A novel mutation in SOX3 polyalanine tract: a case of kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3

Introduction Both duplications encompassing SOX3 and loss-of function mutations in SOX3 have been reported in a minor portion of X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without mental retardation. Patients and methods We report a Japanese male patient with molecularly confirmed Kabuki syndrome who was found to have CPHD. We analyzed all coding exons and flanking introns of currently known nine genes responsible for CPHD by PCR-based sequencing. Results In this CPHD patient, we identified a novel hemizygous 21-base pair deletion, resulting in the loss of 7 alanine residues from polyalanine (PA) tracts of SOX3. The clinically and endocrinologically normal mother of the patient carried the same deletion in a heterozygous manner. In vitro experiments showed that the del 7A SOX3 had increased transactivation of the HESX1 promoter. Conclusion Our study provides additional evidence that deletion in PA tracts of SOX3 is associated with hypopituitarism. Female carriers of SOX3 PA tract deletions will show a broad phenotypic spectrum, ranging from clinically normal to CPHD.