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. 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.

Diagnosis/testing.

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.

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; 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.

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.

Suggestive Findings

MYRF-CUGS should be suspected in individuals with any of the following clinical and imaging findings and family history.

Clinical findings

• Ambiguous genitalia, micropenis, hypospadias, and/or cryptorchidism in 46,XY individuals or müllerian anomalies in 46,XX individuals
• Eye anomalies including high hyperopia and nanophthalmos
• Congenital heart defects including hypoplastic left heart or scimitar syndrome (partial or total anomalous pulmonary venous return of the right lung to the inferior vena cava with dextroposition of the heart, right lung and pulmonary artery hypoplasia, and anomalous systemic blood supply to the lung)
• Congenital diaphragmatic hernia
• Pulmonary hypoplasia, even in the absence of a diaphragmatic abnormality

Imaging findings

• Hypoplasia or aplasia of ovaries and/or müllerian structures in 46,XX individuals
• Presence of müllerian structures in 46,XY individuals
• Intestinal malrotation

Family history. Most probands with MYRF-CUGS reported to date have a de novo pathogenic variant, and thus represent a simplex case (i.e., a single occurrence in a family). Occasionally, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). The presentation can be extremely variable and parents may be very mildly affected.

Establishing the Diagnosis

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 (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous MYRF variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MYRF-CUGS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, more than 60 individuals with MYRF-related cardiac urogenital syndrome (MYRF-CUGS) (more than 20 unpublished, and at least 47 published plus an extremely large multiplex family) have been identified with a pathogenic variant in MYRF [Chitayat et al 2018; Pinz et al 2018; Qi et al 2018; Garnai et al 2019; Guo et al 2019; Hamanaka et al 2019; Rossetti et al 2019; Siggs et al 2019; Xiao et al 2019; Globa et al 2022; Gupta et al 2022; Favier et al 2024; Zhang et al 2025; T Pyle, unpublished data]. The following description of the phenotypic features associated with MYRF-CUGS is based on these reports.

Variations in genitalia may be the only finding in an individual with MYRF-CUGS and manifestations may be subtle.

• 46,XY individuals. The majority of reported individuals have a 46,XY karyotype. The genitourinary anomalies are very broad and range from isolated unilateral cryptorchidism to typical-appearing female genitalia. Common physical findings may include micropenis, hypospadias, chordee, small testes, bifid scrotum, and/or persistent urachus. Müllerian structures including uterus and vagina (typically hypoplastic) may be present. Consistent with the full spectrum of nonbinary (ambiguous) genitalia, some individuals have varying degrees of testicular dysgenesis including Sertoli and/or Leydig cell hyperplasia, paucity of germ cells, tubular atrophy, and decreased fertility / infertility [Hamanaka et al 2019, Globa et al 2022, Gupta et al 2022]. At least one 46,XY affected individual had a premalignant germ cell neoplasia at the time of orchiopexy prior to age two years [T Pyle, personal observation].
• XX individuals. Only six affected individuals have been reported with a 46,XX chromosomal complement. Of these, three had atypical internal genitalia, including absent uterus, fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina.

Ophthalmic involvement. Of 19 individuals with well described and deeply evaluated eye morphology, 16 had high hyperopia (farsightedness). Some were evaluated because of clinical concerns, and some were seen because of their MYRF-CUGS diagnosis. Some were ascertained from cohorts of individuals with nanopthalmos, so this particular finding may be an overestimate. These 19 individuals do not include the family reported by Garnai et al [2019], nor do they include an additional large multiplex family that had ocular phenotyping only (see Genotype-Phenotype Correlations). Overall, nanopthalmos / high hyperopia appears to be one of the most common features of MYRF-CUGS.

Nanophthalmos is associated with secondary complications including amblyopia, esotropia, angle closure glaucoma, and spontaneous and postsurgical choroidal effusions [Carricondo et al 2018]. Peripheral chorioretinal scarring and mild retinal pigment epithelial mottling have been reported in some affected individuals and may represent a primary finding in individuals with MYRF-CUGS as opposed to sequela of nanophthalmos [Garnai et al 2019, Hagedorn et al 2020].

Other reported ophthalmic abnormalities include amblyopia, strabismus, and foveal hypoplasia [Favier et al 2024].

Developmental delay (DD) and intellectual disability (ID). There is a broad range of DD/ID, from typical development and cognition to severe developmental delay and intellectual disability. Severity and rates of intellectual disability or delayed developmental milestones may be affected by cardiopulmonary defects. Of the 15 individuals who had DD/ID:

• Three had speech delay;
• Eight had global delays or severe delays (7 of the 8 had cardiopulmonary issues that required extensive hospitalizations and surgeries);
• Of individuals without cardiopulmonary malformations, only one was reported with a developmental disorder, in this case autism spectrum disorder.

Cardiovascular anomalies. The spectrum of cardiovascular anomalies is broad, ranging from isolated dextrocardia to hypoplastic left heart syndrome. Scimitar syndrome (see Suggestive Findings) is also commonly reported. Other congenital heart defects that have been reported include the following:

• Atrial septal defect
• Ventriculoseptal defect
• Aortic arch hypoplasia
• Coarctation of the aorta
• Bicuspid aortic valve
• Aortic atresia
• Mitral valve atresia
• Tetralogy of Fallot

Pulmonary abnormalities and diaphragmatic issues. Of deeply phenotyped individuals, approximately half have either congenital diaphragmatic hernia (CDH) or pulmonary hypoplasia without CDH. CDH can be left-sided or right-sided, with left-sided predominance. Diaphragmatic eventration has also been reported.

Gastrointestinal issues. Five individuals have been reported with intestinal malrotation [Chitayat et al 2018; Favier et al 2024; J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].

• There are further reports of affected individuals having gastroesophageal reflux disease, poor feeding, and gastrostomy tube dependence, although some of these issues may be secondary to cardiopulmonary disease.
• Two individuals had liver lobation abnormalities and three had hepatomegaly.
• There has also been one report of a 46,XY individual with hepatotesticular fusion and splenotesticular fusion [Chitayat et al 2018] and one individual with appendiculo-umbilical fistula [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].

Splenic anomalies. Six individuals had spleen abnormalities including an accessory spleen [Qi et al 2018], cleft spleen [Pinz et al 2018], polysplenia, and hypoplastic spleen [Favier et al 2024].

Renal. Five individuals with renal anomalies have been reported. Anomalies include horseshoe kidney with associated hydronephrosis [Rossetti et al 2019], pyelic dilatation, hyperechogenic kidneys, ectopic kidney, and hypoplastic kidney [Favier et al 2024].

Growth/feeding

• One individual is reported to have short stature [Qi et al 2018]; intrauterine growth restriction was seen in another individual [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• Microcephaly has been observed in three affected individuals [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
• Poor feeding, which may be secondary to neurologic issues and the effects of severe cardiopulmonary disease, has also been reported.

Dysmorphology. The majority of reported individuals who were evaluated have no recognizable dysmorphic features. Widely spaced eyes have been observed in three affected individuals [Chitayat et al 2018; J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].

Other rarely reported features. The following have been reported in a few known affected individuals to date. It is unclear if these findings are rare features of MYRF-CUGS or rare co-occurrences of two unrelated findings.

• Neurologic
  • Hypotonia has been reported in four affected individuals.
  • One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.
  • One individual who underwent brain MRI had a posterior fossa cyst [Hagedorn et al 2020].
  • Two affected individuals had delayed myelination patterns noted on brain MRI.
• Endocrinologic
  • One affected individual had thymic fibrosis and involution [Pinz et al 2018].
  • One individual had hypothyroidism [J Kaplan, B Stewart, L Prasov, T Pyle, personal observations].
  • One individual had a growth hormone-secreting pituitary tumor [Zhang et al 2025].

Genotype-Phenotype Correlations

Individuals with truncating/altering C-terminal pathogenic variants (splicing or single-base deletion) that are predicted to alter or truncate the C terminus of the myelin regulatory factor (MYRF) protein tend to have high hyperopia and nanophthalmos as the predominant feature [Garnai et al 2019, Guo et al 2019, Siggs et al 2019]. Some of the individuals reported with "isolated" eye findings in large families of affected individuals were not sufficiently evaluated for features of MYRF-CUGS. Additionally, some of these individuals have related family members with the same pathogenic MYRF variant who have other system manifestations consistent with the MYRF-CUGS spectrum.

• In one large kindred in which nanophthalmos segregated with a pathogenic c.3376-1G>A splice site variant in MYRF, several of the affected individuals had dextrocardia and one had pulmonary hypoplasia [Garnai et al 2019].
• In another family of five affected individuals, the proband had nanophthalmos only and the father had nanophthalmos and unilateral cryptorchidism; the other three individuals had more classic MYRF-CUGS findings [Gupta et al 2022].

Currently it is felt that these individuals can have other features of MYRF-CUGS, albeit typically with reduced penetrance and severity, and that this is part of the spectrum of MYRF-CUGS.

Nomenclature

Because nanopthalmos / high hyperopia appears to be one of the most common features in MYRF-CUGS, the authors suggest that the disorder be referred to as MYRF-related ocular cardiac urogenital syndrome or MYRF-OCUGS.

Prevalence

The prevalence of MYRF-CUGS is unknown; it has been identified in more than 60 individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MYRF-CUGS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in cardiology, endocrinology, genetics, gastroenterology, gynecology, ophthalmology, pulmonology, psychology, and urology (see Table 5).

Surveillance

Agents/Circumstances to Avoid

Contraindications to hormone replacement therapy include hormone-responsive cancers.

Oral androgens such as methyltestosterone and fluoxymesterone should not be given in hormone replacement therapy (especially for long-term therapy) because of 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. Intrafamilial variability of affected individuals is high, and features may be previously underappreciated in a family.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals with MYRF-CUGS reported to date have the disorder as the result of a de novo MYRF pathogenic variant.
• In some families, individuals with MYRF-CUGS have the disorder as the result of a pathogenic variant inherited from a heterozygous parent [Gupta et al 2022]. Of note, the presentation of MYRF-CUGS can be extremely variable within families and a heterozygous parent may be asymptomatic or very mildly affected.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, determine their need for screening and treatment (see Management), and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a MYRF pathogenic variant may be asymptomatic or mildly/minimally affected [Garnai et al 2019].

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The manifestations of MYRF-CUGS within a family are highly variable and sibs who inherit a MYRF pathogenic variant may have significantly more or fewer manifestations than the proband. Molecular genetic testing is recommended for the sibs of the proband to determine their need for screening and treatment (see Management).
• If the MYRF pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [Garnai et al 2019].
• If the parents have not been tested for the MYRF pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MYRF-CUGS because of the possibility of variable expressivity in a heterozygous parent or parental gonadal mosaicism.

Offspring of a proband

• 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.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MYRF pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the MYRF pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MYRF encodes myelin regulatory factor, a membrane-bound transcription factor which is proteolytically cleaved into its C- and N-terminal domains. The C-terminal fragment remains in the endoplasmic reticulum while the N-terminal region, which contains the DNA-binding domain, travels to the nucleus, where it promotes the expression of target genes. MYRF has been shown to be expressed in a wide range of tissues including the heart, lung, diaphragm, eye, and coelomic epithelium of the fetal gonads. The coelomic epithelium of fetal gonads forms the germinal epithelium, which may account for the differences of sex development phenotype seen in some individuals with pathogenic variants in MYRF. It has therefore been postulated that MYRF may be involved in the development of coelomic epithelium-derived cells and tissues.

Author Notes

Tucker (Louise) C Pyle, MD, PhD, is a clinical geneticist and physician-scientist specializing in genetics of genitourinary (GU) differences and cancer. Dr Pyle's clinical interests are diagnostic evaluation and care for individuals with intersex (I) traits and differences of sex development (DSD), and other GU differences. They focus on multidisciplinary integration, molecular diagnosis, and cancer predisposition counseling for their patients and their families. Dr Pyle's research applies genomics and human models to understand vulnerability to infertility and germ cell tumor (GCT). They have identified and characterized clinical risk factors that predispose people to GCT by studying individuals diagnosed with this malignancy, as well as patients carrying a diagnosis of I/DSD. Dr Pyle's goal is to supply new tools that will facilitate improved care for individuals with I/DSD traits. Web page: childrensnational.org/visit/find-a-provider/louise-pyle

Lev Prasov, MD, PhD, is a physician-scientist practicing ophthalmic genetics. His clinical interests are in the diagnostic evaluation and treatment of inherited ocular disorders with specific interests in disorders of refractive error, glaucoma, ocular malformations and inherited retinal diseases. Dr Prasov's research seeks to identify novel genes and pathways in inherited ocular conditions with the hope of developing or improving therapies for these conditions. He uses a combination of human genetics and mammalian and cell culture models to identify and validate disease genes and to identify novel pathways for pathogenesis. Web page: prasov.lab.medicine.umich.edu/about

Julie D Kaplan, MD, is Medical Director and Clinical Geneticist for the Center for Personalized Genetic Healthcare in Cleveland Clinic's Genomic Medicine Institute. Her clinical interests include dysmorphology, prenatal genetics, DSD, and international genetics. Web page: my.clevelandclinic.org/staff/29174-julie-kaplan

Acknowledgments

We thank all of the patients and their families for their participation in our studies.

Dr Pyle's work has been supported by T32GM008638 and K08CA248704. Dr Prasov's work has been supported in part by K08EY032098 and the E Matilda Ziegler Foundation for the Blind, and the Research to Prevent Blindness Career Development Award, the Bright Focus Foundation, and the Glaucoma Research Foundation.

Revision History

• 31 July 2025 (ma) Comprehensive update posted live
• 10 November 2022 (ma) Review posted live
• 22 June 2022 (jk) Original submission

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