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.

Any primary ovarian failure in which the cause of the disease is a mutation in the POF1B gene.

Progesterone prepares the endometrium for blastocyst implantation and allows maintenance of pregnancy. The major sources of progesterone are the corpus luteum during the second half of the menstrual cycle and at the beginning of pregnancy, and the placenta. The main hormones responsible for stimulation of progesterone secretion are luteinizing hormone (LH) for the corpus luteum of the menstrual cycle and chorionic gonadotropin for the corpus luteum of pregnancy. Complete end-organ resistance to progesterone would be incompatible with reproductive competence in females. Males would not be expected to be affected since progesterone has no known function in men. Failure of the uterus to respond to progesterone would lead to the development of a 'constantly proliferative' endometrium incompatible with blastocyst implantation. Partial resistance to progesterone, on the other hand, would be expected to be associated with various degrees of incomplete maturation of the endometrium, perhaps expressed clinically as infertility or early abortions. The syndrome would present with the clinical and histologic picture of a luteal phase defect in which the life span of the corpus luteum and the plasma progesterone concentrations would be normal or elevated.

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

Any 46 XX gonadal dysgenesis in which the cause of the disease is a mutation in the PSMC3IP gene.

Female infertility due to zona pellucida defect is a rare, genetic, female infertility disorder characterized by the presence of abnormal oocytes that lack a zona pellucida. Affected individuals are unable to conceive despite having normal menstrual cycles and sex hormone levels, as well as no obstructions in the fallopian tubes or defects of the uterus or adnexa.

Maternal genes play a critical role in the very early stages of embryonic development because of the lag in transcribing genes derived from the male pronucleus. TLE6 mutations are a rare cause of human female-limited fertility and appear to represent the earliest known human embryonic lethality that is due to a single gene mutation. In affected women, ovulation proceeds normally and the retrieved oocytes appear normal, but zygote formation is severely impaired (Alazami et al., 2015). For a general phenotypic description and discussion of genetic heterogeneity of OZEMA, see 615774.

Any inherited oocyte maturation defect in which the cause of the disease is a mutation in the TUBB8 gene.

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).

Oocyte/zygote/embryo maturation arrest-3 (OZEMA3) is characterized by infertility, caused by absence of the zona pellucida that results in degeneration of oocytes and 'empty follicle syndrome' on in vitro fertilization procedures (Chen et al., 2017). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte maturation defects due to mutation in PATL2 show phenotypic variability, with some oocytes exhibiting maturation arrest at the germinal vesicle stage and others at the metaphase I stage. In some patients, a few oocytes progress to polar body I; those oocytes either undergo fertilization failure or, in those that are fertilized, early embryonic arrest (Chen et al., 2017).

Oocyte/zygote/embryo maturation arrest-5 (OZEMA5) is characterized by female infertility due to inability of the oocyte to exit metaphase II, resulting in fertilization failure (Sang et al., 2018). For a discussion of genetic heterogeneity of OZEMA, see 615774.

A rare genetic endocrine disorder characterized by persistently high prolactin serum levels (not associated with gestation, puerperium, drug intake or pituitary tumor) in multiple affected family members. Clinically it manifests with signs usually observed in hyperprolactinemia, which are: secondary medroxyprogesterone acetate (MPA)-negative amenorrhea and galactorrhea in female patients, and hypogonadism and decreased testosterone level-driven sexual disfunction in male patients. Oligomenorrhea and primary infertility have also been reported in some female patients.

Oocyte/zygote/embryo maturation arrest-6 (OZEMA6) is characterized by primary infertility due to defective sperm-binding to an abnormally thin zona pellucida (ZP) in patient oocytes. Successful pregnancy may be achieved by intracytoplasmic sperm injection in these patients (Dai et al., 2019). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Hydatidiform mole is a human pregnancy with abnormal or no embryonic development and excessive trophoblastic proliferation. Partial hydatidiform moles have a triploid dispermic genome, with 2 sets of paternal chromosomes and 1 set of maternal chromosomes; complete hydatidiform moles have a diploid androgenetic genome with all chromosomes originating from 1 (monospermic) or 2 (dispermic) sperms, and no maternal chromosomes (summary by Nguyen et al., 2018). For a discussion of genetic heterogeneity of recurrent hydatidiform mole, see HYDM1 (231090).

Hydatidiform mole is a human pregnancy with abnormal or no embryonic development and excessive trophoblastic proliferation. Partial hydatidiform moles have a triploid dispermic genome, with 2 sets of paternal chromosomes and 1 set of maternal chromosomes; complete hydatidiform moles have a diploid androgenetic genome with all chromosomes originating from 1 (monospermic) or 2 (dispermic) sperms, and no maternal chromosomes (summary by Nguyen et al., 2018). For a discussion of genetic heterogeneity of recurrent hydatidiform mole, see HYDM1 (231090).

Oocyte/zygote/embryo maturation arrest-7 (OZEMA7) is characterized by infertility due to oocyte death, which may occur before or after fertilization (Sang et al., 2019). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-8 (OZEMA8) is characterized by female infertility due to failure of the fertilized ovum to undergo zygotic cleavage (Zheng et al., 2020). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-9 (OZEMA9) is characterized by female infertility due to oocyte meiotic arrest at metaphase I in most patients. Abnormal zygotic cleavage has also been observed (Zhang et al., 2020). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-10 (OZEMA10) is characterized by high rates of abnormal fertilization of mature oocytes, with development of multiple pronuclei or absent pronucleus. Morphologically normal zygotes often undergo early embryonic arrest, and surviving embryos fail to establish a successful pregnancy after implantation (Wang et al., 2020). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Premature ovarian failure-19 (POF19) is characterized by irregular menses that cease in the third decade of life, associated with infertility (Felipe-Medina et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is an autosomal recessive systemic disorder characterized by progressive muscle weakness, sensorineural hearing loss, and endocrine abnormalities, mainly primary amenorrhea due to ovarian insufficiency. Features of the disorder appear soon after birth, although endocrine anomalies are not noted until puberty. The severity of the phenotype is variable: some patients may lose ambulation and have significant respiratory insufficiency, whereas others retain the ability to walk (Foley et al., 2020).

Oocyte/zygote/embryo maturation arrest-11 (OZEMA11) is characterized by reduced or absent fertility and poor embryonic outcomes with assisted reproductive technology. Oocytes with multiple sperm heads and multiple pronuclei have been observed after overnight in vitro fertilization (Maddirevula et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-12 (OZEMA12) is characterized by female infertility due to early embryonic arrest (Wang et al., 2021). Mutation in the FBXO43 gene can also cause male infertility due to spermatogenic failure (see SPGF64, 619696). For a general phenotypic description and discussion of genetic heterogeneity of OZEMA, see 615774.

Premature ovarian failure-20 (POF20) is characterized by female infertility due to secondary amenorrhea. Some patients exhibit atrophic ovaries lacking follicles (Carlosama et al., 2017; Akbari et al., 2021; Wyrwoll et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of POF, see POF1 (311360).

Oocyte/zygote/embryo maturation arrest-13 (OZEMA13) is characterized by female infertility due to recurrent preimplantation embryonic arrest (Zheng et al., 2022). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-14 (OZEMA14) is characterized by female infertility due to oocyte maturation arrest, fertilization failure, and/or early embryonic arrest. The rare fertilized embryos that are transferred to the uterus fail to establish pregnancy after transfer (Zhao et al., 2020, Zhao et al., 2021, Huang et al., 2021, Xu et al., 2021). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-17 (OZEMA17) is characterized by female infertility due to arrest of the embryo after the first rounds of cleavage or failure to establish pregnancy after implantation (Wang et al., 2023). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-18 (OZEMA18) is characterized by female infertility due to early embryonic arrest. Most oocytes can be fertilized and begin cleavage, but very few viable embryos are obtained and most fail to establish pregnancy (Mu et al., 2019). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-19 (OZEMA19) is characterized by female infertility due to oocyte maturation arrest and early embryonic arrest. Oocyte arrest at the germinal vesicle stage has been observed. In other patients, most oocytes can be fertilized and begin cleavage, but they undergo maturation arrest at the 2- to 7-cell stage on day 3 (Mu et al., 2019; Huang et al., 2022). For a discussion of genetic heterogeneity of OZEMA, see 615774.

Oocyte/zygote/embryo maturation arrest-20 (OZEMA20) is characterized by early embryonic arrest with fragmentation. Extrusion of a large polar body 1 is observed in some patients (Zhang et al., 2021; Zhang et al., 2022). For a discussion of genetic heterogeneity of OZEMA, see 615774.