal Stoke Hospital, Stoke, UK; 8Birmingham Children’s Hospital, Birmingham, UK.

Objectives: Patients with homozygous 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.