How is 46,XX sex reversal 4 inherited?

46,XX sex reversal 4 follows an autosomal dominant inheritance pattern. This means inheriting just one copy of the altered gene from either parent can cause the condition.

How is 46,XX sex reversal 4 diagnosed?

Information about diagnosis is currently limited for this condition.

Are there treatments for 46,XX sex reversal 4?

Information about treatment is currently limited for this condition.

What complications might arise from 46,XX sex reversal 4?

Information about complications related to 46,XX sex reversal 4 is currently limited. However, since this condition affects sexual development, individuals may face challenges related to their sexual characteristics. Ongoing research aims to provide more insight into potential complications.

How does 46,XX sex reversal 4 affect daily life?

The impact of 46,XX sex reversal 4 on daily life can vary, but due to its effects on sexual development, individuals may experience unique challenges. These could include social or emotional aspects related to their identity and development. More information is needed to understand how it specifically affects daily activities.

What is the prognosis for someone with 46,XX sex reversal 4?

Currently, information about the prognosis for individuals with 46,XX sex reversal 4 is limited. Since this condition is rare and research is ongoing, it is difficult to predict long-term outcomes. Families are encouraged to stay informed as new findings emerge.

Are there any specialists recommended for managing 46,XX sex reversal 4?

There is no specific information about recommended specialists for 46,XX sex reversal 4 at this time. However, individuals may benefit from consulting with healthcare providers who specialize in genetics or endocrinology. These specialists can help manage any related health concerns as more information becomes available.

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46,XX sex reversal 4 - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

46,XX sex reversal 4

MONDO:0060489

Also known as:46, XX sex reversal 446,XX Sex reversal, Sry-NegativeSRXX4

Overview

GeneticsAutosomal dominant · NR5A1 (chr 9)

OnsetCONGENITAL

ResearchLimited published research (5 articles)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include common findings: Ovotestis and Ambiguous genitalia; and sometimes findings: Penoscrotal hypospadias, Micropenis, Fused labia majora, and Retractile testis and others. 8 total HPO annotations.

Age of onset: at birth.

GeneReviews

Clinical Guidance

By definition, nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are not associated with dysmorphic features, congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. Approximately 85% of males with a 46,XX sex chromosome complement present after puberty with typical male pubic hair and penile size but small testes, gynecomastia, and sterility resulting from azoospermia . These typically represent individuals with nonsyndromic 46,XX testicular DSD, but ovotesticular DSD cannot be excluded as testicular biopsy is not clinically warranted and thus rarely performed. Differences of the penis. Most affected individuals have an orthotopic urethral meatus and no abnormalities of phallic size (i.e.

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

NR5A1 encodes nuclear receptor subfamily 5 group A member 1 (461 aa). Transcriptional activator. Essential for sexual differentiation and formation of the primary steroidogenic tissues. Highest expression in Spleen (221.6 TPM) and Adrenal Gland (216.7 TPM).

46,XX sex reversal 4 is associated with mutations in the NR5A1 gene on chromosome 9.

The NR5A1 protein participates in PIAS1,3 SUMOylates NR5A1 with SUMO2, PIAS1,3 SUMOylates NR5A1 with SUMO1, and SRY and NR5A1 (SF1) bind SOX9 gene pathways.

NR5A1 is classified as a druggable target (Druggable Genome and Nuclear Hormone Receptor categories) with score 3.3.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

No consensus clinical diagnostic criteria for nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have been published. However, algorithms have been developed for the evaluation and diagnosis of DSD, including nonsyndromic 46,XX testicular DSD .

Suggestive Findings

Nonsyndromic 46,XX testicular DSD should be considered in individuals with the following clinical, supportive laboratory, and imaging findings.

Clinical findings

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for 46,XX sex reversal 4. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have been published. Evaluations Following Initial Diagnosis To establish the extent of the condition and needs in an individual diagnosed with nonsyndromic 46,XX testicular DSD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 7. Recommended Surveillance for Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

System/Concern

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for 46,XX sex reversal 4.

5 publications have been identified in PubMed for 46,XX sex reversal 4. Research spans Case Report / Case Series (40%), Review / Meta-Analysis (20%), and Basic Science / Preclinical (20%).

Recent Publications

Wang X (2026). [PMID: 41621845](https://pubmed.ncbi.nlm.nih.gov/41621845/). *Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics*. [Case Report / Case Series]
Atasay R (2025). [PMID: 40475171](https://pubmed.ncbi.nlm.nih.gov/40475171/). *Molecular syndromology*. [Basic Science / Preclinical]
Luppino G (2024). [PMID: 38785542](https://pubmed.ncbi.nlm.nih.gov/38785542/). *Current issues in molecular biology*. [Review / Meta-Analysis]
Banerjee B (2024). [PMID: 38708796](https://pubmed.ncbi.nlm.nih.gov/38708796/). *Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology*. [Epidemiology / Natural History]
Berglund A (2024). [PMID: 39380113](https://pubmed.ncbi.nlm.nih.gov/39380113/). *Biology of sex differences*. [Case Report / Case Series]

Data assembled from 6 of 12 sources · Last updated Sep 20, 2026, 8:44 AM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:617480

Questions for Your Care Team

→Should I pursue genetic testing for NR5A1, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

FAQ

Frequently Asked Questions

Common questions about 46,XX sex reversal 4

46,XX sex reversal 4 is a rare condition where individuals with two X chromosomes may exhibit differences in the expected development of sexual characteristics. Although detailed definitions are not available, this condition is recognized in medical classifications and is sometimes noted as Sry-Negative due to the absence of the typical SRY gene found on the Y chromosome. A gene called NR5A1 is known to be associated with this condition. While the understanding of its complete impact is still developing, ongoing research hopes to clarify the natural history of the disorder and how it affects those diagnosed with it.

Information about symptoms is currently limited for this condition.

46,XX sex reversal 4 has a genetic basis. It is linked to changes in the NR5A1 gene, which plays a role in the development of sexual characteristics. The exact mechanisms by which these changes lead to the condition are still under study. Associated genes include NR5A1.

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System/Concern	Evaluation	Comment
Constitutional	Measurement of length/height	To assess for short stature
Endocrinology	Measurement of LH, FSH, total testosterone levels	In those age 10 yrs Assessment of libido, energy, erectile function, acne, breast tenderness, presence of gynecomastia
Urology	Physical exam for evidence of undervirilization	Incl assessment of length width of phallus; location of urethral meatus; location of gonads through palpation size measurement w/orchidometer Digital rectal exam measurement of PSA1
Psychology	Assessment of mood gender identity	By mental health professional Genetic
counseling	By genetics professionals2	To inform affected persons their families re nature, MOI, implications of nonsyndromic 46,XX testicular DSD to facilitate medical personal decision making Individual family support/ resources
Treatment of Manifestations in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Manifestation/Concern	Treatment	Considerations/Other
Short stature	Growth hormone therapy may be considered.	Referral to endocrinologist recommended Low or absent serum testosterone levels1
Gynecomastia	Reduction mammoplasty may be considered if gynecomastia is causing psychological distress.	Regression of gynecomastia may occur w/testosterone replacement therapy.
Osteopenia	Standard treatment per endocrinologist	May incl calcium, exercise, vitamin D, biphosphonates, or calcitonin
Undervirilization	Standard therapy per urologist	May incl orchidopexy /or hypospadias repair Psychological
distress	Referral to mental health professional	Sensitivity is necessary when conveying information to persons w/nonsyndromic 46,XX testicular DSD about genetic cause of the disorder assoc sterility.

Kisho

46,XX sex reversal 4

Overview

Clinical Presentation

Clinical Guidance

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

Explore clinical features

Penetrance

Differential Diagnosis

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Latest News & Developments

Gene therapy for children with sickle cell disease approved by FDA

46,XX sex reversal 4

Overview

Clinical Presentation

Clinical Guidance

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

What is 46,XX sex reversal 4?

What are the symptoms of 46,XX sex reversal 4?

What causes 46,XX sex reversal 4?

How is 46,XX sex reversal 4 inherited?

How is 46,XX sex reversal 4 diagnosed?

Are there treatments for 46,XX sex reversal 4?

What complications might arise from 46,XX sex reversal 4?

How does 46,XX sex reversal 4 affect daily life?

What is the prognosis for someone with 46,XX sex reversal 4?

Are there any specialists recommended for managing 46,XX sex reversal 4?

Explore clinical features

Penetrance

Differential Diagnosis

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Latest News & Developments

Gene therapy for children with sickle cell disease approved by FDA