BSPED2012 Oral Communications Oral Communications 2 (10 abstracts)
Genetic screening in a large cohort of patients with congenital hypopituitarism; current knowledge and future directions
Kyriaki S Alatzoglou 1 , James P G Turton 2 , Daniel Kelberman 3 , Marc J McCabe 1 , Louise C Gregory 1 , Emma A Webb 1 , David E G McNay 1 , Kathryn S Woods 1 , Ameeta Mehta 1 & Mehul T Dattani 1
1Developmental Endocrinology Research Group, UCL Institute of Child Health, London, UK; 2Division of Molecular Neuro-Endocrinology, National Institute for Medical Research, London, UK; 3Ulverscroft Vision Research Group, Developmental Biology Unit, UCL Institute of Child Health, London, UK.
Background and aims: Congenital hypopituitarism (CH) encompasses a spectrum of phenotypes. Known genetic factors account for variable percentage of cases depending on the cohort screened. We analysed the results of genetic screening in a large cohort of patients with CH with the following aims: i) to clarify the genetic aetiology of CH ii) identify any phenotype genotype correlations and iii) propose a screening strategy.
Patients and methods: Over 15 years we screened 2032 patients with CH and 334 unaffected family members referred from national and international centres. Our cohort included 540 patients with combined pituitary hormone deficiencies (CPHD), 522 with variable hypopituitarism, 540 with septo-optic dysplasia (SOD) and its variants (26%), 368 with isolated GH deficiency (IGHD) (18%) and 62 with midline clefts including holoprosencephaly (3%). In 17.4% (n=362) there was a positive family history. According to phenotype, patients were screened for mutations in known genetic factors including HESX1, SOX2, SOX3, OTX2, LHX3/LHX4, SIX3, SHH, GLI2, CHD7, FGF8/FGFR1, KAL-1, PROK2/PROKR2, PROP1, POU1F1, GH1, GHRHR.
Results: In patients with SOD HESX1 mutations were identified in 1.3% (7/540), whilst changes in SOX3 dosage were rare (n=6). Mutations in SOX2 (n=13) and OTX2 (n=4) were also rare in patients with SOD, but accounted for 28% and 4.5% respectively of patients with severe eye phenotypes (13/45 and 4/45). PROKR2 variations were the commonest (2%), whilst variations in FGF8 and KAL-1 were rare (<1%). In patients with CPHD 3.3% (n=18) had mutations in PROP1 whilst POU1F1 mutations were identified in 2.2% (n=12). Genetic changes (GH1, GHRHR) were identified in 34 patients (9%) with IGHD. Six patients with complex phenotypes had variations in genes including SHH, GLI2, LHX3 or CHD7.
Conclusion: With the current screening methods, known genetic factors account for 7% of cases of CH (n=115); this percentage is higher in familial cases or if specific phenotypes are taken into account. Next generation sequencing in combination with careful phenotyping will be critical in the identification of other factors implicated in its aetiology.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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