BSPED2018 Oral Communications Oral Communications 5 (9 abstracts)
Patients with short stature and GH/IGF-1 insensitivity harbour copy number variants causing a Silver-Russell-like phenotype
Emily Cottrell 1 , Sumana Chatterjee 1 , Gudrun Moore 2 , Miho Ishida 2 , James Greening 3 , Neil Wright 4 , Artur Bossowski 5 , Asma Deeb 6 , Iman Al Basiri 7 , Stephen Rose 8 , Avril Mason 9 , JooWook Ahn 10 , Susan Bint 11 , Martin O Savage 1 , Louise A Metherell 1 & Helen L Storr 1
1Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University London, London, UK; 2Great Ormond Street Institute of Child Health, University College London, London, UK; 3University Hospitals of Leicester NHS Trust, Leicester, UK; 4Sheffield Children’s Hospital, Sheffield, UK; 5Medical University of Bialystok, Bialystok, Poland; 6Al Mafraq Hospital, Abu Dhabi, UAE; 7Mubarak Al-kabeer Hospital, Jabriya, Kuwait; 8Birmingham Heartlands Hospital, Birmingham, UK; 9Royal Hospital for Children, Glasgow, UK; 10Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 11Viapath, Guy’s Hospital, London, UK.
Introduction: Our Centre receives international referrals for genetic analysis of children with short stature (SS) and features of GH/IGF-1 insensitivity. Copy number variation (CNV) hasn’t previously been investigated in GH/IGF-1 insensitivity. We hypothesised CNVs contribute to the phenotype in our undiagnosed cohort.
Experimental design/methodology: CGH was performed with oligonucleotide array using ~60,000 probes in 60 patients (38 M, mean age 7.0 yrs (range 1.1–16.5), mean height SDS −3.87 (range −1.58 to −7.44)).
Results: We identified CNVs in 10/60 (17%) patients (8M), mean height SDS −3.70 (range −1.6 to −5.7). 7/10 and 3/10 patients had likely pathogenic CNVs and CNVs of uncertain significance, respectively. Patients 1–7 have features of Silver-Russell Syndrome (SRS), scoring 2–3/6 on the Netchine-Harbison Clinical Scoring System. Patients 1–6 have CNVs previously associated with SRS phenotypes. Causative genes within many CNV regions below have yet to be established.
| Patient | Age (years) | Height SDS | Clinical details | CNV |
| 1 | 12.8 | −3.6 | Small triangular face, high arched palate, feeding difficulties | 1q21 deletion |
| 2 | 10.1 | −1.6 | Feeding difficulties, dyslexia | 1q21 deletion |
| 3 | 9.1 | −3.7 | Clinodactly, feeding difficulties | 1q21 deletion |
| 4 | 11.3 | −5.1 | Triangular face, high pitched voice | 12q14 deletion |
| 5 | 1.9 | −5.7 | Low set ears, triangular face, SGA | 7q21 deletion, 7q31 deletion |
| 6 | 14.4 | −2.7 | SGA | 7q21 duplication, Xp22 duplication |
| 7 | 2.8 | −4.9 | Triangular face, frontal bossing, feeding difficulties | 15q11 deletion |
| 8 | 17.0 | −4.0 | Learning difficulties, delayed puberty | 5q12 deletion |
| 9 | 2.7 | −2.0 | Adrenal insufficiency, SGA | 7q36 duplication |
| 10 | 2.5 | −3.6 | Short limbs | 3p22 deletion, 15q13 duplication |
Conclusion: Our cohort was enriched for rare CNVs. Interestingly, 7/10 patients with CNVs had features of SRS, a heterogeneous syndrome with no genetic cause identified in 40% patients. Consistent with previous reports, the SRS phenotype in our CNV patients appears milder than classic 11p15LOM/upd(7)mat cases and only 2/7 with SRS features were born SGA. Our study is the first to report CNVs in GH/IGF-1 insensitivity patients and contributes to the emerging SRS-like phenotype. Our findings emphasise the importance of CNV testing in SS patients, especially those with SRS features.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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