Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by a complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and primary ovarian insufficiency; BPES type II includes only the four major features. Other ophthalmic manifestations that can be associated with BPES include dysplastic eyelids, lacrimal duct anomalies, strabismus, refractive errors, and amblyopia. Other craniofacial features may include a broad nasal bridge and low-set ears.

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).

Virtually all individuals with Woodhouse-Sakati syndrome (WSS) have the endocrine findings of hypogonadism (evident at puberty) and progressive childhood-onset hair thinning that often progresses to alopecia totalis in adulthood. More than half of individuals have the neurologic findings of progressive extrapyramidal movements (dystonic spasms with dystonic posturing with dysarthria and dysphagia), moderate bilateral postlingual sensorineural hearing loss, and mild intellectual disability. To date, more than 40 families (including 33 with a molecularly confirmed diagnosis) with a total of 88 affected individuals have been reported in the literature.

Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is characterized by uterovaginal atresia in an otherwise phenotypically normal female with a normal 46,XX karyotype. Anomalies of the genital tract range from upper vaginal atresia to total mullerian agenesis with urinary tract abnormalities. It has an incidence of approximately 1 in 5,000 newborn girls (Cheroki et al., 2006). The abnormality of sexual development in MRKH syndrome is the same as that in the MURCS association (601076), in which cervicothoracic somite anomalies, unilateral renal agenesis, and conductive deafness are also seen. Mullerian aplasia and hyperandrogenism (158330) is caused by mutation in the WNT4 gene (603490). Familial cases of unilateral or bilateral renal agenesis in combination with mullerian anomalies have also been reported (see urogenital adysplasia, 191830).

The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85% to 90% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years).

Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay / intellectual disability. The most common anterior chamber defect is Peters' anomaly, consisting of central corneal clouding, thinning of the posterior cornea, and iridocorneal adhesions. Cataracts and glaucoma are common. Developmental delay is observed in about 80% of children; intellectual disability can range from mild to severe.

Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, usually involving the face and neck, which are present at birth and heal with age, leaving minimal residual scarring. Other findings can include a wide variety of other ocular abnormalities (e.g., corneal anomalies, orbital cysts, cataracts), central nervous system involvement (e.g., structural anomalies, developmental delay, infantile seizures), cardiac concerns (e.g., hypertrophic or oncocytic cardiomyopathy, atrial or ventricular septal defects, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, hearing impairment, and genitourinary malformations. Inter- and intrafamilial variability is described.

Syndromic microphthalmia-9 (MCOPS9), also referred to as pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect, is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The phenotype is variable, ranging from isolated clinical anophthalmia or microphthalmia to complex presentations involving the cardiac, pulmonary, diaphragmatic, and renal systems. At its most severe, infants are born without pulmonary structures and die soon after birth (Marcadier et al., 2015).

Satoyoshi syndrome is a rare disorder characterized by progressive, painful, intermittent muscle spasms, diarrhea or unusual malabsorption, endocrinopathy with amenorrhea, and secondary skeletal abnormalities. The disorder is also called komuragaeri disease by the Japanese; in Japanese 'komura' means calf and 'gaeri' means 'turnover' or spasm. All cases have apparently been sporadic, even when occurring in large families (Ehlayel and Lacassie, 1995).

Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis. Ovarian dysgenesis accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003). Most cases are associated with major X chromosome abnormalities. Accordingly, genetic studies have identified several loci at Xq and Xp11.2-p.22.1 whose functions are relevant for ovarian development (Zinn et al., 1998; Simpson and Rajkovic, 1999; Marozzi et al., 2000).

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.

Any primary ovarian failure in which the cause of the disease is a mutation in the FIGLA gene.

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.

Any primary ovarian failure in which the cause of the disease is a mutation in the NR5A1 gene.

Sex reversal in an individual associated with a 9p24.3 deletion.

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.

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.

Microcephalic primordial dwarfism, Dauber type is a rare, genetic developmental defect during embryogenesis characterized by severe pre- and postnatal growth retardation, severe microcephaly, severe developmental delay and intelletual disability, severe adult short stature and facial dysmorphism (incl. hypotelorism, small ears, prominent nose). Other reported features include skeletal anomalies (Madelung deformity, clinodactyly, mild lumbar scoliosis, bilateral hip dysplasia) and seizures. Absence of thelarche and menarche is also associated.

Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.

Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.

Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).

Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism (IDDMOH) is characterized by mildly impaired intellectual development and microcephaly. Patients may also have ocular malformations, ocular apraxia, or hypogonadotropic hypogonadism. The disorder shows a unique DNA methylation signature (summary by Al-Jawahiri et al., 2022).

A rare genetic developmental defect during embryogenesis malformation syndrome with characteristics of intrauterine growth restriction, flexion arthrogryposis of all joints, severe microcephaly, renal cystic dysplasia/agenesis/hypoplasia and complex malformations of the brain (cerebral and cerebellar hypoplasia, vermis, corpus callosum and/or occipital lobe agenesis, with or without arhinencephaly), as well as of the genitourinary tract (ureteral agenesis/hypoplasia, uterine hypoplasia and/or vaginal atresia), leading to fetal demise.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 2, a form of MRKH syndrome (see this term), is characterized by congenital aplasia of the uterus and upper 2/3 of the vagina that is associated with at least one other malformation such as renal, vertebral, or, less commonly, auditory and cardiac defects. The acronym MURCS (MÜllerian duct aplasia, Renal dysplasia, Cervical Somite anomalies) is also used.

Premature ovarian failure-13 (POF13) is characterized by female infertility due to secondary amenorrhea in the third decade of life. Patients exhibit atrophic ovaries devoid of follicles (Guo et al., 2017). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).

Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.

Ovarian dysgenesis-6 is characterized by absence of spontaneous pubertal development in females with elevated gonadotropin levels, small uterus, and absence of ovarian tissue on imaging studies. Males appear to be unaffected (Weinberg-Shukron et al., 2015). For a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).

Ovarian dysgenesis-7 (ODG7) is characterized by primary amenorrhea, delayed puberty, elevated gonadotropic hormones, and small uterus and ovaries. Ovarian histology shows fibrotic ovaries without follicles (Chen et al., 2018). For a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).

Myoectodermal gonadal dysgenesis syndrome (MEGD) is characterized by 46,XY complete or partial gonadal dysgenesis, or 46,XX gonadal dysgenesis, in association with extragonadal anomalies, including low birth weight, typical facies, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. Dysmorphic facial features along with muscular habitus are the hallmarks of the syndrome. Abnormal hair patterning with frontal upsweep and additional whorls, eyebrow abnormalities comprising broad, arched, and sparse or thick eyebrows, underdeveloped alae nasi, smooth philtrum, and low-set ears with overfolded helices facilitate a gestalt diagnosis. (Guran et al., 2019; Altunoglu et al., 2022).

AMED syndrome (AMEDS) is an autosomal recessive digenic multisystem disorder characterized by global developmental delay with impaired intellectual development, onset of bone marrow failure and myelodysplastic syndrome (MDS) in childhood, and poor overall growth with short stature (summary by Oka et al., 2020). For a discussion of genetic heterogeneity of bone marrow failure syndrome (BMFS), see BMFS1 (614675).

Premature ovarian failure-18 (POF18) is characterized by irregular menstrual cycles and cessation of menstruation in the third decade of life. The uterus is small; ovaries may be small or rudimentary, and do not show follicular activity (Fan et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).

Ovarian dysgenesis-9 (ODG9) is characterized by severe nonsyndromic primary ovarian insufficiency with primary amenorrhea, hypoplastic or absent ovaries, and delayed bone age. Patient cells show evidence of chromosomal instability (Smirin-Yosef et al., 2017; Heddar et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).

Most commonly, IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. In rare instances, IRF6 pathogenic variants have also been reported in individuals with nonsyndromic orofacial cleft (18/3,811; 0.47%) and in individuals with spina bifida (2/192). Individuals with VWS show one or more of the following anomalies: Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip. Cleft lip (CL). Cleft palate (CP). Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP). The PPS phenotype includes the following: CL±P. Fistulae of the lower lip. Webbing of the skin extending from the ischial tuberosities to the heels. In males: bifid scrotum and cryptorchidism. In females: hypoplasia of the labia majora. Syndactyly of fingers and/or toes. Anomalies of the skin around the nails. A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic). In some nonclassic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). Other musculoskeletal anomalies may include spina bifida occulta, talipes equinovarus, digital reduction, bifid ribs, and short sternum. In VWS, PPS, IRF6-related neural tube defect, and IRF6-related orofacial cleft, growth and intelligence are typical.