MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is primarily characterized by anomalies of the internal and external genitalia, congenital heart defects, and eye anomalies. 46,XY individuals can have a range of anomalies of the genitalia, from isolated unilateral cryptorchidism to ambiguous genitalia to typical-appearing female genitalia. Although the data is extremely limited, there may be an increased risk of gonadoblastoma in affected 46,XY individuals. 46,XX individuals can have atypical internal genitalia including absent uterus, absent fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina. A number of congenital heart defects have been described, with scimitar syndrome being the most common. Eye issues, present in a vast majority of affected individuals, include high hyperopia and nanophthalmos (an ocular malformation featuring short axial length due to small anterior and posterior segments with thickened choroid and sclera and normal lens volume). Because of the common nature of the eye anomalies, it has been suggested that this condition may be more accurately referred to as "MYRF-related ocular cardiac urogenital syndrome." Other features of the condition include a broad range of developmental delay /intellectual disability (DD/ID), from typical development and cognition to severe DD/ID; pulmonary abnormalities and diaphragmatic issues (congenital diaphragmatic hernia / diaphragmatic eventration); intestinal malrotation; and mild growth and feeding problems. The diagnosis of MYRF-CUGS is established in a proband with suggestive findings and a heterozygous pathogenic variant in MYRF identified by molecular genetic testing. Treatment of manifestations: Standard treatment for differences of sex development (DSD) conditions, including hormone therapy, psychosocial support, gender identity assessment, and surgical intervention (e.g., orchidopexy and/or hypospadias repair); thyroid replacement therapy for hypothyroidism; standard treatment of refractive error, nanophthalmos, DD/ID, congenital heart defects, diaphragmatic defects, pulmonary hypoplasia, intestinal malrotation, splenic anomalies, and renal anomalies. Surveillance: Measurement of growth parameters, assessment of developmental progress and educational needs, and monitoring for respiratory insufficiency at each visit; at least annual ophthalmic evaluations; monitoring for onset and progression of puberty at each visit from around age seven years until puberty is complete; assessment of mood, libido, energy, erectile function, acne, breast tenderness, and presence or progression of gynecomastia at each visit in undervirilized 46,XY adolescents and adults; monitoring for gonadoblastoma in 46,XY individuals with remaining gonads, particularly in those with a history of cryptorchidism; DXA scan in individuals with DSD every three to five years after puberty, or annually if osteopenia is identified. For those on testosterone replacement therapy, measurement of serum testosterone levels at three-month intervals to help establish an optimal dose with subsequent annual measurements; measurement of hematocrit, prostate-specific antigen level, and digital rectal exam three, six, and 12 months after initiation of testosterone therapy and then annually; lipid profile and liver function tests annually. Agents/circumstances to avoid: Hormone replacement therapy in those with hormone-responsive cancers; oral androgens (e.g., methyltestosterone or fluoxymesterone) for long-term therapy due to liver toxicity. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening and treatment measures. MYRF-CUGS is inherited in an autosomal dominant manner. Many affected individuals reported to date have the disorder as the result of a de novo MYRF pathogenic variant. Each child of an individual with MYRF-CUGS has a 50% chance of inheriting the MYRF pathogenic variant. Manifestations within a family are highly variable, and offspring may have significantly more or fewer manifestations than the proband. Once the MYRF pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

46,XY differences/disorders of sex development (DSD) are genetically heterogeneous conditions characterized by atypical development of the reproductive system. MYRF, a gene encoding a transcription factor, has been identified as a potential causative gene for DSD and cardiac urogenital syndrome (CUGS). This study aims to delineate the clinical manifestations of patients with 46,XY DSD and MYRF mutations, encompassing both from our cohort and cases reported in the literature. Patients with 46,XY DSD were recruited from Peking Union Medical College Hospital and identified through a comprehensive review of published literature. Whole-exome sequencing was conducted to elucidate the genetic etiology. Comprehensive clinical data, including physical examination findings, hormonal profiles, and imaging results, were retrospectively gathered from medical records and published sources. Three of our patients with 46,XY DSD were found to harbor heterozygous loss-of-function mutations in the MYRF gene, including the recurrent variant c.789dup and two novel variants c.1915C>T and c.2154del. The patients exhibited underdeveloped testicular tissue, inadequate masculinization, and the persistence of Müllerian ducts. A review of the literature indentified 31 MYRF-linked 46,XY DSD patients and two 46,XX DSD patients. Among these, 11 cases presented with isolated testicular dysgenesis, 20 cases exhibited severe cardiopulmonary issues, and the majority of patients had congenital diaphragmatic hernia. Genetic analysis revealed 26 distinct MYRF variants among these patients, including 10 missense, 8 frameshift, 5 nonsense, and 3 splice site alterations, affecting critical domains of the MYRF gene. Our study broadens the spectrum of MYRF mutations in 46,XY DSD patients and highlighting the gene's indispensable role in gonadal development. However, a clear genotype-phenotype correlation in MYRF-related DSD remain elusive.

Cardiac-Urogenital Syndrome (CUGS) is a recently identified genetic disease characterized by urogenital, diaphragmatic, ophthalmic, and cardiac abnormalities caused by heterozygous pathogenic variants in the Myelin Regulatory Factor (MYRF) gene. The complete spectrum of disease characteristics and prevalence is not yet defined. This report documents the first known cases of anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) in MYRF-associated Cardiac-Urogenital Syndrome (MYRF-CUGS).

The Myelin Regulator Factor (MYRF) is a master regulator governing myelin formation and maintenance in the central nervous system. The conservation of MYRF across metazoans and its broad tissue expression suggest it has functions extending beyond the well-established role in myelination. Loss of MYRF results in developmental lethality in both invertebrates and vertebrates, and MYRF haploinsufficiency in humans causes MYRF-related Cardiac Urogenital Syndrome, underscoring its importance in animal development; however, these mechanisms are largely unexplored. MYRF, an unconventional transcription factor, begins embedded in the membrane and undergoes intramolecular chaperone mediated trimerization, which triggers self-cleavage, allowing its N-terminal segment with an Ig-fold DNA-binding domain to enter the nucleus for transcriptional regulation. Recent research suggests developmental regulation of cleavage, yet the mechanisms remain enigmatic. While some parts of MYRF's structure have been elucidated, others remain obscure, leaving questions about how these motifs are linked to its intricate processing and function.

MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant. Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases. Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants). We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging.