Phenotypic females with normal chromosomal complements (46,XX or 46,XY) may have gonadal failure. External appearance may be identical in the two situations, and gonadal findings similarly indistinguishable from 45,X gonadal dysgenesis (Turner syndrome). The general term XX gonadal dysgenesis can be applied to those 46,XX cases. Mosaicism with a coexisting 45,X line is always a possibility, but usually this seems to be excluded. In this chapter the genetic (mendelian) course of ovarian failure in 46,XX women is discussed. A wide spectrum of disorders exists (Table 1). In this chapter premature ovarian failure, sometimes caused by the same factors that cause complete ovarian failure (primary amenorrhea), is also considered. Chapter 5-85 considers ovarian failure caused by abnormalities of the X chromosome (Turner syndrome), and begins with a review of reproductive embryology to which the reader may wish to refer. In Chapter 5-87, 46,XY females, who have complete failure of testicular development and sometimes present with similar appearance, are discussed.

TABLE 1. The Spectrum of XX Gonadal Dysgenesis^a

  XX gonadal dysgenesis without somatic anomalies
  XX gonadal dysgenesis with neurosensory deafness (Perrault syndrome)
  XX gonadal dysgenesis with cerebellar ataxia (hetereogeneous)
  XX gonadal dysgenesis in malformation syndrome (Table 3)
  XX gonadal dysgenesis as one component of pleiotropic mendelian disorders (Table 4)
  FSHR mutations
  LHR mutations
  Blepharophimosis-ptosis-epicanthus (FOXL2)
  Germ cell absence in both sexes (46,XX)

  Without somatic anomalies^36,37
  Associated hypertension and deafness³⁸
  Associated alopecia³⁹
  Associated microcephaly and short stature⁴⁰

  17α-hydroxylase (CYP17)
  Aromatase (CYP19)

  Galactosemia (galactose uridyl-transferase deficiency [GALT])
  Carbohydrate-deficient glycoprotein (Phosphomannomutase deficiency [PMM2])

  Fragile X (FRAXA)
  Myotonic dystrophy (uncommon)

  Trisomy 13
  Trisomy 18

XX Gonadal Dysgenesis Without Anomalies

The forms of 46,XX gonadal dysgenesis not associated with somatic anomalies is most often inherited in autosomal recessive fashion. Affected individuals are normal in stature (mean height, 165 cm)¹; somatic features of Turner’s stigmata are usually absent. Presence of consanguinity pointed to autosomal recessive inheritance decades ago. Segregation analysis by the author and colleagues revealed the segregation ratio to be 0.16 for female sibs.² Thus, two thirds of gonadal dysgenesis in 46,XX individuals is genetic. The nongenetic phenocopies could be caused by infection, infarction, infiltrative or autoimmune phenomena (see Chapter 5-88 for further discussion).

Of clinical relevance is the variable expressivity in XX gonadal dysgenesis. In some families one sib has streak gonads, whereas another had primary amenorrhea and extreme ovarian hypoplasia (presence of a few oocytes).^1,2,3,4,5,6 If the mutant gene responsible for XX gonadal dysgenesis were capable of variable expression, that gene may be responsible for some sporadic cases of premature ovarian failure (POF).

The mechanism underlying failure of germ-cell persistence in XX gonadal dysgenesis without somatic anomalies is unknown, but there are many candidate genes. Any abnormality of meiosis could be manifested as ovarian failure and infertility in otherwise normal women. Other mechanisms by which mutant genes could act include interference with germ-cell migration, connective tissue abnormalities, or gonadotropin receptor abnormalities.

Identifying the specific autosomal genes responsible for the various forms of XX gonadal dysgenesis has been difficult. In many monogenic disorders efforts toward positional cloning are facilitated by the fortuitous family in which an autosomal translocation cosegregates with the disorder. Sporadic cases of XX gonadal dysgenesis have long been associated with reciprocal autosomal translocations, but there seems to be little reproducibility among autosomes involved. Genome-wide sib-pair analysis using polymorphic DNA markers (dinucleotide repeats; single nucleotide polymorphism) should theoretically identify chromosomal region(s) worthy of sequencing. Indeed, this method was used successfully in Finland to elucidate the form of XX gonadal dysgenesis caused by follicle-stimulating hormone receptor (FSHR) mutation, which we shall discuss below.^5,7 Construction of cDNA libraries of ovarian specific genes represent a more omnibus approach, combined with use of gene knockout technology in the mouse and sequencing of candidate genes in the human. Many mouse genes are of potential relevance (Table 2), and perturbations in their human homologues can be sought. Many of these genes may only manifest as ovarian failure, in contrast to predictions that other organ systems would also be disturbed. An example is bone morphogenetic protein (bmp). The conclusion is that ovarian meiosis is easily perturbed, secondarily leading to germ-cell failure.

TABLE 2. Selected Mouse Models of Ovarian Failure

XX gonadal dysgenesis associated with neurosensory deafness is called Perrault syndrome.⁸ Perrault syndrome is inherited in autosomal recessive fashion.^1,9,10,11,12 Endocrine features seem identical to XX gonadal dysgenesis without deafness.

XX Gonadal Dysgenesis Caused by Follicle Stimulating Hormone Receptor Mutation (Val566 A1a)

This disorder is found predominantly in Finland, where Aittomaki and colleagues^5,7 searched hospitals and cytogenetic laboratories throughout the country to identify 75 subjects having the XX gonadal dysgenesis phenotype. Diagnostic criteria consists of 46,XX women with primary or secondary amenorrhea whose serum FSH was 40 MIU/mL or more. The 75 included 57 sporadic cases and 18 cases having an affected relative (7 different families). Most resided in north central Finland, a more sparsely populated part of the country. Prevalence was 1 per 8300 liveborn Finnish females. This relatively high incidence is attributed to a founder effect. The segregation ratio of 0.23 for female sibs was almost identical with theoretical expectations for autosomal recessive inheritance. This is consistent with a high consanguinity rate (12%).

Sib pair analysis using polymorphic DNA markers first localized the gene to chromosome 2p, a region previously known to contain the genes for both the FSHR and the luteinizing hormone receptor (LHR). One specific mutation (Val to Ala) in exon 7 of the FSHR gene was found in 6 families^5,7 (Fig. 1). This cytosine-thymidine transition (called C566T) was later found in an additional 6 families.^7,13

Not all Finnish XX gonadal dysgenesis cases show the C566T mutation. Thus, the C566T-negative cases in Finland could represent the previously discussed condition XX gonadal dysgenesis with no somatic anomalies. Indeed, the C566T mutation is only rarely being detected in women with 46,XX ovarian failure who reside outside Finland. In the United States, Layman and colleagues¹⁴ failed to find a mutation in FSHR gene in 35 46,XX women having hypergonadotopic hypogonadism (15 with primary amenorrhea; 20 with secondary amenorrhea). Negative findings were reported in 46,XX POF or primary amenorrhea cases from Germany,¹⁵ Brazil,¹⁶ and Mexico.¹⁷ The last report analyzed all exons of FSHR. Liu and colleagues¹⁸ found no FSHR abnormalities in one multigenerational U.S. POF family, four sporadic POF cases and two other hypergonadotopic hypogonadism cases.

Aittomaki and colleagues¹³ compared the phenotype of Finnish C566T XX gonadal dysgenesis (C566T) with non-C566T XX gonadal dysgenesis. The former were more likely to have ovarian follicles by ultrasound. C566T XX gonadal dysgenesis thus showed at least some of the features gynecologists have long predicted for a gonadotropin resistance disorder (so-called Savage syndrome). In general, however, the phenotype found by Aittomaki⁵ was unexpected, bilateral streak gonads being found. FSHR (knockout) mice similarly show failure of oogenesis; thus, the necessity of FSH for progression of oogenesis is clear.¹⁹ Interestingly, FSH is less pivotal for spermatogenesis.²⁰

Inactivating Luteinizing Hormone Receptor Mutation (46,XX)

Another trophic hormone receptor gene, the perturbation of which causes XX gonadal dysgenesis, is the LHR. The gene is 75 kd in length and consists of 17 exons. Located on 2p near FSHR, the first 10 exons in LHR are extracellular; the last 6 are intracellular, and the 11th, transmembrane. LHR mutations have been reported predominately in 46,XY individuals, where the phenotype may extend to complete LH resistance and XY gender reversal (female). 46,XX cases are more rare than 46,XY cases, and have occurred only in sibships in which an affected 46,XY male had Leydig cell hypoplasia (XY gender reversal).

46,XX women with LHR mutations show oligomenorrhea or, less often, primary amenorrhea. Ovulation does not occur. Gametogenesis proceeds until the preovulatory stage, but not beyond. This is consistent with findings in the mouse knockout model.

Mutations in LHR are molecularly heterogeneous. Most mutations have been found in the transmembrane domain (exon). Latronico and colleagues²¹ reported primary amenorrhea in a 22-year-old woman whose family also included three affected males (46,XY), like the 46,XX sib homozygous for a nonsense mutation at codon 554 (Arg554ter). The resulting stop codon produced a truncated protein. The affected 46,XX female showed breast development but only a single episode of menstrual bleeding at age 20 years; LH was 37 mIU/mL, FSH 9 mIU/mL. The mutation reduced signal transduction activity of the LHR gene.

Toledo and colleagues²² studied the 46,XX female sib of two 46,XY affected males reported by Cramer and colleagues.²³ The sister showed elevated gonadotropins but anatomically normal ovaries. The mutation was Ala593Pro. Two sisters reported by Laue and colleagues²⁴ had the nonsense mutation cys545ter in exon 11; LHR function was lost. The father but not the mother had the mutation. The authors found a dominant negative effect, but more likely the mutant allele transmitted from the probably heterozygous mother has simply not yet been detected.

Cerebellar Ataxia and XX Gonadal Dysgenesis

XX gonadal dysgenesis can be found in association with a heterogeneous group of cerebellar ataxias. The hereditary ataxias are confusing nosologically, principally because of ill-defined diagnostic criteria and lack of direct access to the cerebellum. Forms of ataxia characterized by hypogonadotrophic hypogonadism also exist, but these are not considered here.

The association between hypergonadotrophic hypogonadism and ataxia was first reported by Skre and colleagues.²⁵ In one family, a 16-year old girl was affected, whereas in the other family there were three affected sisters. In the sporadic case and in one of the three sibs, ataxia was observed shortly after birth; in the two other sibs, age of onset occurred later in childhood. Cataracts were present in all individuals described by Skre and colleagues.²⁵

Hypergonadotropic hypogonadism and ataxia was subsequently reported by De Michele and colleagues,²⁶ Linssen and colleagues,²⁷ Gottschalk and colleagues,²⁸ Fryns and colleagues,²⁹ Nishi and colleagues,¹² and Amor and colleagues.³⁰ In these various reports the clinical features of ataxia have varied. Findings similar to those of Skre and colleagues²⁵ were reported by De Michele and colleagues,²⁶ Nishi and colleagues,¹² and Amor and colleagues³⁰; ataxia was usually not progressive. Mitochondrial enzymopothy was evident in one case reported by De Michele and colleagues,²⁶ but in no other cases were mitochondrial studies conducted. Only Skre and colleagues²⁵ observed cataracts and only Linssen and colleagues²⁷ observed amelogenesis. Neurosensory deafness was reported by Amor and colleagues³⁰ Mental retardation is likewise variable.³⁰

In conclusion, a single mutant gene is unlikely to explain every single case of XX gonadal dysgenesis and cerebella ataxia. However, not every family need to be unique.

XX Gonadal Dysgenesis and Multiple Malformation Syndromes

Several other pleiotropic genes cause XX gonadal dysgenesis and various somatic features. All are rare and in perhaps even unique to a specific family. Table 3 lists these syndromes: XX gonadal dysgenesis, microcephaly, and arachnodactyly³¹; XX gonadal dysgenesis, cardiomyopathy, blepharoptosis, and broad nasal bridge^30,32; XX gonadal dysgenesis and epibulbar dermoid³³; XX gonadal dysgenesis, short stature and metabolic acidosis.³⁴ Assuming mendelian etiology, these disorders are presumably autosomal recessive. However, subtle chromosomal rearrangements cannot be excluded.

TABLE 3. Malformation Syndromes with 46,XX Gonadal Dysgenesis

Primary ovarian failure is observed frequently in well-established and not necessarily uncommon in mendelian disorders. All are characterized by distinct somatic features (Table 4). Pleiotrophy for these mutant genes allows clear distinction from disorders previously discussed.

TABLE 4. Autosomal Recessive Disorders the Phenotype of Which is Predominately Somatic but in Which Ovarian Failure is also Observed

Of special note is Denys-Drash syndrome and Frasier syndrome, which are caused by mutations in WT-1 (Wilms’ tumor-1), a gene located on 11p. WT-1 mutations can cause either 46,XY gender reversal or 46,XY genital ambiguity. One 46,XX individual with Frasier syndrome has been reported.³⁵ This woman manifested not only the renal parenchymal disease characteristic of Frasier syndrome, but also primary amenorrhea and ovarian failure. Gonadal failure in 46,XX Frasier syndrome could easily pass unappreciated if the primary amenorrhea is assumed to occur secondary to azotemia.

Germ-Cell Failure in Male (46,XY) and Female (46,XX) Sibs

In several sibships, male and female sibs have shown germinal cell failure. Affected 46,XX females showed streak gonads, whereas 46,XY affected males showed germ-cell aplasia (Sertoli-cell–only syndrome). In two families, parents were consanguineous, and in each there were no somatic anomalies.^36,37 In three other families (see Table 1), characteristic somatic anomalies suggested distinct entities. Hamet and colleagues³⁸ observed germ-cell failure, hypertension, and deafness; Al-Awadi and colleagues³⁹ found germ-cell failure and alopecia; Mikati and colleagues⁴⁰ reported germ-cell failure, microcephaly and short stature.

In each of these families a single autosomal gene is presumed to affect germ cell development deleteriously in both sexes. This gene(s) could act either at a specific site common to early germ cell development or exert its effect through meiotic breakdown. Elucidating such genes could help explain normal germ cell development. Indeed, a variety of attractive candidate genes exist in mouse and Drosphila (see Table 2). An example is gcd, a mouse mutant in which germ cells are deficient in both males and females.

Galactosemia

Galactosemia is caused by deficiency of galactose 1-phosphate uridyl transferase (GALT). The gene is located on 9p. Long-recognized features included renal, hepatic, and ocular defects. Kaufman and colleagues⁴¹ reported POF in 12 of 18 galactosemic women, and Waggoner and colleagues⁴² observed ovarian failure in 8 of 47 females. Pathogenesis presumed to involve galactose toxicity during infancy or childhood; elevated fetal levels of toxic metabolites should be cleared rapidly in utero by maternal enzymes. Consistent with this hypothesis, a neonate with galactosemia showed normal ovarian histology.⁴³

Given the clinical severity of galactosemia and the absolute necessity for dietary treatment during childhood to prevent mental retardation, it seems highly unlikely that previously undiagnosed galactosemia would prove to be the cause of ovarian failure in women presenting solely with primary amenorrhea or POF. Of greater relevance to gynecology, therefore, was the report in 1989 by Cramer and colleagues⁴⁴ that GALT heterozygotes were at increased risk for POF.⁴⁴ However, the same author later failed to observe GALT abnormalities in another sample of women with early menopause,²³ and Kaufman and colleagues⁴⁵ likewise failed to confirm the observation. Moreover, not all homozygotes for human galactosemia are abnormal, nor are transgenic mice in which GALT is inactivated.⁴⁶

Carbohydrate-Deficient Glycoprotein Intrauterine Contraceptives (Cdg) [Phosphomannomutase Deficiency [PMM2])

In type 1 carbohydrate-deficient-glycoprotein (CDG) deficiency, mannose-6-phosphate cannot be converted to mannose-1-phosphate. Thus, the lipid-linked mannose-containing oligosaccharides needed for secretory glycoproteins are lacking. The CDG gene is located on 16p13. The molecular pathogenesis is usually a missense mutation.⁴⁷

The wide spectrum of neurologic abnormalities includes hypotonia, hyperreflexia, unprovoked eye movements, ataxia, joint contractions, epilepsy, and stroke-like episodes.⁴⁸ Subcutaneous fat deposits, hepatomegaly, cardiomyopathy, pericardial effusion, and factor XI (clotting) deficiency develop.

Of interest here is that ovarian failure occurs; the ovaries are devoid of follicular activity.^49,50

Deficiency of 17α-Hydroxylase/17,20-Desmolase (Lyase) Deficiency (Cyp17)

Sex steroid synthesis requires intact adrenal and gonadal biosynthetic pathways. Various gene products (enzymes) are necessary to convert cholesterol to testosterone and androstenedione and, hence, estrogens. The various enzyme blocks have varying but predictable consequences, depending on their site in the biosynthetic pathway (Fig. 2). The most common adrenal biosynthetic problem is involving deficiency of 21- or 11β-hydroxylase, either of which causes pseudohermaphroditism. These disorders cause genital ambiguity because of virilization, but need not be considered in the differential diagnosis of XX gonadal dysgenesis.

If the cytochrome P450 enzyme 17α-hydroxylase/17-20-lyase is deficient, pregnenolone cannot be converted to 17α-hydroxy-pregnenolone. If the enzyme defect were complete, cortisol, androstenedione, testosterone, and estrogens could not be synthesized; however, 11-deoxycorticosterone and corticosterone could. With compensatory increase in adrenocorticotropic hormone (ACTH secretion), 11-deoxycorticosterone and corticosterone increase to result in hypernatremia, hypokalemia, and hypervolemia. Hypertension occurs. Aldosterone is decreased, presumably because hypervolemia suppresses the renin-angiotensin system.

Females (46,XX) with 17α-hydroxylase deficiency have normal external genitalia, but at puberty fail to undergo normal secondary sexual development (primary amenorrhea). Affected males (46,XY) usually have genital ambiguity (male pseudohermaphroditism) because partial expression of the gene produced some androgens. Affected females are ordinarily encountered in differential diagnosis of XX gonadal dysgenesis. Hypertension is the major distinguishing clue. Oocytes appear incapable of spontaneously exceeding a diameter greater than 2.5 mm,⁵¹ but ovaries nonetheless respond to exogenous gonadotropins.⁵²

17α-hydroxylase deficiency is inherited in autosomal recessive fashion. The gene (CYP17) is located on 10q24-25, and the gene product is a cytochrome P450 enzyme. More than 20 different mutations have been identified in CYP17, scattered among the 8 exons. Mutations include missense mutations, duplications, deletions, and premature protein truncation.⁵³ Most mutations have been observed in only a single family, yet another example of molecular hetereogeneity. An exception exists in Mennonites of Dutch origin, where a 4-base duplication in exon 8 accounts for most cases.⁵⁴ This founder mutation originated in Friesland.

This single gene (and enzyme) is responsible for both 17α-hydroxylase and 17,20-desmolase (lyase) actions (see Fig. 2). A few patients having deficiency of both 17α-hydroxylase and 17,20 lyase activities have been analyzed, with mutations different from those only showing deficient 17α-hydroxylase activity have been found.^55,56 Transfection experiments show that only 5% of 17α-hydroxylase activity is sufficient for the estrogen production necessary for normal secondary sexual characteristics in a 46,XX individual; however, 25% of enzyme activity is necessary to virilize external genitalia in males.^53,55 Targeted mutagenesis in the rat gene indicates that mutations closer to the 5′ end are more deleterious.

Aromatase Mutations (Cyp19)

Conversion of androgens (Δ4-androstenedione) to estrogens (estrone) requires cytochrome P-450 aromatase, an enzyme product of a 40-kb gene located on chromosome 15q21.1.⁵⁷ Deficiency of the aromatase enzyme in 46,XX individuals is most often associated with clitoral hypertrophy or genital ambiguity, but 46,XX aromatase deficiency may present as primary amenorrhea in phenotypic females.

Ito and colleagues⁵⁸ reported aromatase mutation (CYP19) in an 18-year-old 46,XX Japanese woman having primary amenorrhea and cystic ovaries. Compound heterozygosity, existed for two point mutations in exon 10. The mutant protein had no activity. Conte and colleagues⁵⁹ reported aromatase deficiency in a 46,XX woman presenting with primary amenorrhea, elevated gonadatropins, and ovarian cysts. Compound heterozygositly also existed for two mutations in exon 10. One mutation was ′ C1303T (cysteine rather than arginine); the other was ′ G1310A (tyrosine rather than cysteine).

Mullis and colleagues⁶⁰ reported clitoral enlargement at puberty. No breast development occurred. FSH was elevated; estrone and estradiol were decreased. Multiple ovarian follicular cysts were evident. Hormonal (estrogen and progesterone) therapy produced a growth spurt, breast development, menarche, and decreased numbers of follicular cysts. Compound heterozygosity existed in CYP19.

46,XX Agonadia

Agonadia usually occurs in 46,XY individuals but, rare 46,XX cases exist. As in 46,XY agonadia, gonads are absent, in 46,XX agonadia. This contrasts with persistence in the form of streaks (gonadal dysgenesis). External genitalia are abnormal but female-like; no more than rudimentary Müllerian or wolffian derivatives are present. External genitalia usually consist of a phallus about the size of a clitoris, underdeveloped labia majora, and nearly complete fusion of labioscrotal folds. Thus, external genitalia are nearly or somewhat female in appearance. In approximately one half of cases, somatic anomalies coexist: craniofacial anomalies, vertebral anomalies, and mental retardation.

Agonadia must be considered in the differential diagnosis of 46,XX primary amenorrhea. The 46,XX agonadia cases reported by Duck,⁶¹ and Levinson⁶² were sporadic. Mendonca and colleagues⁶³ reported agonadia without somatic anomalies in phenotypic sibs having unlike chromosomal complements (46,XY and 46,XX). Kennerknecht and colleagues⁶⁴ reported agonadism, hypoplasia of the pulmonary artery and lung, and dextrocardia in XX and XY sibs.

Premature ovarian failure can result from nongenetic causes as well as several different genetic causes (Table 5). Genetic or familial POF can be stratified into these four general etiologies: (1) autosomal rearrangements, (2) X-chromosomal abnormalities, (3) autosomal recessive genes (sometimes the same genes resulting in the various forms of XX gonadal dysgenesis; see above); (4) autosomal chromosomal rearrangements, and (5) autosomal dominant genes including whose action may or may not be restricted to POF. In addition, the possibility exists that some cases of POF merely represent the lower end of the normal population with respect to ovarian number and function (i.e., early but normally executed menopause). We shall first consider this concept.

TABLE 5. Genetic Causes of Premature Ovarian Failure

  Premature ovarian failure as normal continuous variation: heritable early menopause
  Autosomal chromosomal rearrangements
  X-chromosomal abnormalities
  Autosomal recessive premature ovarian failure (Table 1)
  Autosomal dominant premature ovarian failure (Table 6)
  Blepharophimosis-ptosis-epicanthus (FOXL2) (Table 7)
  Fragile X syndrome and expansion of triplet nucleotide repeats (CGG) (Table 8)
  Myotonic dystrophy and expansion of triplet repeats (CTG)
  Premature ovarian failure and polyglandular autoimmune syndrome
  Premature ovarian failure associated with anti-ovarian antibodies or oophorities (genetic basis?)

Premature Ovarian Failure as Normal Continuations Variation: Heritabile Early Menopause

Oocyte number (reservoir) could be low in some women simple on statistical (stochastic) grounds. Normal distribution exists for all common anatomic traits (e.g., height), and this principle must apply to oocyte number and reservoir at birth. Different rodent strains show characteristic breeding duration, implying genetic control over either the rate of oocyte depletion or the number of oocytes initially present. That a normal distribution of germ cell number exists in ostensibly normal females is thus well established in animals, but difficulty to prove in humans. Nonetheless, some ostensibly normal (menstruating) women should have decreased oocyte reservoir or increased oocyte attrition on a genetic basis, analogous to animal models.

In humans, a genetic basis for the above can also be presumed by analogy to the heritability of age at human menopause, a characteristic that clearly shows familiar tendencies. However, determining heritability of age of menopause in humans is complicated because of iatrogenic factors (e.g, hysterectomy) and other confounders (e.g., presence of leiomyomata). Cramer and colleagues²³ took these confounders into account in a case-control study of 10,606 U.S. women. Women with an early menopause (40 to 45 years) were age-matched with controls who were either still menstruating or who had experienced menopause after age 46. Of 129 early menopause cases, 37.5% had a similarly affected mother, sister, aunt, or grandmother. Only 9% of controls had such a relative (odds ratio after adjustment 6.1, 95% confidence interval [CI] 3.9 to 9.4). As predicted on the basis of polygenic inheritance, the odds ratio was greatest (9.1) for sisters and greater when menopause occurred prior to 40 years. Incidentally, frequency of galactose 1-phosphate uridyltransferase (GALT) variants (N314D or Q188R) did not deviate from that expected in early menopause cases, in contrast to earlier studies by the same authors.⁴⁴ The results of Cramer and colleagues²³ were confirmed by Torgerson and colleagues,⁶⁵ who studied women undergoing menopause during the 5-year centile ages 45 to 49 years. The likelihood was increased that menopause would occur in a similar 5-year centile in their daughters.

Twin studies have confirmed heritability of age at menopause.⁶⁶ Snieder and colleagues⁶⁷ studied 275 monozygotic (MZ) and 353 dizygotic (DZ) U.K. twin pairs. For age at menopause, correlation (r) was 0.58 for MZ and 0.39 DZ twins; heritability (h²) was calculated to be 63%. The study of Treloar and colleagues⁶⁸ involved 466 MZ and 262 DZ Australian twin pairs. For age at menopause the correlation (r) was 0.49 to 0.57 for MZ and 0.31 to 0.33 for DZ twin pairs. Differences between MZ and DZ held when iatrogenic causes of menopause was taken into account.

Autosomal Chromosomal Rearrangements

Autosomal chromosomal rearrangements can also lead to premature ovarian failure with many different reciprocal translocations involved. The underlying mechanism is presumably meiotic breakdown. About 2% of azoospermic or oligospermic men who present for intracytoplamic sperm injection (ICSI) but are otherwise clinically normal show balanced autosomal translocations.^69,70

Approximately 2% of their ostensibly normal female partners also show balanced translocations. A relation thus also exists between balanced translocations and infertility in women, but lack of a readily assayed end point to pinpoint infertility makes studies more difficult in females than in men. The frequency in infertile women having normal male partners has not been crisply defined because of pronounced biases of ascertainment in almost all series. However, the prevalence is surely at least 2% and probably higher. The same translocation almost certainly predisposes to POF or early menopause.

Detecting individuals with a chromosomal rearrangement is important not only as an explanation for their offspring are at risk far unbalanced chromosomal abnormalities.

Autosomal Dominant Premature Ovarian Failure

Autosomal dominant familial tendencies per se have long been recognized in cytogenetically normal women with POF who have no other clinical abnormalities. Thus, discussion here excludes X-abnormalities [del(Xp) and (Xq)] and the syndrome blepharophimosis-ptosis-epicanthus as a result of FOXL2 perturbations. Other samples of women with POF report high frequencies of associated abnormalities, such as Kim and colleagues⁷¹; 22 of 119 women with POF (18.5%) were hypothyroid, and 3 had Addison’s disease. Although this seems atypical, for many years it was widely assumed that familial tendencies in POF merely reflected autoimmune phenomena. In women with POF, antibodies against adrenal,^72,73,74 thyroid,⁷⁵ and pancreas⁷³ may be detected⁷⁶; however, autoimmune factors are not always or even often observed. Familial tendencies in the absence of autoimmune findings are more common. This was observed decades ago. Coulam and colleagues⁷⁷ reported POF in sibs who had an affected mother and aunt. Affected individuals in more than one generation were reported by Starup and Sele,⁷⁸ Austin and colleagues,⁷⁹ and Mattison and colleagues.⁸⁰ In none of these families were autoimmune phenomena observed.

In Italy, Testa and colleagues⁸¹ and Vegetti and colleagues⁸² are systematically studying women first with POF (menopause at younger than 40 years of age) recruited from a large northern Italian population. After excluding 10 cases with known etiologies (5 chromosomal, 3 prior ovarian surgery, 1 prior chemotherapy, 1 galactosemia), 71 probands remained. Of the 71, 22 (31%) had other affected relatives (Table 6). An expanded sample of 130 cases found 28.5% familial cases.⁸³ Patterns of inheritance observed were consistent with autosomal or X-linked dominant inheritance; transmission through both maternal and paternal lineage was observed. Among 30 other women experiencing early menopause (40 to 50 years) half showed other affected relatives. There further is evidence that POF (younger than 40 years) and early menopause (menopause at 40 to 50 years) represent the same phenomena. The two different phenotypes have been observed within a single kindred, transmission through either a paternal or maternal relative.

TABLE 6. Frequency of Heritable Premature Ovarian Failure in an Italian Referral Sample

Pathogenic mechanisms for autosomal dominant premature ovarian failure include decreased number of primordial follicles or human homologous of mouse cited in Table 2. Nongenetic etiologies (phenocopies) might include infiltrative disease (e.g., sarcoidosis), toxins, or autoimmune phenomenon. Environmental causes are unlikely to explain intergenerational familial aggregates.

Blepharophimosis-Ptosis-Epicanthus (FOX L2)

Blepharophimosis-ptosis-epicanthus (BPE) is an autosomal dominant multiple malformation syndrome long known to be associated with ovarian failure. Usually POF exists, not complete ovarian failure^84,85. In one unusual case, Fraser and colleagues⁸⁶ reported that the ovaries of an affected individual were unresponsive to gonadatropins.

Sib-pair analysis using polymorphic DNA variants⁸⁷ localized the gene to chromosome 3 (3q22→24), a region that contains no obvious candidate gene.⁸⁸ Positional cloning revealed mutation in the one exam, winged helix/forkhead transcription factor gene (FOXL2), yielding a truncated protein⁸⁹ in each of four cases (Table 7). This indicates the mechanism of gene action is haplo-insufficiency. Mutations observed included three stop codons (X) and a 17–base pair duplication causing a frameshift and, hence, truncated gene product. Postulated FOXL2 gene function includes inhibition of proapoptotic genes such as tumor necrosis factor (TNF)-α, thus, on sustaining follicle viability.

TABLE 7. FOXL2 Mutations in Blepharophimosis-Ptosis Epicanthus Syndrome (BPES, type 1)

The gene is expressed in mesenchyma of mouse eyelids and in adult ovarian follides, consistent with phenotype observed in the mutation of the human homologue BPE.

Fragile X Syndrome and Expansion of Triplet Nucleotide Repeats (CGG)

A molecular mechanism seemingly relevant to ovarian development is expansion of triplet nucleotide repeats. The prototype is the fragile X syndrome, caused by mutation of the FMRI gene on Xq27. Fragile refers to a tendency toward chromosomal breakage when affected cells are cultured in folic acid-deficient media. Various fragile sites exist in humans, but only FRAXA and FRAXE in particular are relevant to the present discussion.

In FRAXA, males show mental retardation, characteristic facial features, and large testes. The molecular basis involves repetition of the triplet repeat CGG (CGG)ⁿ 230 times or more (Fig. 3). Ordinarily, the normal number of repeats in males is only 6 to 50. When heterozygous females show 50 to 200 repeats, a permutation is said to be present. During female (but not male) meiosis the number of triplet repeats may increase (expand). A woman with a FRAXA premutation may have an affected son if the number of CGG repeats on the X transmitted to her offspring were to expand during meiosis to more than 230 repeats; her son would then inherit that expanded X and, hence, be affected. These molecular changes are readily seen by straightforward molecular studies (Fig. 4). Females may also be affected if expansion occurs, but show a less severe phenotype than males.

Females with the FRAXA premutation may show POF. Schwartz and colleagues⁹⁰ reported that fragile X carrier females more often showed oligomenorrhea than noncarrier female relatives (38% versus 6%). Murray and colleagues⁹¹ analyzed 1268 controls, 50 familial POF cases, and 244 sporadic POF cases. Of familial cases, 16% showed FRAXA premutation; among sporadic cases, only 1.6% showed POF (Table 8). In the same sample POF was not increased in FRAXE. An international collaborative survey⁹² of 395 premutation carriers revealed 63 (16%) underwent menopause under 40 years of age; only 0.4% of controls did. Surprisingly, frequency of POF was not increased in 128 FRAXA cases having a full mutation. Consistent with the above are observations that heterozygous FRAXA women respond poorly to ovulation-inducing agents, producing fewer oocytes and fewer embryos in assisted reproductive technologies (ART).⁹³

TABLE 8. Premature Ovarian Failure and Fragile X

The consensus seems to be that FRAXA is associated with POF. However, Kennerson and colleagues⁹⁴ do not agree. They argue that data are best explained by a contiguous gene syndrome. That is, they postulate two separate but closely linked loci. Both may or may not be deleted in a given individual. That Xq27-28 contains both FMR-1 (FRAXA) and a region important for ovarian maintenance is consistent with, but does not prove, this hypothesis.

Myotonic Dystrophy and Expansion of Triplet Repeats (CTG)

Myotonic dystrophy is an autosomal dominant disorders are characterized by muscle wasting (head, neck, extremities), frontal balding, cataracts, and male hypogonadism (80%) caused by testicular atrophy. Female hypogonadism is much less common, if increased at all. Despite frequent textual citations, ovarian failure is actually not well documented.

Pathogenesis of myotonic dystrophy involves nucleotide expansion of CTG in the 3[prime] untranslated region of a protein located on chromosome 19. Normally, 5 to 27 CTG repeats are present. Heterozygotes usually have at least 50 repeats; severely affected individuals show 600 or more. As in FRAXA, poor response to ovulation induction regions is observed. Sermon and colleagues⁹⁵ report fewer embryos per cycle than in standard ART; thus, pregnancy rates in preimplantation genetic diagnosis are decreased.

Premature Ovarian Failure and Polyglandular Autoimmune Syndrome

Type 1 polyglandular autoimmune syndrome is an autosomal recessive disorder characterized by deficiencies of the parathyroids, adrenals and gonad exist; moniliasis secondary to immune deficiencies is common. Hypergonadotropic ovarian failure occurs in 60% of cases. The disorder is common in Finland and in the Iranian Jewish population,⁹⁶ but rare in other populations. Localized to human 2q22.3 the gene has a murine homologue: autoimmune regulation gene (AIRE).

Type II polyglandular autoimmune syndrome is also called Schmidt syndrome. Inheritance is autosomal dominant. Failure or hypofunction occurs in gonads, adrenals, thyroid, and pancreas. Hematologic, gastrointestinal, ocular, and integumental (hair) defects also occur; immunologic dysfunction is often pronounced.

Premature Ovarian Failure Associated with Anti-Ovarian Antibodies or Oophorities

Anti-ovarian antibodies may be either generalized in nature or directed against a specific cellular component (e.g., gonadotropin receptor, stromal cells, zona pellucida). Anasti⁹⁷ reviewed the role of anti-ovarian antibodies in ovarian failure. In our opinion, a casual relation seems less likely than a secondary effect (epiphenomenon), antibodies arising only after ovarian damage has occurred for unrelated but primary reasons.

Similar reasoning applies to the hypothesis of oophoritis as a common cause of premature ovarian failure.

1. Simpson JL: Gonadal dysgenesis and sex chromosome abnormalities. Phenotypic/karyotypic correlations In Vallet HL, Perter IH (eds): Genetic Mechanisms of Sexual Development. pp 365, 405 New York, Academic Press, 1994

2. Meyers CM, Boughman JA, Rivas M, et al: Gonadal (ovarian) dysgenesis in 46,XX individuals: frequency of the autosomal recessive form. Am J Med Genet 63:518, 1996

3. Simpson JL, Christakos AC, Horwith M, et al: Gonadal dysgenesis associated with apparently normal chromosomal complements. Birth Defects 12(6):215, 1971

4. Boczkowski K: Pure gonadal dysgenesis and ovarian dysplasia in sisters. Am J Obstet Gynecol 106:626, 1970

5. Aittomaki K: The genetics of XX gonadal dysgenesis. Am J Hum Genet 54:844, 1994

6. Portuondo JA, Neyro JL, Benito JA, et al: Familial 46,XX gonadal dysgenesis. Int J Fertil 32:56, 1987

7. Aittomaki K, Lucena JL, Pakarinen P, et al: Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959, 1995

8. Perrault M, Klotz P, Housset E: Deux cas de syndrome de Turner avec surdi-mutite dans une meme fratrie. Bull Soc Med Hop Paris 67:79, 1951

9. Christakos AC, Simpson JL, Younger JB, et al: Gonadal dysgenesis as an autosomal recessive condition. Am J Obstet Gynecol 104:1027, 1969

10. Pallister PD, Opitz JM: The Perrault syndrome: Autosomal recessive ovarian dysgenesis with facultative, non-sex–limited sensorineural deafness. Am J Med Genet 4:239, 1979

11. McCarthy DJ, Opitz JM: Perrault syndrome in sisters. Am J Med Genet 22:629, 1985

12. Nishi Y, Hamamoto K, Kajiyama M, et al: The Perrault syndrome: Clinical report and review. Am J Med Genet 31:623, 1988

13. Aittomaki K, Herva R, Stenman UH, et al: Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab 81:3722, 1996

14. Layman LC, Amde S, Cohen DP, et al: The Finnish follicle-stimulating hormone receptor gene mutation is rare in North American women with 46,XX ovarian failure. Fertil Steril 69:300, 1998

15. Simoni M, Gromoll J, Nieschlag E: The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev 18:739, 1997

16. da Fonte Kohek MB, Batista MC, Russell et al: No evidence of the inactivating mutation (C566T) in the follicle-stimulating hormone receptor gene in Brazilian women with premature ovarian failure. Fertil Steril 70:565, 1998

17. de la Chesnaye E, Canto P, Ulloa-Aguirre A, et al: No evidence of mutations in the follicle-stimulating hormone receptor gene in Mexican women with 46,XX pure gonadal dysgenesis. Am J Med Genet 98:125, 2001

18. Liu JY, Gromoll J, Cedars MI, et al: Identification of allelic variants in the follicle-stimulating hormone receptor genes of females with or without hypergonadotropic amenorrhea. Fertil Steril 70:326, 1998

19. Simpson JL, Rajkovic A: Ovarian differentiation and gonadal failure. Am J Med Genet 89:186, 1999

20. Tapanainen JS, Aittomaki K, Min J, et al: Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet 15:205, 1997

21. Latronico AC, Anasti J, Arnhold IJ, et al: Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N Engl J Med 334:507, 1996

22. Toledo SP, Brunner HG, Kraaij R, et al: An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female. J Clin Endocrinol Metab 81:3850, 1996

23. Cramer DW, Xu H, Harlow BL: Family history as a predictor of early menopause. Fertil Steril 64:740, 1995

24. Laue L, Wu SM, Kudo M, et al: A nonsense mutation of the human luteinizing hormone receptor gene in Leydig cell hypoplasia. Hum Mol Genet 4:1429, 1995

25. Skre H, Bassoe HH, Berg K, et al: Cerebellar ataxia and hypergonadotropic hypogonadism in two kindreds. Chanceconcurrence, pleiotropism or linkage? Clin Genet 9:234, 1976

26. De Michele G, Filla A, Striano S, et al: Heterogeneous findings in four cases of cerebellar ataxia associated with hypogonadism (Holmes’ type ataxia). Clin Neurol Neurosurg 95:23, 1993

27. Linssen WH, Van den Bent MJ, Brunner HG, et al: Deafness, sensory neuropathy, and ovarian dysgenesis: A new syndrome or a broaderspectrum of Perrault syndrome? Am J Med Genet 51:81, 1994

28. Gottschalk ME, Coker SB, Fox LA: Neurologic anomalies of Perrault syndrome. Am J Med Genet 65:274, 1996

29. Fryns JP, Van Lingen C, Devriendt K, et al: Two adult females with a distinct familial mental retardation syndrome: non-progressive neurological symptoms with ataxia and hypotonia, similar facial appearance, hypergonadotrophic hypogonadism, and retinal dystrophy. J Med Genet 35:333, 1998

30. Amor DJ, Delatycki MB, Gardner RJ, et al: New variant of familial cerebellar ataxia with hypergonadotropic hypogonadism and sensorineural deafness. Am J Med Genet 99:29, 2001

31. Maximilian C, Ionescu B, Bucur A: [Two sisters with major gonadal dysgenesis, dwarfism, microcephaly, arachnodactyly,and normal karyotype 46,XX]. J Genet Hum 18:365, 1970

32. Malouf J, Alam S, Kanj H, et al: Hypergonadotropic hypogonadism with congestive cardiomyopathy: Anautosomal-recessive disorder? Am J Med Genet 20:483, 1985

33. Quayle SA, Copeland KC: 46,XX gonadal dysgenesis with epibulbar dermoid. Am J Med Genet 40:75, 1991

34. Pober BR, Zemel S, Hisama FM: 46,XX gonadal dysgenesis, short stature and recurrent metabolic acidosis in two sisters. Am J Hum Genet 63:A117, 1998

35. Bailey WA, Zwingman TA, Reznik VM, et al: End-stage renal disease and primary hypogonadism associated with a 46,XX karyotype. Am J Dis Child 146:1218, 1992

36. Smith A, Fraser IS, Noel M: Three siblings with premature gonadal failure. Fertil Steril 32:528, 1979

37. Granat M, Amar A, Mor-Yosef S, et al: Familial gonadal germinative failure: Endocrine and human leukocyte antigen studies. Fertil Steril 40:215, 1983

38. Hamet P, Kuchel O, Nowaczynski W, et al: Hypertension with adrenal, genital, renal defects, and deafness. A new familial syndrome Arch Intern Med 131:563, 1973

39. Al Awadi SA, Farag TI, Teebi AS, et al: Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet 22:619, 1985

40. Mikati MA, Najjar SS, Sahli IF, et al: Microcephaly, hypergonadotropic hypogonadism, short stature, and minor anomalies: a new syndrome. Am J Med Genet 22:599, 1985

41. Kaufman FR, Kogut MD, Donnell GN, et al: Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 304:994, 1981

42. Waggoner DD, Buist NR, Donnell GN: Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inherit Metab Dis 13:802, 1990

43. Levy HL, Driscoll SG, Porensky RS, et al: Ovarian failure in galactosemia. N Engl J Med 310:50, 1984

44. Cramer DW, Harlow BL, Barbieri RL, et al: Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history. Fertil Steril 51:609, 1989

45. Kaufman FR, Devgan S, Donnell GN: Results of a survey of carrier women for the galactosemia gene. Fertil Steril 60:727, 728 1993

46. Leslie ND, Yager K, Bai S: A mouse model for transferase deficiency galactosemia. Am J Hum Genet 57:191, 1995

47. Bjursell C, Stibler H, Wahlstrom J, et al: Fine mapping of the gene for carbohydrate-deficient glycoprotein syndrome, type I (CDG1): linkage disequilibrium and founder effect in Scandinavian families. Genomics 39:247, 1997

48. Matthijs G, Schollen E, Pardon E, et al: Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 16:88, 1997

49. de Zegher F, Jaeken J: Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res 37:395, 1995

50. Kristiansson B, Stibler H, Wide L: Gonadal function and glycoprotein hormones in the carbohydrate-deficient glycoprotein (CDG) syndrome. Acta Paediatr 84:655, 1995

51. Araki S, Chikazawa K, Sekiguchi I, et al: Arrest of follicular development in a patient with 17 alpha-hydroxylase deficiency: Folliculogenesis in association with a lack of estrogen synthesis in the ovaries. Fertil Steril 47:169, 1987

52. Rabinovici J, Blankstein J, Goldman B, et al: In vitro fertilization and primary embryonic cleavage are possible in 17 alpha-hydroxylase deficiency despite extremely low intrafollicular 17 beta-estradiol. J Clin Endocrinol Metab 68:693, 1989

53. Yanase T: 17alpha-Hydroxylase/17,20-lyase defects. J Steroid Biochem Mol Biol 53:153, 1995

54. Imai T, Yanase T, Waterman MR, et al: Canadian Mennonites and individuals residing in the Friesland region of The Netherlands share the same molecular basis of 17 alpha-hydroxylase deficiency. Hum Genet 89:95, 1992

55. Miura K, Yasuda K, Yanase T, et al: Mutation of cytochrome P-45017 alpha gene (CYP17) in a Japanese patient previously reported as having glucocorticoid-responsive hyperaldosteronism: With a review of Japanese patients with mutations of CYP17. J Clin Endocrinol Metab 81:3797, 1996

56. Kaneko S, Oshio S, Kobayashi T, et al: Human X- and Y-bearing sperm differ in cell surface sialic acid content. Biochem Biophys Res Commun 124:950, 1984

57. Simpson ER: Genetic mutations resulting in estrogen insufficiency in the male. Mol Cell Endocrinol 145:55, 1998

58. Ito Y, Fisher CR, Conte FA, et al: Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci USA 90:11673, 1993

59. Conte FA, Grumbach MM, Ito Y, et al: A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 78:1287, 1994

60. Mullis PE, Yoshimura N, Kuhlmann B, et al: Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: Impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab 82:1739, 1997

61. Duck SC, Sekhon GS, Wilbois R, et al: Pseudohermaphroditis, with testes and a 46,XX karyotype. J Pediatr 87:58, 1975

62. Levinson G, Zarate A, Guzman-Toledano R, et al: An XX female with sexual infantilism, absent gonads, and lack of Mullerian ducts. J Med Genet 13:68, 1976

63. Mendonca BB, Barbosa AS, Arnhold IJ, et al: Gonadal agenesis in XX and XY sisters: Evidence for the involvement of an autosomal gene. Am J Med Genet 52:39, 1994

64. Kennerknecht I, Sorgo W, Oberhoffer R, et al: Familial occurrence of agonadism and multiple internal malformations in phenotypically normal girls with 46,XY and 46,XX karyotypes, respectively: A new autosomal recessive syndrome. Am J Med Genet 47:1166, 1993

65. Torgerson DJ, Thomas RE, Reid DM: Mothers and daughters menopausal ages: Is there a link? Eur J Obstet Gynecol Reprod Biol 74:63, 1997

66. Treloar SA, Do KA, Martin NG: Genetic influences on the age at menopause. Lancet 352:1084, 1998

67. Snieder H, MacGregor AJ, Spector TD: Genes control the cessation of a woman’s reproductive life: A twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 83:1875, 1998

68. Treloar SA, Martin NG, Heath AC: Longitudinal genetic analysis of menstrual flow, pain, and limitation in a sample of Australian twins. Behav Genet 28:107, 1998

69. Guttenbach M, Engel W, Schmid M: Analysis of structural and numerical chromosome abnormalities in sperm of normal men and carriers of constitutional chromosome aberrations. A review Hum Genet 100:1, 1997

70. Gekas J, Thepot F, Turleau C, et al: Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men. Hum Reprod 16:82, 2001

71. Kim TJ, Anasti JN, Flack MR, et al: Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 89:777, 1997

72. Karlsson FA, Kampe O, Winqvist O, et al: Autoimmune disease of the adrenal cortex, pituitary, parathyroid glands and gastric mucosa. J Intern Med 234:379, 1993

73. LaBarbera AR, Miller MM, Ober C, et al: Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol Microbiol 16:115, 1988

74. Rebar RW, Erickson GF, Yen SS: Idiopathic premature ovarian failure: Clinical and endocrine characteristics. Fertil Steril 37:35, 1982

75. Alper MM, Garner PR: Premature ovarian failure: Its relationship to autoimmune disease. Obstet Gynecol 66:27, 1985

76. Belvisi L, Bombelli F, Sironi L, et al: Organ-specific autoimmunity in patients with premature ovarian failure. J Endocrinol Invest 16:889, 1993

77. Coulam CB, Stringfellow S, Hoefnagel D: Evidence for a genetic factor in the etiology of premature ovarian failure. Fertil Steril 40:693, 1983

78. Starup J, Sele V: Premature ovarian failure. Acta Obstet Gynecol Scand 52:259, 1973

79. Austin GE, Coulam CB, Ryan RJ: A search for antibodies to luteinizing hormone receptors in premature ovarian failure. Mayo Clin Proc 54:394, 1979

80. Mattison DR, Evans MI, Schwimmer WB, et al: Familial premature ovarian failure. Am J Hum Genet 36:1341, 1984

81. Testa G, Vegetti W, Tibiletti MC, et al: Pattern of inheritance in familial premature ovarian failure. Hum Reprod 12:P-174, 1997

82. Ragni G, Parazzini F, Sapienza F, et al: Semen parameters and conception rates after intraperitoneal insemination. Gynecol Obstet Invest 44:239, 1997

83. Vegetti W, Marozzi A, Manfredini E, et al: Premature ovarian failure. Mol Cell Endocrinol 161:537, 2000

84. Zlotogora J, Sagi M, Cohen T: The blepharophimosis, ptosis, and epicanthus inversus syndrome: Delineation of two types. Am J Hum Genet 35:1020, 1983

85. Panidis D, Rousso D, Vavilis D, et al: Familial blepharophimosis with ovarian dysfunction. Hum Reprod 9:2034, 1994

86. Fraser IS, Shearman RP, Smith A, et al: An association among blepharophimosis, resistant ovary syndrome, and true premature menopause. Fertil Steril 50:747, 1988

87. Harrar HS, Jeffery S, Patton MA: Linkage analysis in blepharophimosis-ptosis syndrome confirms localisation to 3q21-24. J Med Genet 32:774, 1995

88. Amati P, Gasparini P, Zlotogora J, et al: A gene for premature ovarian failure associated with eyelid malformation maps to chromosome 3q22-q23. Am J Hum Genet 58:1089, 1996

89. Crisponi L, Deiana M, Loi A, et al: The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159, 2001

90. Schwartz CE, Dean J, Howard-Peebles PN, et al: Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet 51:400, 1994

91. Murray A, Webb J, Grimley S, et al: Studies of FRAXA and FRAXE in women with premature ovarian failure. J Med Genet 35:637, 1998

92. Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, et al: Fragile X premutation is a significant risk factor for premature ovarian failure: The International Collaborative POF in Fragile X study. Preliminary data Am J Med Genet 83:322, 1999

93. Black SH, Levinson G, Harton GL, et al: Preimplanatation genetic testing (PGT) from fragile X (fraxX). Am J Hum Genet 57:A31, 1995

94. Kenneson A, Cramer DW, Warren ST: Fragile X premutations are not a major cause of early menopause. Am J Hum Genet 61:1362, 1997

95. Sermon K, De Vos A, Van de Velde V, et al: Fluorescent PCR and automated fragment analysis for the clinical application of preimplantation genetic diagnosis of myotonic dystrophy (Steinert’s disease). Mol Hum Reprod 4:791, 1998

96. Ahonen P, Myllarniemi S, Sipila I, et al: Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 322:1829, 1990

97. Anasti JN: Premature ovarian failure: An update. Fertil Steril 70:1, 1998

98. Luoh SW, Bain PA, Polakiewicz RD, et al: Zfx mutation results in small animal size and reduced germ cell number in male and female mice. Development 124:2275, 1997

99. Pellas TC, Ramachandran B, Duncan M, et al: Germ-cell deficient (gcd), an insertional mutation manifested as infertility in transgenic mice. Proc Natl Acad Sci USA 88:8787, 1991

100. Manova K, Bachvarova RF: Expression of c-kit encoded at the W locus of mice in developing embryonic germ cells and presumptive melanoblasts. Dev Biol 146:312, 1991

101. Matsui Y, Zsebo KM, Hogan BL: Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature 347:667, 1990

102. Luo X, Ikeda Y, Parker KL: A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481, 1994

103. Edelmann W, Cohen PE, Kneitz B, et al: Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21:123, 1999

104. Ratts VS, Flaws JA, Kolp R, et al: Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad. Endocrinology 136:3665, 1995

105. Soyal S, Rankin TDJ: International Workshop of Early Folliculogenesis and Oocytes Development: basis and clinical aspects. London: Abstract Presentation 1999

106. Dong J, Albertini DF, Nishimori K, et al: Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383:531, 1996

107. Kumar TR, Wang Y, Lu N, et al: Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 15:201, 1997

108. Dierich A, Sairam MR, Monaco L, et al: Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci USA 95:13612, 1998

109. Lubahn DB, Moyer JS, Golding TS, et al: Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162, 1993

110. Simon AM, Goodenough DA, Li E, et al: Female infertility in mice lacking connexin 37. Nature 385:525, 1997

111. Edelmann W, Cohen PE, Kane M, et al: Meiotic pachytene arrest in MLH1-deficient mice. Cell 85:1125, 1996

112. Rankin T, Familari M, Lee E, et al: Mice homozygous for an insertional mutation in the Zp3 gene lack a zona pellucida and are infertile. Development 122:2903, 1996

113. Topilko P, Schneider-Maunoury S, Levi G, et al: Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice. Mol Endocrinol 12:107, 1998

114. Hisama FM, Zemel S, Cherniske EM, et al: 46,XX gonadal dysgenesis, short stature, and recurrent metabolic acidosis in two sisters. Am J Med Genet 98:121, 2001

115. Narahara K, Kamada M, Takahashi Y, et al: Case of ovarian dysgenesis and dilated cardiomyopathy supports existence of Malouf syndrome. Am J Med Genet 44:369, 1992

116. Waldmann TA, Misiti J, Nelson DL, et al: Ataxia-telangiectasis: A multisystem hereditary disease with immunodeficiency, impaired organ maturation, x-ray hypersensitivity, and a high incidence of neoplasia. Ann Intern Med 99:367, 1983

117. Nance MA, Berry SA: Cockayne syndrome: Review of 140 cases. Am J Med Genet 42:68, 1992

118. Sugarman GI, Landing BH, Reed WB: Cockayne syndrome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 16:225, 1977

119. Martsolf JT, Hunter AG, Haworth JC: Severe mental retardation, cataracts, short stature, and primary hypogonadism in two brothers. Am J Med Genet 1:291, 1978

120. Harbord MG, Baraitser M, Wilson J: Microcephaly, mental retardation, cataracts, and hypogonadism in sibs: Martsolf’s syndrome. J Med Genet 26:397, 1989

121. Hennekam RC, van de Meeberg AG, van Doorne JM, et al: Martsolf syndrome in a brother and sister: clinical features and pattern of inheritance. Eur J Pediatr 147:539, 1988

122. Weemaes CM, Hustinx TW, Scheres JM, et al: A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 70:557, 1981

123. Conley ME, Spinner NB, Emanuel BS, et al: A chromosomal breakage syndrome with profound immunodeficiency. Blood 67:1251, 1986

124. Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M, et al: Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet 57:462, 1995

125. Hall JG, Pallister PD, Clarren SK, et al: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly: A new syndrome? Part I: Clinical, causal, and pathogenetic considerations Am J Med Genet 7:47, 1980

126. Starr DG, McClure JP, Connor JM: Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet 27:102, 1985

127. Goto M, Tanimoto K, Horiuchi Y, et al: Family analysis of Werner’s syndrome: A survey of 42 Japanese families with a review of the literature. Clin Genet 19:8, 1981

128. Vegetti W, Grazia TM, Testa G, et al: Inheritance in idiopathic premature ovarian failure: Analysis of 71 cases. Hum Reprod 13:1796, 1998