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. Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia and diaphragm eventration, hypoplasia, or agenesis); characteristic facial appearance (coarse facies, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, long philtrum, low-set and anomalous ears, tented vermilion of the upper lip, wide mouth, and a small jaw); short distal phalanges of the fingers and toes (the nails may also be small); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia). Survival beyond the neonatal period is rare in those with severe pulmonary hypoplasia and/or multiple malformations. Data on postnatal growth and psychomotor development remain limited; however, severe developmental delays and intellectual disability are common among individuals with PIGN-related Fryns syndrome. The clinical diagnosis of Fryns syndrome can be established in a proband based on clinical diagnostic criteria; the molecular diagnosis can be established in a proband with suggestive findings and biallelic loss-of-function variants in PIGN identified by molecular genetic testing. Treatment of manifestations: For congenital diaphragmatic hernia, the neonate is immediately intubated to prevent inflation of herniated bowel; surgery and/or supportive measures performed as for the general population. Additional anomalies may require consultations and management by a craniofacial specialist, cardiologist, urologist, nephrologist, gastroenterologist, and ophthalmologist. Standardized treatment with anti-seizure medications by an experienced neurologist. Developmental services as needed, including feeding, motor, adaptive, cognitive, and speech-language therapy as well as family and social work support. Surveillance: Those with successful congenital diaphragmatic hernia repair should be followed in a specialized center with periodic evaluations by a multidisciplinary team (pediatric surgeon, nurse specialist, cardiologist, pulmonologist, nutritionist). Follow up with a craniofacial specialist, cardiologist, urologist, nephrologist, gastroenterologist, and ophthalmologist as needed. Monitor those with seizures as clinically indicated. Assess for new onset of seizures. Monitor developmental progress and educational and family needs. Fryns syndrome is inherited in an autosomal recessive manner. Assuming that both parents are heterozygous for a Fryns syndrome-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If a molecular diagnosis of PIGN-related Fryns syndrome has been established in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diaphragmatic eventration is a rare congenital anomaly characterized by the replacement of diaphragmatic muscle with fibroelastic tissue, leading to diaphragm elevation and functional impairment. While it can occur in isolation, it is sometimes associated with congenital syndromes, including septo-optic dysplasia (SOD). This report presents a case of diaphragmatic eventration in a neonate with Fryns syndrome presenting with cleft palate and SOD, highlighting diagnostic challenges. A late preterm female neonate, born via cesarean at 36 weeks gestation, presented with respiratory distress and required intubation and surfactant therapy. Physical examination revealed features suggestive of Fryns syndrome, including coarse facies, microphthalmia, and cleft palate. Imaging studies, including chest X-ray and thoracic ultrasound, raised suspicion of diaphragmatic hernia, but subsequent MRI confirmed diaphragmatic eventration. Additional cranial imaging identified agenesis of the corpus callosum, colpocephaly, and optic nerve hypoplasia, leading to the diagnosis of SOD. Diaphragmatic eventration, though rare, can present in neonates with other congenital anomalies, making diagnosis challenging. In this case, the overlapping symptoms with cleft palate and SOD complicated the clinical picture. Early imaging, including MRI, is crucial for accurate diagnosis and timely management. Multidisciplinary follow-up is essential for optimal patient care.

Mediator complex subunit 12 (MED12) is required for the assembly of the kinase module of Mediator, a regulatory complex that controls the formation of the RNA polymerase II-mediated preinitiation complex. MED12-related disorders display unique gender-specific genotype-phenotype associations and include X-linked recessive Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, and nonspecific intellectual disability in males predominantly carrying missense variants, and X-linked dominant Hardikar syndrome and nonspecific intellectual disability in females known to predominantly carry de novo nonsense/frameshift and nonsense/missense variants, respectively. MED12 was previously identified as a low-penetrance candidate gene for non-isolated congenital diaphragmatic hernia (CDH+). At the time, however, there was insufficient evidence to confirm this association. In a clinical database search, we identified 18 individuals who were molecularly diagnosed with MED12-related disorders by exome or genome sequencing, including eight missense, four frameshift, two nonsense, and one splice variant. Nine of these variants have not been previously reported. Two females with nonspecific intellectual disability were found to carry a de novo frameshift variant, indicating that potentially truncating variants causing nonspecific intellectual disability are not limited to nonsense variants. Notably, CDH was reported in three out of seven females with Hardikar syndrome or nonspecific intellectual disability but was not reported in males with MED12-related disorders. These results suggest that pathogenic MED12 variants are a cause of CDH+ in females with Hardikar syndrome and nonspecific intellectual disability.

Fryns syndrome is an extremely rare autosomal recessive disorder and is characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal limb hypoplasia, pulmonary hypoplasia, and characteristic-associated anomalies that lead to a high mortality rate. We present a prenatally diagnosed new case of Fryns "anophthalmia-plus" syndrome (FAPS) in a 41-year-old pregnant woman. An ultrasonographic examination at 22 weeks of gestation demonstrated left CDH with mediastinal shift, hypoplastic thorax with presumptive pulmonary hypoplasia, craniofacial anomalies, left anophthalmia, and distal limb hypoplasia. A genetic analysis of the fetal karyotype was held, which was negative for any known chromosomal or single gene abnormalities. After genetic counseling about the risks associated with these ultrasonographic findings, the parents opted for pregnancy termination. Timely identification or suspicion of Fryns syndrome during the early stages of pregnancy could facilitate parental guidance and enable the development of suitable strategies for prenatal treatment and/or perinatal care.

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients.