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.

Leydig cell hypoplasia is an autosomal recessive disorder in which loss of function of the LHCGR gene in the male prevents normal sexual development. Two types of LCH have been defined (Toledo, 1992). Type I, a severe form caused by complete inactivation of LHCGR, is characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high LH levels, total lack of responsiveness to LH/CG challenge, lack of breast development, and absent development of secondary male sex characteristics. Type II, a milder form caused by partial inactivation of the gene, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. Females with inactivating mutations in the LHCGR gene display a mild phenotype characterized by defective follicular development and ovulation, amenorrhea, and infertility (review by Themmen and Huhtaniemi, 2000). Reviews Arnhold et al. (2009) noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to isolated LH deficiency (HH23; 228300) are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor: all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB (152780) mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; 118860) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility.

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). Genetic Heterogeneity of Ovarian Dysgenesis Even in its isolated form, 46,XX ovarian dysgenesis is etiologically heterogeneous. See ODG2 (300510), caused by mutation in the BMP15 gene (300247); ODG3 (614324), caused by mutation in the PSMC3IP gene (608665); ODG4 (616185), caused by mutation in the MCMDC1 gene (610098); ODG5 (617690), caused by mutation in the SOHLH1 gene (610224); ODG6 (618078), caused by mutation in the NUP107 gene (607617); ODG7 (618117), caused by mutation in the MRPS22 gene (605810); ODG8 (618187), caused by mutation in the ESR2 gene (601663); ODG9 (619665), caused by mutation in the SPIDR gene (615384); and ODG10 (619834), caused by mutation in the ZSWIM7 gene (614535). See also ovarian dysgenesis with sensorineural deafness, or Perrault syndrome (233400).

Chromosome Xq27.3-q28 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by mild mental retardation, mild facial dysmorphism, short stature, and primary testicular failure manifest as high-pitched voice, sparse body hair, abdominal obesity, and small testes. Female carriers may have short stature and premature ovarian failure (summary by Rio et al., 2010).

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.

Fragile X-associated primary ovarian insufficiency (FXPOI) is a condition that affects women and is characterized by reduced function of the ovaries. The ovaries are the female reproductive organs in which egg cells are produced. As a form of primary ovarian insufficiency, FXPOI can cause irregular menstrual cycles, early menopause, an inability to have children (infertility), and elevated levels of a hormone known as follicle stimulating hormone (FSH). FSH is produced in both males and females and helps regulate the development of reproductive cells (eggs in females and sperm in males). In females, the level of FSH rises and falls, but overall it increases as a woman ages. In younger women, elevated levels may indicate early menopause and fertility problems.\n\nThe severity of FXPOI is variable. The most severely affected women have overt POI (formerly called premature ovarian failure). These women have irregular or absent menstrual periods and elevated FSH levels before age 40. Overt POI often causes infertility. Other women have occult POI; they have normal menstrual periods but reduced fertility, and they may have elevated levels of FSH (in which case, it is called biochemical POI). The reduction in ovarian function caused by FXPOI results in low levels of the hormone estrogen, which leads to many of the common signs and symptoms of menopause, such as hot flashes, insomnia, and thinning of the bones (osteoporosis). Women with FXPOI undergo menopause an average of 5 years earlier than women without the condition.