Buasri K.Pakhathirathien P.Sananmuang T.Dumrongwongsiri S.Thatrimontrichai A.Maneenil G.Khongkraparn A.Ngiwsara L.Sawangareetrakul P.Svasti J.Slavotinek A.Wattanasirichaigoon D.Mahidol University2025-08-222025-08-222025-01-01Journal of Medical Genetics (2025)00222593https://repository.li.mahidol.ac.th/handle/123456789/111732Background: Duplication of the pituitary gland (DPG)-plus syndrome is an extremely rare developmental malformation of unknown aetiology. Methods: Two unreported patients of DPG-plus syndrome are described. Underlying genetic defects were explored, including chromosomal microarray (CMA), whole exome sequencing (WES) and mRNA analysis. A literature review was presented. Results: Patient 1 had DPG, palatal cleft, bifid tongue, intraoral teratoma, lingual hamartoma and duplicated basilar artery and odontoid process. Patient 2 had DPG, epignathus teratoma, a nasal mass, choanal atresia, cleft palate, bifid tongue, abnormal basilar artery and fused upper cervical spine. CMA yielded normal results. WES of patient 1 disclosed a novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids. WES of patient 2 revealed no candidate variants. A literature review of 51 cases showed mostly reported in childhood and female sex (80%). The leading anomalies identified included DPG (100%), cleft palate (68.6%), anomalous cervical spine (56.9%), hypothalamic mass/enlargement (58.8%), intraoral teratoma (58.8%), basilar arterial abnormalities (43.1%) and bifid/trifid tongue (23.5%). Non-craniofacial anomalies were found in <10% of cases. Late complications included precocious puberty, all in female patients, and hypogonadotropic hypogonadism in a few patients. Conclusions: Two new cases of DPG-plus syndrome were reported, with rare findings of epignathus and choanal atresia. We propose that DPG-plus syndrome may result from a double hit in one of the genes involved in SHH signalling, arising from a germline pathogenic variant with mosaicism for a somatic pathogenic variant or digenic/oligogenic inheritance of the SHH signalling-related genes.Biochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1136/jmg-2024-1104172-s2.0-10501306065714686244