ESPE2022 Poster Category 2 GH and IGFs (14 abstracts)
Growpati Study: Clinical and genetic characterization of a cohort of patients with short stature due to severe primary IGF1 deficiency
Athanasia Stoupa 1,2 , Isabelle Flechtner 1 , Magali Viaud 1,3 , Graziella Pinto 1 , Dinane Samara-Boustani 1,3 , Laura Gonzalez-Briceno 1 , Caroline Thalassinos 1 , Serge Amselem 4 , Marie Legendre 4 , Irene Netchine 5 , Frederic Brioude 5 & Michel Polak 1,2,3,6
1Pediatric Endocrinology, Diabetology and Gynecology Department, Necker Children’s University Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France; 2Institut Imagine Affiliate, INSERM U1163 and U1016, Institut Cochin, Paris, France; 3Centre de Référence des Maladies Endocriniennes Rares de la Croissance et de Développement, Paris, France; 4Sorbonne Université, INSERM UMR_S933, Trousseau Hospital, Genetics Department, Paris, France; 5Sorbonne Université, INSERM UMR_S938 Centre de Recherche Saint-Antoine, Trousseau Hospital, Paris, France; 6Université de Paris Cité, Paris, France
Background: Severe primary insulin-growth factor-1 (IGF1) deficiency (SPIGF1D) is a rare cause of short stature. Diagnosis is based on low basal IGF1 concentration, short stature, normal or elevated growth hormone concentrations and absence of any secondary causes of growth failure. Thanks to advances in next-generation sequencing (NGS) technologies, genetic etiology of SPIGF1D is expanding.
Objectives: • Identify the molecular causes of SPIGF1D in a large cohort of patients referred with growth delay
• Describe the growth pattern and pubertal status
Methods: Patients have been recruited during 2004-2009 (Historical Study Cohort, HSC, n=30) and 2016- present (New Study Cohort, NSC, n=25). Genetic analyses used array comparative genomic hybridization, candidate gene approach or NGS gene panel, including genes involved in GH-IGF1 axis. Data were collected concerning growth, puberty, and final height (FH) or near adult-FH, if available.
Results: Fifty-five patients (29 males/26 females) have participated, with mean current age in the HSC and NSC of 20.2 and 11.8 years respectively. Nine patients were lost during follow-up and 2 patients refused genetic tests, leading to 44 patients eligible for genetic analyses. Among 21 patients screened so far, we report a diagnostic rate of 47.6 % with a proven molecular diagnosis in 10/21 patients. The remaining 11 patients have variants of unknown significance or non-pathogenic variants (ACMG criteria), in GH-IGF1 axis genes. Constitutional bone disease has been detected in five patients. Molecular diagnosis concerned hypochondroplasia (n=1), Laron syndrome (n=1), heterozygous GHR mutations (n=2), Noonan syndrome (n=3), Silver-Russell syndrome (n=2), heterozygous ACAN mutation (n=1). At inclusion all patients were prepubertal (T1). Mean (SD) age at last registration of Tanner stage 1 (T1) and first registration of T5 was 12.1 (0.9) and 16.7 (1.1) years, respectively, in boys and 10.3 (1.5) and 14.8 (1.5) years, respectively, in girls. Mean growth puberty spurt for patients who have achieved their puberty with available data (8 males, 6 females) was 24 cm (4.1) in boys and 18.2 cm (5.9) in girls. Among patients with available data in FH, mean adult FH was -2.2 SD (0.5) for 7 boys and -2 SD (0.8) for 6 girls.
Conclusions: Genetic analysis reflects the heterogeneous spectrum of the disease. Detailed clinical and genetic evaluation are necessary to provide a diagnosis in most cases and orient clinical management. Long term follow-up of patients will provide us more insights in the understanding of SPIGF1D.
This work was in part supported by a grant from IPSEN Pharma
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