Version May 2024
| Disorder (MIM phenotype) | Gene | Protein | Inheritance | Gonad | Müllerian structures | Associated features/variant phenotypes |
| Global defects in testicular function (genes involved in gonadal development) | ||||||
| NR5A1 mutation (MIM #612965) | NR5A1 (SF1) | Nuclear receptor TF | AD/AR | Dysgenetic testis | +/– | Homozygous mutations associated with primary adrenal insufficiency. Heterozygous mutations are usually associated with isolated gonadal dysgenesis (although some cases with adrenal insufficiency have been reported). Asplenia may be present. |
| SRY-related gonadal dysgenesis (MIM #400044) | SRY | TF | Y | Dysgenetic testis or ovotestis | +/– | Loss of SRY function can result in complete or partial testicular dysgenesis, XY ovarian DSD, or ovotesticular DSD. |
| SOX9 deficiency (MIM #114290) | SOX9 | TF | AD | Dysgenetic testis or ovotestis | +/– | Camptomelic dysplasia (a skeletal dysplasia syndrome). 17q24 rearrangements have milder phenotype than point mutations. |
| WT1 mutation (MIM #194072, WAGR) (MIM #194080, Denys-Drash) (MIM #136680, Frasier) | WT1 | TF | AD | Dysgenetic testis | +/– | Wilms tumor, kidney abnormalities, gonadal tumors (WAGR, Denys-Drash, and Frasier syndromes). |
| DHX37 mutation (MIM #273250) | DHX37 | RNA helicase | AD | Dysgenetic testis or absent gonad | +/– | Also associated with testicular regression syndrome. |
| MAP3K1-related gonadal dysgenesis (MIM #613762) | MAP3K1 | Signal transduction | AD | Dysgenetic testis | ||
| DHH-related gonadal dysgenesis (MIM #233420) | DHH | Signaling molecule | AR | Dysgenetic testis | + | The severe phenotype of 1 patient included minifascicular neuropathy; other patients have isolated gonadal dysgenesis. |
| NR0B1 duplication (MIM #300018) | NR0B1 (DAX1) | Nuclear receptor TF | dupXp21 | Dysgenetic testis or ovary | +/– | |
| Lissencephaly, X-linked 2 (MIM #300215) | ARX | TF | X | Dysgenetic testis | – | X-linked lissencephaly, epilepsy, temperature instability. |
| ATRX-related gonadal dysgenesis (MIM #301040) | ATRX | Helicase (chromatin remodeling) | X | Dysgenetic testis | – | Alpha-thalassemia, intellectual disability. |
| DMRT1-related gonadal dysgenesis (MIM #154230) | DMRT1 | TF | Monosomic deletion, chromosome 9p24 | Dysgenetic testis | +/– | Intellectual disability. |
| PPP2R3C-related gonadal dysgenesis (MIM #618419) | PPP2R3C | Protein phosphatase | AR | Dysgenetic testis | +/– | Characteristic facial features, cutaneous syndactyly, thick/stiff muscles, dry/scaly skin. |
| SOX8 | SOX8 | TF | AD | Dysgenetic testis | ||
| WNT4 overexpression (MIM *603490) | WNT4 | Signaling molecule | dup1p35 | Dysgenetic testis | + | Intellectual disability. |
| ZFPM2 deficiency (MIM #616067) | ZFPM2 (FOG2) | Modulator of GATA4 activity | AD | Gonadal dysgenesis | +/– | Dysgenetic gonads, rudimentary müllerian structures, learning and language difficulties (some patients). |
| Disrupted müllerian inhibition | ||||||
| Persistent müllerian duct syndrome type 1 (MIM #261550) | AMH | Signaling molecule | AR | Testis | + | External genitalia have typical male appearance, but there may be cryptorchidism. Persistent müllerian duct structures (uterus, fallopian tubes, and upper vagina). |
| Persistent müllerian duct syndrome type 2 (MIM #261550) | AMHR2 | Serine-threonine kinase transmembrane receptor | AR | Testis | + | |
| Disorders of androgen synthesis | ||||||
| Leydig cell hypoplasia (MIM #238320) | LHCGR | G-protein receptor | AR | Testis | – | Range of phenotypes, depending on severity of LH/hCG receptor inactivation. |
| Smith-Lemli-Opitz syndrome (MIM #270400) | DHCR7 | Enzyme (converts 7-dehydrocholesterol to cholesterol) | AR | Testis | – | Coarse facies, second-third toe syndactyly, failure to thrive, developmental delay, cardiac and visceral abnormalities. |
| 17-beta-hydroxysteroid dehydrogenase type 3 deficiency (MIM #264300) | HSD17B3 | Enzyme (converts androstenedione to testosterone) | AR | Testis | – | Partial virilization at puberty, elevated androstenedione:testosterone ratio. |
| 5-alpha-reductase type 2 deficiency (MIM #264600) | SRD5A2 | Enzyme (converts testosterone to dihydrotestosterone) | AR | Testis | – | Partial androgenization at puberty, elevated testosterone:dihydrotestosterone ratio. |
| Forms of CAH associated with underproduction of testosterone | ||||||
| 3-beta-hydroxysteroid dehydrogenase type 2 deficiency (MIM #201810) | HSD3B2 | Enzyme (several steps in steroidogenesis) | AR | Testis | – | CAH, defective production of testosterone, but partial virilization caused by DHEA. Both XX and XY infants may have atypical genital appearance. |
| 17-alpha-hydroxylase deficiency (MIM #202110) | CYP17A1 | Enzyme (17-alpha-hydroxylase and 17,20-lyase) | AR | Testis | – | CAH, hypertension caused by corticosterone and 11-deoxycorticosterone (except in isolated 17,20-lyase deficiency). |
| P450 oxidoreductase deficiency (MIM #613571) | POR | CYP enzyme electron donor (cofactor for 21-hydroxylase, 17-alpha-hydroxylase, and aromatase) | AR | Testis | – | CAH, with mixed features of 21-hydroxylase deficiency, 17-alpha-hydroxylase/17,20-lyase deficiency, and aromatase deficiency; sometimes associated with Antley-Bixler craniosynostosis. Both XX and XY infants may have atypical genital appearance. May cause mild maternal virilization during pregnancy. |
| Lipoid CAH (MIM #201710) | STAR | Mitochondrial membrane protein (transports cholesterol to mitochondrion) | AR | Testis | – | CAH (primary adrenal failure), high risk for salt-losing crisis, typical female external genital appearance, absent or incomplete pubertal development. |
| P450scc deficiency (MIM #613743) | CYP11A1 | Enzyme (converts cholesterol to pregnenolone) | AR | Testis | – | CAH, absent or incomplete pubertal development. |
| Disorders of androgen insensitivity | ||||||
| Androgen insensitivity syndrome (MIM #312300) | AR | Nuclear receptor TF | X | Testis | – | PAIS presents with a range of phenotypes from largely female genital appearance (with mild virilization) to typical male genital appearance with infertility. Patients with CAIS have typical female external genital appearance. |
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