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Ambiguous genitalia

MedGen UID:
78596
Concept ID:
C0266362
Congenital Abnormality
Synonyms: Ambiguities, Genital; Ambiguity, Genital; Ambiguous Genitalia; Genital Ambiguities; Genital Ambiguity; Genitalia, Ambiguous
SNOMED CT: Ambiguous genitalia (21321009)
 
HPO: HP:0000062

Definition

A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale [from HPO]

Conditions with this feature

Short-rib thoracic dysplasia 6 with or without polydactyly
MedGen UID:
44252
Concept ID:
C0024507
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Asphyxiating thoracic dystrophy 3
MedGen UID:
19860
Concept ID:
C0036069
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Smith-Lemli-Opitz syndrome
MedGen UID:
61231
Concept ID:
C0175694
Disease or Syndrome
Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described.
Deficiency of steroid 17-alpha-monooxygenase
MedGen UID:
82782
Concept ID:
C0268285
Disease or Syndrome
17 alpha(a)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. The gonads direct sexual development before birth and during puberty and are important for reproduction. The adrenal glands, which are located on top of the kidneys, regulate the production of certain hormones, including those that control salt levels in the body. People with 17a-hydroxylase/17,20-lyase deficiency have an imbalance of many of the hormones that are made in these glands. 17a-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation.\n\nHormone imbalances lead to the characteristic signs and symptoms of 17a-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development. The severity of the features varies. Two forms of the condition are recognized: complete 17a-hydroxylase/17,20-lyase deficiency, which is more severe, and partial 17a-hydroxylase/17,20-lyase deficiency, which is typically less so.\n\nMales and females are affected by disruptions to sexual development differently. Females (who have two X chromosomes) with 17a-hydroxylase/17,20-lyase deficiency are born with normal external female genitalia; however, the internal reproductive organs, including the uterus and ovaries, may be underdeveloped. Women with complete 17a-hydroxylase/17,20-lyase deficiency do not develop secondary sex characteristics, such as breasts and pubic hair, and do not menstruate (amenorrhea). Women with partial 17a-hydroxylase/17,20-lyase deficiency may develop some secondary sex characteristics; menstruation is typically irregular or absent. Either form of the disorder results in an inability to conceive a baby (infertility).\n\nIn affected individuals who are chromosomally male (having an X and a Y chromosome), problems with sexual development lead to abnormalities of the external genitalia. The most severely affected are born with characteristically female external genitalia and are generally raised as females. However, because they do not have female internal reproductive organs, these individuals have amenorrhea and do not develop female secondary sex characteristics. These individuals have testes, but they are abnormally located in the abdomen (undescended). Sometimes, complete 17a-hydroxylase/17,20-lyase deficiency leads to external genitalia that do not look clearly male or clearly female. Males with partial 17a-hydroxylase/17,20-lyase deficiency may have a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum). Males with either complete or partial 17a-hydroxylase/17,20-lyase deficiency are also infertile.
3 beta-Hydroxysteroid dehydrogenase deficiency
MedGen UID:
452446
Concept ID:
C0342471
Disease or Syndrome
Classic 3-beta-hydroxysteroid dehydrogenase deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (summary by Rheaume et al., 1992).
Type IV short rib polydactyly syndrome
MedGen UID:
96578
Concept ID:
C0432198
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). Patients with a clinical diagnosis of Beemer-Langer syndrome have been found to carry mutations in the IFT80 gene (611177); see SRTD2, 611263. For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Filippi syndrome
MedGen UID:
163197
Concept ID:
C0795940
Disease or Syndrome
Filippi syndrome is characterized by short stature, microcephaly, syndactyly, intellectual disability, and facial dysmorphism consisting of bulging forehead, broad and prominent nasal bridge, and diminished alar flare. Common features include cryptorchidism, speech impairment, and clinodactyly of the fifth finger, Some patients exhibit visual disturbances, polydactyly, seizures, and/or ectodermal abnormalities, such as nail hypoplasia, long eyelashes, hirsutism, and microdontia (summary by Hussain et al., 2014).
46,XY disorder of sex development due to testicular 17,20-desmolase deficiency
MedGen UID:
333416
Concept ID:
C1839840
Disease or Syndrome
X-linked lissencephaly with abnormal genitalia
MedGen UID:
375832
Concept ID:
C1846171
Disease or Syndrome
X-linked lissencephaly-2 (LISX2) is a developmental disorder characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia. Males are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype (Bonneau et al., 2002). LISX2 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly to Proud syndrome (300004) to infantile spasms without brain malformations (DEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
46,XX disorder of sex development-skeletal anomalies syndrome
MedGen UID:
341514
Concept ID:
C1849696
Disease or Syndrome
A rare disorder of sex development characterized by primary amenorrhea and ambiguous external genitalia (enlarged clitoris with marked fusion of the labioscrotal folds) in association with skeletal anomalies (such as hypoplasia of the mandibular condyles and the maxilla, and ulnar dislocation of the radial heads), in the presence of a 46,XX karyotype and regular ovaries, fallopian tubes, and uterus. There have been no further descriptions in the literature since 1972.
Bartsocas-Papas syndrome 1
MedGen UID:
337894
Concept ID:
C1849718
Disease or Syndrome
Bartsocas-Papas syndrome-1 (BPS1) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by Mitchell et al., 2012). Genetic Heterogeneity of Bartsocas-Papas Syndrome Bartsocas-Papas syndrome-2 (BPS2) is caused by mutation in the CHUK gene (600664). A less severe form of popliteal pterygium syndrome (PPS; 119500) is caused by mutation in the IRF6 gene (607199).
Mosaic variegated aneuploidy syndrome 1
MedGen UID:
338026
Concept ID:
C1850343
Disease or Syndrome
Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder in which some cells in the body have an abnormal number of chromosomes instead of the usual 46 chromosomes, a situation known as aneuploidy. Most commonly, cells have an extra chromosome, which is called trisomy, or are missing a chromosome, which is known as monosomy. In MVA syndrome, some cells are aneuploid and others have the normal number of chromosomes, which is a phenomenon known as mosaicism. Typically, at least one-quarter of cells in affected individuals have an abnormal number of chromosomes. Because the additional or missing chromosomes vary among the abnormal cells, the aneuploidy is described as variegated.\n\nThere are at least three types of MVA syndrome, each with a different genetic cause. Type 1 is the most common and displays the classic signs and symptoms described above. Type 2 appears to have slightly different signs and symptoms than type 1, although the small number of affected individuals makes it difficult to define its characteristic features. Individuals with MVA syndrome type 2 grow slowly before and after birth; however, their head size is typically normal. Some people with MVA syndrome type 2 have unusually short arms. Individuals with MVA syndrome type 2 do not seem to have an increased risk of cancer. Another form of MVA syndrome is characterized by a high risk of developing Wilms tumor. Individuals with this form may also have other signs and symptoms typical of MVA syndrome type 1.\n\nIn MVA syndrome, growth before birth is slow (intrauterine growth restriction). After birth, affected individuals continue to grow at a slow rate and are shorter than average. In addition, they typically have an unusually small head size (microcephaly). Another common feature of MVA syndrome is an increased risk of developing cancer in childhood. Cancers that occur most frequently in affected individuals include a cancer of muscle tissue called rhabdomyosarcoma, a form of kidney cancer known as Wilms tumor, and a cancer of the blood-forming tissue known as leukemia.\n\nLess commonly, people with MVA syndrome have eye abnormalities or distinctive facial features, such as a broad nasal bridge and low-set ears. Some affected individuals have brain abnormalities, the most common of which is called Dandy-Walker malformation. Intellectual disability, seizures, and other health problems can also occur in people with MVA syndrome.
Beemer-Ertbruggen syndrome
MedGen UID:
347174
Concept ID:
C1859526
Disease or Syndrome
A lethal malformation syndrome reported in 2 brothers of first-cousin parents with characteristics of hydrocephalus, cardiac malformation, dense bones and unusual facies with down-slanting palpebral fissures, bulbous nose, broad nasal bridge, micrognathia and a long upper lip. Transmission is likely autosomal recessive. There have been no further descriptions in the literature since 1984.
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
MedGen UID:
348008
Concept ID:
C1860042
Disease or Syndrome
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.
Ablepharon macrostomia syndrome
MedGen UID:
395439
Concept ID:
C1860224
Disease or Syndrome
Ablepharon-macrostomia syndrome (AMS) is a congenital ectodermal dysplasia characterized by absent eyelids, macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and ears, variable abnormalities of the nipples, genitalia, fingers, and hands, largely normal intellectual and motor development, and poor growth (summary by Marchegiani et al., 2015).
Endocrine-cerebro-osteodysplasia syndrome
MedGen UID:
390740
Concept ID:
C2675227
Disease or Syndrome
Endocrine-cerebro-osteodysplasia (ECO) syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.
46,XY sex reversal 1
MedGen UID:
412662
Concept ID:
C2748896
Disease or Syndrome
Sex reversal in an individual with 46,XY karyotype caused by point mutations or deletions in the SRY gene, encoding sex-determining region Y protein.
Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome
MedGen UID:
461281
Concept ID:
C3149931
Disease or Syndrome
Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome is characterised by sex reversal in males with a 46, XX (SRY-negative) karyotype, palmoplantar hyperkeratosis and a predisposition to squamous cell carcinoma. To date, five cases (four of whom were brothers) have been described. The aetiology is unknown.
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
MedGen UID:
461449
Concept ID:
C3150099
Disease or Syndrome
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.
Meckel syndrome, type 9
MedGen UID:
481785
Concept ID:
C3280155
Disease or Syndrome
Meckel syndrome is a severe autosomal recessive ciliopathy classically defined by the triad of encephalocele, polydactyly, and renal and biliary ductal dysplasia (summary by Hopp et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).
Joubert syndrome 15
MedGen UID:
482527
Concept ID:
C3280897
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
46,XY sex reversal 3
MedGen UID:
483746
Concept ID:
C3489793
Congenital Abnormality
Pontocerebellar hypoplasia type 7
MedGen UID:
767140
Concept ID:
C3554226
Disease or Syndrome
Pontocerebellar hypoplasia type 7 (PCH7) is a severe neurologic condition characterized by delayed psychomotor development, hypotonia, breathing abnormalities, and gonadal abnormalities (summary by Anderson et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Short-rib thoracic dysplasia 8 with or without polydactyly
MedGen UID:
816021
Concept ID:
C3809691
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Testicular anomalies with or without congenital heart disease
MedGen UID:
816188
Concept ID:
C3809858
Disease or Syndrome
Meckel syndrome, type 8
MedGen UID:
854220
Concept ID:
C3836857
Disease or Syndrome
Meckel-Gruber syndrome is a severe autosomal recessive ciliopathy classically defined by the triad of encephalocele, polydactyly, and renal and biliary ductal dysplasia. Clinical heterogeneity exists even within families (summary by Shaheen et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).
46,XY sex reversal 9
MedGen UID:
863566
Concept ID:
C4015129
Disease or Syndrome
Seckel syndrome 9
MedGen UID:
907155
Concept ID:
C4225212
Disease or Syndrome
Any Seckel syndrome in which the cause of the disease is a mutation in the TRAIP gene.
Silver-Russell syndrome 3
MedGen UID:
894912
Concept ID:
C4225307
Disease or Syndrome
Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay (Begemann et al., 2015; Yamoto et al., 2017). For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860).
46,XY sex reversal 10
MedGen UID:
897538
Concept ID:
C4225331
Disease or Syndrome
46,XY females with gonadal dysgenesis have streak gonads but look like normal females at birth. They do not develop secondary sexual characteristics at puberty and do not menstruate. They are chromatin-negative and are usually of normal stature, without the somatic stigmata of Turner syndrome (see 163950) (summary by Mann et al., 1983). For a discussion of genetic heterogeneity of 46,XY sex reversal, see SRXY1 (400044).
Short-rib thoracic dysplasia 13 with or without polydactyly
MedGen UID:
898712
Concept ID:
C4225378
Disease or Syndrome
An asphyxiating thoracic dystrophy that has material basis in homozygous mutation in the CEP120 gene on chromosome 5q23.
Methemoglobinemia type 4
MedGen UID:
925090
Concept ID:
C4285231
Disease or Syndrome
Methemoglobinemia and ambiguous genitalia (METAG) is due to isolated 17,20-lyase deficiency, defined by apparently normal 17-alpha-hydroxylase activity but severely reduced 17,20-lyase activity of the CYP17A1 enzyme (609300), which results in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. The clinical phenotype is characterized by male undermasculinization, with absent or disturbed pubertal development in both 46,XY and 46,XX individuals. Mild to severe methemoglobinemia has been reported in these patients (Idkowiak et al., 2012). Other autosomal recessive methemoglobinemias include types I and II (see 250800), caused by mutation in the CYB5R3 gene (613213). Isolated 17,20-lyase deficiency can also be caused by mutation in the CYP17A1 gene (609300), and mutation in the POR gene can manifest clinically as isolated 17,20-lyase deficiency (see 124015.0016).
Sifrim-Hitz-Weiss syndrome
MedGen UID:
934655
Concept ID:
C4310688
Disease or Syndrome
CHD4 neurodevelopmental disorder (CHD4-NDD) is associated with developmental delay, speech delay, and usually mild-to-moderate intellectual disability. Variability between individuals with CHD4-NDD is significant, and a few have normal intelligence. Other manifestations can include brain anomalies, heart defects, and skeletal abnormalities; less common features are hypogonadism in males, hearing impairment, and ophthalmic abnormalities. Most affected individuals have mild nonspecific dysmorphic facial features with or without macrocephaly.
46,XX sex reversal 4
MedGen UID:
1373282
Concept ID:
C4479552
Congenital Abnormality
Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are characterized by: the presence of a 46,XX karyotype; external genitalia ranging from typical male to ambiguous; two testicles; azoospermia; absence of müllerian structures; and absence of other syndromic features, such as congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia. Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia. Gender role and gender identity are reported as male. If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency.
Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
MedGen UID:
1612119
Concept ID:
C4539968
Disease or Syndrome
CAKUTHED is an autosomal dominant highly pleiotropic developmental disorder characterized mainly by variable congenital anomalies of the kidney and urinary tract, sometimes resulting in renal dysfunction or failure, dysmorphic facial features, and abnormalities of the outer ear, often with hearing loss. Most patients have global developmental delay (summary by Heidet et al., 2017 and Slavotinek et al., 2017).
Fraser syndrome 2
MedGen UID:
1624349
Concept ID:
C4540036
Disease or Syndrome
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of Fraser syndrome, see 219000.
Short-rib thoracic dysplasia 19 with or without polydactyly
MedGen UID:
1635837
Concept ID:
C4693524
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).
Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome
MedGen UID:
1648412
Concept ID:
C4748348
Disease or Syndrome
MFRG is an autosomal recessive syndrome in which microcephaly, unilateral renal agenesis, ambiguous genitalia, and facial dysmorphisms, including severe micrognathia, are observed in most patients. Variable brain, cardiac, and skeletal anomalies are present, including corpus callosum agenesis or dysgenesis, lissencephaly, atrial and ventricular septal defects, patent ductus arteriosus, hypoplastic right ventricle, and joint contractures (Shaheen et al., 2016).
Cardiac-urogenital syndrome
MedGen UID:
1648333
Concept ID:
C4748946
Disease or Syndrome
Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism (Pinz et al., 2018).
46,xx sex reversal 5
MedGen UID:
1713956
Concept ID:
C5394441
Disease or Syndrome
SRXX5 is characterized by genital virilization in 46,XX individuals, associated with congenital heart disease and variable somatic anomalies including blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and congenital diaphragmatic hernia (Bashamboo et al., 2018).
DEGCAGS syndrome
MedGen UID:
1794177
Concept ID:
C5561967
Disease or Syndrome
DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections. Death in childhood may occur (summary by Bertoli-Avella et al., 2021).
Meckel syndrome 14
MedGen UID:
1809650
Concept ID:
C5676989
Disease or Syndrome
Meckel syndrome-14 (MKS14) is a lethal disorder characterized by occipital encephalocele, postaxial polydactyly of the hands and feet, and polycystic kidneys. Stillbirth has been reported, as well as death within hours in a live-born affected individual (Shaheen et al., 2016; Ridnoi et al., 2019). For a general phenotypic description and discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).

Professional guidelines

PubMed

van Bever Y, Groenenberg IAL, Knapen MFCM, Dessens AB, Hannema SE, Wolffenbuttel KP, Diderich KEM, Hoefsloot LH, Srebniak MI, Bruggenwirth HT
Prenat Diagn 2023 Feb;43(2):162-182. Epub 2022 Aug 20 doi: 10.1002/pd.6205. PMID: 35808910
Vats P, Dabas A, Jain V, Seth A, Yadav S, Kabra M, Gupta N, Singh P, Sharma R, Kumar R, Polipalli SK, Batra P, Thelma BK, Kapoor S
Indian Pediatr 2020 Jan 15;57(1):49-55. PMID: 31937698
Brain CE, Creighton SM, Mushtaq I, Carmichael PA, Barnicoat A, Honour JW, Larcher V, Achermann JC
Best Pract Res Clin Endocrinol Metab 2010 Apr;24(2):335-54. doi: 10.1016/j.beem.2010.01.006. PMID: 20541156Free PMC Article

Recent clinical studies

Etiology

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
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, Deeb A
Best Pract Res Clin Endocrinol Metab 2006 Dec;20(4):577-98. doi: 10.1016/j.beem.2006.11.003. PMID: 17161333
Girard C, Bigorre M, Guillot B, Bessis D
Arch Dermatol 2006 Jul;142(7):884-8. doi: 10.1001/archderm.142.7.884. PMID: 16847205

Diagnosis

Stambough K, Magistrado L, Perez-Milicua G
Curr Opin Obstet Gynecol 2019 Oct;31(5):303-308. doi: 10.1097/GCO.0000000000000565. PMID: 31425174
León NY, Reyes AP, Harley VR
Lancet Diabetes Endocrinol 2019 Jul;7(7):560-574. Epub 2019 Feb 22 doi: 10.1016/S2213-8587(18)30339-5. PMID: 30803928
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
Witchel SF
J Pediatr Adolesc Gynecol 2017 Oct;30(5):520-534. Epub 2017 Apr 24 doi: 10.1016/j.jpag.2017.04.001. PMID: 28450075Free PMC Article
González R, Piaggio LA
Curr Opin Urol 2006 Jul;16(4):273-6. doi: 10.1097/01.mou.0000232049.89589.30. PMID: 16770127

Therapy

Romao RLP, Pippi Salle JL
Semin Perinatol 2017 Jun;41(4):218-226. Epub 2017 May 3 doi: 10.1053/j.semperi.2017.03.015. PMID: 28478087
Bulsari K, Falhammar H
Endocrine 2017 Jan;55(1):19-36. Epub 2016 Dec 7 doi: 10.1007/s12020-016-1189-x. PMID: 27928728
Turcu AF, Auchus RJ
Endocrinol Metab Clin North Am 2015 Jun;44(2):275-96. doi: 10.1016/j.ecl.2015.02.002. PMID: 26038201Free PMC Article
Anhalt H, Neely EK, Hintz RL
Pediatr Rev 1996 Jun;17(6):213-20. doi: 10.1542/pir.17-6-213. PMID: 8857201
Federman DD, Donahoe PK
Adv Endocrinol Metab 1995;6:91-116. PMID: 7671103

Prognosis

Guerra-Junior G, Andrade KC, Barcelos IHK, Maciel-Guerra AT
Sex Dev 2018;12(1-3):95-99. Epub 2017 Aug 22 doi: 10.1159/000479453. PMID: 28848186
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
McCann-Crosby B, Sutton VR
Clin Perinatol 2015 Jun;42(2):395-412, ix-x. Epub 2015 Mar 29 doi: 10.1016/j.clp.2015.02.006. PMID: 26042911
Mendoza N, Motos MA
Gynecol Endocrinol 2013 Jan;29(1):1-5. Epub 2012 Jul 20 doi: 10.3109/09513590.2012.705378. PMID: 22812659
Gooren LJ
Semin Reprod Med 2002 Aug;20(3):285-96. doi: 10.1055/s-2002-35375. PMID: 12428208

Clinical prediction guides

Shafaay EA, Aldriweesh MA, Aljahdali GL, Babiker A, Alomar AO, Alharbi KM, Aldalaan H, Alenazi A, Alangari AS, Alsagheir A, Adriaansen BPH, Claahsen-van der Grinten HL, Al Alwan I
Front Endocrinol (Lausanne) 2023;14:1122435. Epub 2023 Jun 6 doi: 10.3389/fendo.2023.1122435. PMID: 37347111Free 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
Mendoza N, Motos MA
Gynecol Endocrinol 2013 Jan;29(1):1-5. Epub 2012 Jul 20 doi: 10.3109/09513590.2012.705378. PMID: 22812659
Girard C, Bigorre M, Guillot B, Bessis D
Arch Dermatol 2006 Jul;142(7):884-8. doi: 10.1001/archderm.142.7.884. PMID: 16847205
Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber P, Barthez MA, Radi S, Biran-Mucignat V, Rodriguez D, Gélot A
Ann Neurol 2002 Mar;51(3):340-9. doi: 10.1002/ana.10119. PMID: 11891829

Recent systematic reviews

Fan L, Zhang B, Li L, Gong C
Clin Endocrinol (Oxf) 2020 Dec;93(6):687-695. Epub 2020 Jul 27 doi: 10.1111/cen.14277. PMID: 32623730

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