Clinical characteristics: 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. 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.

Diagnosis/testing: The diagnosis of MYRF-CUGS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in MYRF identified by molecular genetic testing.

Management: 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; 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.

Genetic counseling: 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.