Differentiating the Clinical and Variant Spectrum of Hardikar Syndrome From Other MED12 -Related Developmental...

The rare X-linked female-restricted Hardikar syndrome (HDKR, OMIM # 301068) is characterized by multiple congenital anomalies including orofacial clefts, gastrointestinal, genitourinary, and cardiac anomalies, but cognitive and neurobehavioral development is rarely impaired. HDKR is caused by heterozygous frameshift, splice or nonsense variants in the MED12 gene. Besides HDKR, MED12 pathogenic variants cause a broad spectrum of developmental disorders, collectively referred to as MED12-related disorders, including Opitz-Kaveggia syndrome or FG syndrome type 1 (OKS, OMIM #305450), Lujan-Fryns syndrome (MRXSLF, OMIM #309520), X-linked Ohdo syndrome (OHDOX, OMIM #300895) and isolated intellectual disability. Here we report four individuals with HDKR, including the first of maternally inherited HDKR, and we review molecular and clinical data from 33 individuals with HDKR and 215 individuals with other MED12-related disorders retrieved through a literature and public database search. We highlight sella turcica cysts as a new Hardikar syndrome-related feature, and we introduce clinical guidelines for the diagnosis and management of individuals with HDKR.