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.

MED12-related disorders are a rare group of intellectual disability syndromes with a broad range of phenotypic characteristics. The phenotypic spectrum of MED12-related disorders currently includes X-Linked Ohdo Syndrome, Lujan-Fryns Syndrome (LS), and FG syndrome type 1 (FG), also known as Opitz-Kaveggia Syndrome. The MED12 gene encodes the largest component of the mediator complex of RNA polymerase II, which is critical for recruiting activators and repressors to regulate the transcription of genes critical to growth, development, and differentiation. We performed a systematic literature review of previously published cases to highlight the key ocular features in individuals with MED12-related disorders. In addition, we present a new case of a female patient with a de novo pathogenic c. 3866A>G, p.Q1289R variant. Ocular manifestations are not uncommon in MED12-related disorders, but have not been characterized in literature reports. Commonly reoccurring reported eye and ocular adnexa features within the spectrum include ptosis, downslanting palpebral fissures, and hypertelorism. Other less common findings include strabismus, astigmatism, and optic nerve hypoplasia. Our patient presented with developmental delay, mild hypotonia and dysmorphic features including frontal bossing, high arched palate, and syndactyly of the 2nd and 3rd toes bilaterally. Ocular manifestations identified in this patient included intermittent esotropia, hyperopic astigmatism, epicanthal folds and ptosis bilaterally. MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders. The diagnosis of an MED12-related disorder is established in a male by identification of a hemizygous MED12 pathogenic variant on molecular genetic testing. The diagnosis of an MED12-related disorder is established in a female with suggestive findings and a heterozygous pathogenic variant in MED12 identified by molecular genetic testing. Treatment of manifestations: Early individualized education; physical therapy, occupational therapy, and speech therapy for developmental delays; individualized management of behavior problems; routine management of seizures, strabismus and other ocular anomalies, imperforate anus, chronic constipation, joint contractures, genitourinary anomalies, congenital heart defects, hearing loss, palate anomalies, and dental anomalies; social work support. Treatment of aneurysms, intestinal malrotation, and liver disease in females with HS as recommended by the appropriate specialist. Surveillance: At each visit, assess growth, development, behavior concerns, neurologic issues, gastrointestinal functioning, and musculoskeletal manifestations. Annual eye examination with attention to retinal changes for individuals with HS. Annual audiology evaluation. Dental evaluation every six months, particularly for individuals with XLOS and LS. Females with HS should have an annual echocardiogram, carotid ultrasound, gastroenterology evaluation with liver function testing and consideration of clotting studies, serum bile acids, and liver ultrasound based on recommendations of a gastroenterologist; and MRA of the head and neck for aneurysms every two years. MED12-related disorders are inherited in an X-linked manner. If the mother of a proband is heterozygous for a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit a pathogenic variant associated with FGS1, LS, or XLOS will typically be unaffected while females who inherit a pathogenic variant associated with HS will typically be affected. Females who inherit a MED12 pathogenic variant associated with NSID will be at an increased risk of developing variable clinical features. Males with a MED12-related disorder are not known to reproduce. Once the MED12 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing for MED12-related disorders are possible.