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Ambiguous genitalia, female

MedGen UID:
892752
Concept ID:
C4025891
Congenital Abnormality
Synonyms: Ambiguous genitalia due to virilization; Atypical appearance of female genitals
 
HPO: HP:0000061

Definition

Ambiguous genitalia in an individual with XX genetic gender. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAmbiguous genitalia, female

Conditions with this feature

Deficiency of steroid 11-beta-monooxygenase
MedGen UID:
82783
Concept ID:
C0268292
Disease or Syndrome
Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (White et al., 1991). CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (201910) (White et al., 1991).
Drash syndrome
MedGen UID:
181980
Concept ID:
C0950121
Disease or Syndrome
WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past, those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful.
Ehlers-Danlos syndrome due to tenascin-X deficiency
MedGen UID:
336244
Concept ID:
C1848029
Disease or Syndrome
The clinical features of TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) strongly resemble those seen in classic EDS (cEDS). Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS. There are also several other distinguishing clinical findings including anomalies of feet and hands, edema in the legs in the absence of cardiac failure, mild proximal and distal muscle weakness, and axonal polyneuropathy. Vaginal, uterine, and/or rectal prolapse can also occur. Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals. Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported. Fatigue has been reported in more than half of affected individuals. The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound as a result of severe and painful foot deformities and fatigue.
Pelviscapular dysplasia
MedGen UID:
342400
Concept ID:
C1850040
Disease or Syndrome
Syndrome with characteristics of pelviscapular dysplasia with epiphyseal abnormalities, congenital dwarfism and facial dysmorphism. The facial dysmorphism has manifestations of frontal bossing, hypertelorism, narrow palpebral fissures, deep-set eyes, strabismus, low-set posteriorly rotated and malformed ears, dysplasia of conchae, a small chin, a short neck with redundant skin folds, and a low hairline. Intelligence may vary from normal to moderately impaired. Radiographic features comprise aplasia of the body of the scapula, hypoplasia of the iliac bone, humeroradial synostosis, dislocation of the femoral heads, and moderate brachydactyly. Mutations in the TBX15 gene have been identified as potentially causative. Pelviscapular dysplasia is phenotypically similar to pelvis-shoulder dysplasia.
Exstrophy-epispadias complex
MedGen UID:
338020
Concept ID:
C1850321
Disease or Syndrome
Carey et al. (1978) gave the name OEIS complex to a combination of defects comprising omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. This rare complex is thought to represent the most severe end of a spectrum of birth defects, the exstrophy-epispadias sequence, which, in order of increasing severity, includes phallic separation with epispadias, pubic diastasis, exstrophy of the bladder (600057), cloacal exstrophy, and OEIS complex. Very few instances of recurrence of anomalies in this cluster have been reported.
Desmosterolosis
MedGen UID:
400801
Concept ID:
C1865596
Disease or Syndrome
Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by Waterham et al., 2001).
Meckel syndrome, type 1
MedGen UID:
811346
Concept ID:
C3714506
Disease or Syndrome
Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. There is extensive clinical variability and controversy as to the minimum diagnostic criteria. Early reports, including that of Opitz and Howe (1969) and Wright et al. (1994), stated that the classic triad of Meckel syndrome comprises (1) cystic renal disease; (2) a central nervous system malformation, most commonly occipital encephalocele; and (3) polydactyly, most often postaxial. However, based on a study of 67 patients, Salonen (1984) concluded that the minimum diagnostic criteria are (1) cystic renal disease; (2) CNS malformation, and (3) hepatic abnormalities, including portal fibrosis or ductal proliferation. In a review of Meckel syndrome, Logan et al. (2011) stated that the classic triad first described by Meckel (1822) included occipital encephalocele, cystic kidneys, and fibrotic changes to the liver. Genetic Heterogeneity of Meckel Syndrome See also MKS2 (603194), caused by mutation in the TMEM216 gene (613277) on chromosome 11q12; MKS3 (607361), caused by mutation in the TMEM67 gene (609884) on chromosome 8q; MKS4 (611134), caused by mutation in the CEP290 gene (610142) on chromosome 12q; MKS5 (611561), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; MKS6 (612284), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; MKS7 (267010), caused by mutation in the NPHP3 (608002) gene on chromosome 3q22; MKS8 (613885), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; MKS9 (614209), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; MKS10 (614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; MKS11 (615397), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; MKS12 (616258), caused by mutation in the KIF14 gene (611279) on chromosome 1q32; MKS13 (617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; and MKS14 (619879), caused by mutation in the TXNDC15 gene (617778) on chromosome 5q31.

Professional guidelines

PubMed

Armanini D, Boscaro M, Bordin L, Sabbadin C
Int J Mol Sci 2022 Apr 8;23(8) doi: 10.3390/ijms23084110. PMID: 35456928Free PMC Article
Gravholt CH, Viuff MH, Brun S, Stochholm K, Andersen NH
Nat Rev Endocrinol 2019 Oct;15(10):601-614. Epub 2019 Jun 18 doi: 10.1038/s41574-019-0224-4. PMID: 31213699
Escobar-Morreale HF
Nat Rev Endocrinol 2018 May;14(5):270-284. Epub 2018 Mar 23 doi: 10.1038/nrendo.2018.24. PMID: 29569621

Recent clinical studies

Etiology

Chen N, Song S, Bao X, Zhu L
Front Med 2022 Dec;16(6):859-872. Epub 2022 Dec 23 doi: 10.1007/s11684-022-0969-3. PMID: 36562950
Cools M, Nordenström A, Robeva R, Hall J, Westerveld P, Flück C, Köhler B, Berra M, Springer A, Schweizer K, Pasterski V; COST Action BM1303 working group 1
Nat Rev Endocrinol 2018 Jul;14(7):415-429. doi: 10.1038/s41574-018-0010-8. PMID: 29769693Free PMC Article
Witchel SF
Best Pract Res Clin Obstet Gynaecol 2018 Apr;48:90-102. Epub 2017 Nov 22 doi: 10.1016/j.bpobgyn.2017.11.005. PMID: 29503125Free PMC Article
Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH 3rd, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S; Global DSD Update Consortium
Horm Res Paediatr 2016;85(3):158-80. Epub 2016 Jan 28 doi: 10.1159/000442975. PMID: 26820577
Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES Consensus Group; ESPE Consensus Group
Arch Dis Child 2006 Jul;91(7):554-63. Epub 2006 Apr 19 doi: 10.1136/adc.2006.098319. PMID: 16624884Free PMC Article

Diagnosis

Babu R, Shah U
J Pediatr Urol 2021 Feb;17(1):39-47. Epub 2020 Nov 12 doi: 10.1016/j.jpurol.2020.11.017. PMID: 33246831
Stambough K, Magistrado L, Perez-Milicua G
Curr Opin Obstet Gynecol 2019 Oct;31(5):303-308. doi: 10.1097/GCO.0000000000000565. PMID: 31425174
Witchel SF
Best Pract Res Clin Obstet Gynaecol 2018 Apr;48:90-102. Epub 2017 Nov 22 doi: 10.1016/j.bpobgyn.2017.11.005. PMID: 29503125Free PMC Article
Davies JH, Cheetham T
Arch Dis Child 2017 Oct;102(10):968-974. Epub 2017 Apr 25 doi: 10.1136/archdischild-2016-311270. PMID: 28442467
Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH 3rd, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S; Global DSD Update Consortium
Horm Res Paediatr 2016;85(3):158-80. Epub 2016 Jan 28 doi: 10.1159/000442975. PMID: 26820577

Therapy

Maher JY, Gomez-Lobo V, Merke DP
Rev Endocr Metab Disord 2023 Feb;24(1):71-83. Epub 2022 Nov 18 doi: 10.1007/s11154-022-09770-5. PMID: 36399318Free PMC Article
Herlin MK, Petersen MB, Brännström M
Orphanet J Rare Dis 2020 Aug 20;15(1):214. doi: 10.1186/s13023-020-01491-9. PMID: 32819397Free PMC Article
El-Maouche D, Arlt W, Merke DP
Lancet 2017 Nov 11;390(10108):2194-2210. Epub 2017 May 30 doi: 10.1016/S0140-6736(17)31431-9. PMID: 28576284
Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van Zuuren EJ
Am J Clin Dermatol 2017 Apr;18(2):169-191. doi: 10.1007/s40257-016-0245-x. PMID: 28155090Free PMC Article
Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES Consensus Group; ESPE Consensus Group
Arch Dis Child 2006 Jul;91(7):554-63. Epub 2006 Apr 19 doi: 10.1136/adc.2006.098319. PMID: 16624884Free PMC Article

Prognosis

El-Maouche D, Arlt W, Merke DP
Lancet 2017 Nov 11;390(10108):2194-2210. Epub 2017 May 30 doi: 10.1016/S0140-6736(17)31431-9. PMID: 28576284
Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH 3rd, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S; Global DSD Update Consortium
Horm Res Paediatr 2016;85(3):158-80. Epub 2016 Jan 28 doi: 10.1159/000442975. PMID: 26820577
King TF, Conway GS
Curr Opin Endocrinol Diabetes Obes 2014 Dec;21(6):504-10. doi: 10.1097/MED.0000000000000113. PMID: 25314337
Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES Consensus Group; ESPE Consensus Group
Arch Dis Child 2006 Jul;91(7):554-63. Epub 2006 Apr 19 doi: 10.1136/adc.2006.098319. PMID: 16624884Free PMC Article
Gooren LJ
Semin Reprod Med 2002 Aug;20(3):285-96. doi: 10.1055/s-2002-35375. PMID: 12428208

Clinical prediction guides

Badeau M, Lindsay C, Blais J, Nshimyumukiza L, Takwoingi Y, Langlois S, Légaré F, Giguère Y, Turgeon AF, Witteman W, Rousseau F
Cochrane Database Syst Rev 2017 Nov 10;11(11):CD011767. doi: 10.1002/14651858.CD011767.pub2. PMID: 29125628Free PMC Article
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Genome Biol 2016 Nov 29;17(1):243. doi: 10.1186/s13059-016-1105-y. PMID: 27899157Free PMC Article
Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH 3rd, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S; Global DSD Update Consortium
Horm Res Paediatr 2016;85(3):158-80. Epub 2016 Jan 28 doi: 10.1159/000442975. PMID: 26820577
Welsh M, Suzuki H, Yamada G
Endocr Dev 2014;27:17-27. Epub 2014 Sep 9 doi: 10.1159/000363609. PMID: 25247641
Sumpter JP
Toxicol Lett 1998 Dec 28;102-103:337-42. doi: 10.1016/s0378-4274(98)00328-2. PMID: 10022275

Recent systematic reviews

Noubiap JJ, Nansseu JR, Lontchi-Yimagou E, Nkeck JR, Nyaga UF, Ngouo AT, Tounouga DN, Tianyi FL, Foka AJ, Ndoadoumgue AL, Bigna JJ
Lancet Child Adolesc Health 2022 Mar;6(3):158-170. Epub 2022 Jan 17 doi: 10.1016/S2352-4642(21)00374-6. PMID: 35051409
Babu R, Shah U
J Pediatr Urol 2021 Feb;17(1):39-47. Epub 2020 Nov 12 doi: 10.1016/j.jpurol.2020.11.017. PMID: 33246831
Kocevska D, Lysen TS, Dotinga A, Koopman-Verhoeff ME, Luijk MPCM, Antypa N, Biermasz NR, Blokstra A, Brug J, Burk WJ, Comijs HC, Corpeleijn E, Dashti HS, de Bruin EJ, de Graaf R, Derks IPM, Dewald-Kaufmann JF, Elders PJM, Gemke RJBJ, Grievink L, Hale L, Hartman CA, Heijnen CJ, Huisman M, Huss A, Ikram MA, Jones SE, Velderman MK, Koning M, Meijer AM, Meijer K, Noordam R, Oldehinkel AJ, Groeniger JO, Penninx BWJH, Picavet HSJ, Pieters S, Reijneveld SA, Reitz E, Renders CM, Rodenburg G, Rutters F, Smith MC, Singh AS, Snijder MB, Stronks K, Ten Have M, Twisk JWR, Van de Mheen D, van der Ende J, van der Heijden KB, van der Velden PG, van Lenthe FJ, van Litsenburg RRL, van Oostrom SH, van Schalkwijk FJ, Sheehan CM, Verheij RA, Verhulst FC, Vermeulen MCM, Vermeulen RCH, Verschuren WMM, Vrijkotte TGM, Wijga AH, Willemen AM, Ter Wolbeek M, Wood AR, Xerxa Y, Bramer WM, Franco OH, Luik AI, Van Someren EJW, Tiemeier H
Nat Hum Behav 2021 Jan;5(1):113-122. Epub 2020 Nov 16 doi: 10.1038/s41562-020-00965-x. PMID: 33199855
Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA, Rubin K, Sandberg DE, Sas TCJ, Silberbach M, Söderström-Anttila V, Stochholm K, van Alfen-van derVelden JA, Woelfle J, Backeljauw PF; International Turner Syndrome Consensus Group
Eur J Endocrinol 2017 Sep;177(3):G1-G70. doi: 10.1530/EJE-17-0430. PMID: 28705803
Dyrbye LN, Thomas MR, Shanafelt TD
Acad Med 2006 Apr;81(4):354-73. doi: 10.1097/00001888-200604000-00009. PMID: 16565188

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