Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2017) 51 OC5.8 | DOI: 10.1530/endoabs.51.OC5.8

BSPED2017 Oral Communications Oral Communications 5 (9 abstracts)

Central hypothyroidism with extrathyroidal features due to a partial X-chromosome deletion involving the TBL1X locus

Eva van Walree 1 , Soo-Mi Park 2 , Elena Bochukova 3 , Adeline K Nicholas 1 , Greta Lyons 1 , V Krishna Chatterjee 1 & Nadia Schoenmakers 1

1University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK; 2East Anglian Medical Genetics Service, Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 3Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Introduction: Isolated congenital central hypothyroidism (CeCH) is a rare entity associated with mutations in IGSF1, TSHB, TRHR, or the coding region of TBL1X. We describe a female with CeCH and extrathyroidal features due to a partial X-chromosomal deletion involving TBL1X and other genes. Further studies showed markedly reduced TBL1X expression in patient-derived leukocytes and enabled linkage of particular clinical phenotypes to specific genes.

Case: A 29 year old female was diagnosed with isolated CeCH at age 13 years with fT4 8.3 pmol/l (reference range, RR 9–20), TSH 2.5 mU/l (RR 0.4–4) and normal TSH response to TRH (0 mins: TSH 0.6 mU/l; 20 mins: 10 mU/l). In addition, she exhibited mesomelic short stature (height S.D. −4.5S.D.) a wide carrying angle, Madelung deformity and relative macrocephaly (OFC +4.5S.D.). Significant developmental delay and a diagnosis of autism had necessitated special schooling.

Results: Affymetrix SNP 6.0 array delineated a de novo heterozygous 9.5Mb deletion of the short arm of the X chromosome from band p22.2, including 16 genes in the pseudoautosomal region (PAR1), which escapes X chromosome inactivation: PLCXD1, GTPBP6, PPP2R3B, SHOX, CRLF2, CSF2RA, IL3RA, SLC25A6, ASMTL, P2RY8, AKAP17A, ASMT, DHRSX, ZBED1, CD99, XG. The following non-PAR genes were encompassed by our patient’s deletion: GYG2, ARSD, ARSE, ARSH, ARSF, MXRA5, PRKX, NLGN4X, VCX3A, PUDP, STS, VCX, PNPLA4, VCX2, VCX3B, ANOS1, FAM9A, FAM9B and the proximal exons of TBL1X. However, X-inactivation was almost completely skewed (95:5) and significantly decreased TBL1X mRNA levels in patient-derived leukocytes supported preferential inactivation of the normal X chromosome.

Conclusions: This is the first case of CeCH with partial TBL1X deletion and potentially minimal TBL1X expression. Haploinsufficiency of SHOX in the PAR region (Leri-Weill dyschondrosteosis) and deficiency of NLGN4X in the non-PAR region (autism, intellectual disability) explain extrathyroidal phenotypes.

Volume 51

45th Meeting of the British Society for Paediatric Endocrinology and Diabetes

British Society for Paediatric Endocrinology and Diabetes 

Browse other volumes

Article tools

My recent searches

No recent searches.