Endocrine Abstracts

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.