Turner syndrome has an incidence of 1 in 2500 females and accounts for 4–5 % of all cases of POI [10, 11]. Reproductive disorders in women with Turner syndrome (45,X) arise from the loss of all or part of the X chromosome. Unlike most cells in the body, oocytes require two active X chromosomes to function properly. Haploinsufficiency of many critical X-linked genes in fetuses with Turner syndrome results in accelerated follicular atresia, with oocyte depletion usually occurring within the first 10 years of life [5]. Candidate critical genes responsible for POI in Turner syndrome patients include USP9X (ubiquitin-specific protease 9), ZFX (zinc finger protein, X-linked), and BMP15 (bone morphogenetic protein 15) [12]. These genes will be described in further detail later in the chapter.

If not recognized by phenotype (short stature, webbed neck, low-set ear, widely spaced nipples) during childhood, patients with Turner syndrome generally present near the time of expected puberty with primary amenorrhea and absent secondary sexual development [13]. Approximately 50 % of women with Turner syndrome exhibit mosaicism, where the second X chromosome is present in some cells of the body—45,X/46XX [14]. In these patients, menarche can take place and menstruation can continue for several years before developing complete POI [5]. 40 % of mosaic Turner syndrome patients will reach menarche and menstruate as compared to 10 % of 45,X patients [15]. Although rare, 1–2 % of menstrual Turner syndrome patients can become pregnant spontaneously [16]. IVF (in vitro fertilization) with donor oocytes increases pregnancy rates substantially and must be carefully considered as the cardiovascular demands of pregnancy pose potentially serious risks to patients with Turner syndrome [17, 18].

There remains some debate with regard to a diagnosis of low-level mosaicism. If a karyotype is performed and only two of 20 cells reveal 45,X, does this woman have mosaic Turner syndrome? General genetic textbooks suggest a diagnosis of mosaic Turner syndrome if 10 % or more of cells exhibit the 45,X cell line. However, each organ may be different [19, 20]. Research suggests there is enhanced X allele dropout in white blood cells, which is what a blood karyotype is analyzing, with increasing age [21]. What if other organs do not express mosaicism? What if on follow-up 200-cell karyotype she only has 5 % of cells as 45,X and the rest normal? What if she has no clinical stigmata of Turner syndrome, does she warrant the diagnosis? Research is desperately lacking in this area, especially for the woman with POI who desires future pregnancy. Studies suggest increased mortality due to aortic and vascular insufficiency and rupture for women who are pregnant with Turner syndrome [22, 23]. Does that apply to the woman with a POI diagnosis, no clinical stigmata, a normal cardiac echo and MRI (magnetic resonance imaging), and only 5 % mosaicism on testing? Data in this area is still lacking.

The blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disorder characterized by malformation of the eyelids, small palpebral fissures (blepharophimosis), drooping eyelids (ptosis), small skinfold running inward from the lower lid (epicanthus inversus), and a broad nasal bridge (telecanthus). In BPES type I, these craniofacial abnormalities are associated with POI, while BPES II is associated with normal fertility [24]. The two forms of BPES are caused by a variety of mutations in the gene encoding a forkhead box transcription factor (FOXL2) required for normal granulosa cell function [24–26]. These ovarian somatic cells surround and nourish the oocyte and play an important role in follicle formation and activation. More recent research suggests that the FOXL2 gene product may play a role in maintaining primordial follicles in a quiescent state by regulating granulosa cell proliferation [27]. In type I BPES, mutations create stop codons in the FOXL2 gene , which produce a truncated protein product with significant loss of function. In type II BPES, point mutations, frameshifts, and most importantly, duplications, result in decreased activity of the gene product [14, 27, 28]. The clinical presentation of infertility associated with BPES ranges from primary amenorrhea to irregular menses followed by POI [24]. Ovarian appearance can vary from essentially normal to streak gonads [29]. Pregnancy has been achieved using IVF in patients affected with BPES [30].

Galactosemia is an autosomal recessive disease caused by a deficiency in galactose-1-phosphate uridyltransferase (GALT) as a result of mutations on the GALT gene located on chromosome 9p13 [31]. The disease affects approximately 1 in 60,000 newborns [5]. GALT is responsible for converting galactose to glucose, and its deficiency leads to a buildup of galactose in tissues that typically have high GALT expression such as the liver, kidney, ovary, and heart [14]. More than 180 mutations in the GALT gene have been associated with classical galactosemia, but two common missense mutations account for more than 70 % cases—Q188R and K285N [32]. POI occurs in >80 % of all women homozygous for mutations in the GALT gene [10, 33]. The mechanism causing POI in galactosemia is not well understood, although several hypotheses have been proposed. The prevailing hypothesis is that toxic galactose metabolites induce apoptosis of oocytes and ovarian stromal cells [5, 31]. Diagnosis of galactosemia is made in the first few days of life with jaundice, vomiting, and failure to thrive. A galactose-restricted diet quickly resolves the early signs but cannot prevent the development of later-onset complications such as cognitive, motor, and speech delays in addition to POI with subsequent infertility [31, 33]. Galactosemia is routinely tested for in newborn screens. Spontaneous pregnancy has been reported in patients with galactosemia, and fertility preservation remains an option although ovarian tissue has likely already been damaged at the time of consultation [31].

Ataxia telangiectasia is an autosomal recessive neurodegenerative disorder characterized by uncoordinated movements, ocular telangiectasia, chromosomal instability, immune deficiency, predisposition to cancer, and POI [10]. The ATM (ataxia telangiectasia mutated) gene encodes a protein kinase involved in cell cycle regulation. This protein is required for cellular response to DNA damage and has downstream effects on tumor suppressor proteins p53 and BRCA1 [25]. Mutations in the ATM gene generally result in a total loss of the protein [34]. The exact pathophysiology of POI in patients with ataxia telangiectasia is unknown, but animal models suggest that ATM mutants lack primordial and mature follicles, likely secondary to a disruption of meiosis [14].

Progressive external ophthalmoplegia (PEO) is an autosomal dominant or autosomal recessive disease characterized by weakness of the ocular muscles and fatigue secondary to mitochondrial tissue depletion [14, 35]. The POLG ((polymerase (DNA-directed) gamma) gene is located on chromosome 15q24 and encodes the DNA polymerase γ, the sole enzyme that replicates human mitochondrial DNA and whose mutation results in PEO [15]. In 2004, Luoma et al. described cosegregation of PEO with parkinsonism and POI in three large families with POLG mutations. The study demonstrated that dominant POLG mutations tend to cluster in the polymerase part of the protein and recessive ones affect the proofreading part of the enzyme [36]. The POLG mutations most associated with POI occur in the polymerase part of the protein and therefore tend to be autosomal dominant. After evaluating extended male family members, Luoma et al. noted testicular atrophy, suggesting a defect in steroidogenesis, in which mitochondria have a gatekeeper role [36]. A follow-up study described dominantly maternally inherited POI associated with PEO and parkinsonism carrying a Y955C mutation [37].

Perrault syndrome is an autosomal recessive disorder defined by gonadal dysgenesis and sensorineural hearing loss in 46,XX women [15]. The syndrome is genetically heterogeneous, with mutations in HSD17B4 (encoding 17-beta-hydroxysteroid dehydrogenase 4), HARS2 (encoding mitochondrial histidyl-tRNA synthetase), and CLPP (encoding mitochondrial ATP-dependent chambered protease) all demonstrated to cause POI in Perrault syndrome patients [38]. The disease is extremely rare, and although clinical presentation varies, typically girls present with hearing loss, primary amenorrhea, neurological symptoms, and mild mental retardation [39, 40].

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I (APS1) is an autosomal recessive disorder characterized by the presence of two of several conditions—mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease [41]. Mutations in the AIRE (autoimmune regulator) gene , located on 21q22.3, cause the syndrome [42]. The gene product is a regulator protein expressed in the thymic medulla [15]. Loss of this regulatory protein can lead to many autoimmune diseases and affected patients are at risk for multiple additional autoimmune diseases over time including POI, diabetes, pernicious anemia, and keratitis [41]. Over 60 mutations of the AIRE gene have been discovered; these are distributed throughout the coding region and are either nonsense or frameshift mutations that produce truncated polypeptides [42]. In one study, more than half of affected individuals presented with POI [43]. An autoimmune response to steroidogenic enzymes and ovarian steroid cells appears to mediate destruction of ovarian function [44, 45].

Ovarian leukodystrophy is an autosomal recessive disease of degenerating white matter associated with POI [46]. The disease is phenotypically variable but typically presents in childhood with progressive neurological degeneration [47]. POI may present as either primary or secondary amenorrhea and the age of onset of neurological symptoms predicts the severity of ovarian dysfunction [14]. Ovarian leukodystrophy is caused by mutations in any of the five genes encoding eIF2B (eukaryotic translation initiation factors 2B), particularly EIF2B2, EIF3B4, and EIF2B5, which ultimately allow for protein translation initiation [48]. Authors have speculated that EIF2B mutations (majority missense) may increase apoptosis of ovarian follicles and cause a defect in glial cell development [48]. A recent case report of a patient with ovarian leukodystrophy and no EIF2B mutations suggests other genes may be associated with the disorder; additional research is needed [49].

Rare steroidogenic enzyme defects that block follicular development may result in hypergonadotropic hypogonadism due to functional ovarian failure [13]. Mutations in the genes encoding the steroidogenic acute regulatory (StAR) enzyme (STAR), the 17α-hydroxylase enzyme (CYP17A1), and the aromatase enzyme (CYP19A1) are examples. The StAR enzyme facilitates conversion of cholesterol into pregnenolone, the first and rate-limiting step of in steroid biosynthesis [15]. StAR mutations are inherited in an autosomal recessive fashion and result in impaired synthesis of all adrenal and gonadal steroid hormones and cholesterol accumulation (termed lipoid congenital adrenal hyperplasia) that leads to POI [50, 51]. CYP17A1 encodes 17α-hydroxylase, an enzyme in the cytochrome P450 superfamily that converts 21-carbon progestins to 19-carbon androgens [13, 15]. Its deficiency causes congenital adrenal hyperplasia, an autosomal recessive disease wherein females usually present at birth with ambiguous genitalia or around the time of expected puberty with primary amenorrhea and sexual infantilism [10]. The diversion to mineralocorticoid production also leads to hypertension and hypokalemia which may be life threatening [3, 13]. The CYP19A1 gene , also a member of the P450 superfamily, encodes for aromatase—the enzyme responsible for converting androgens into estrogens. Aromatase deficiency syndrome is an autosomal recessive and rare disorder characterized by ambiguous genitalia, elevated androgens, undetectable estrogens, and complete lack of breast development at puberty [52, 53]. During pregnancy, fetal androgens cannot be aromatized to estrogen in the placenta resulting in masculinization of both the fetus and the mother [52, 53].

Werner’s syndrome is an autosomal recessive disorder characterized by premature aging leading to deterioration of many body systems including nervous, immune, connective tissue, and the endocrine system. Worldwide, the syndrome is found in less than 1/100,000 live births but is higher in countries with strong founder effect such as Japan and Sardinia [54, 55]. The syndrome is caused by a mutation in the WRN (Werner) gene, located on chromosome 8p12 [56]. The gene encodes a RecQ helicase that plays an important role in DNA repair, replication, and telomere maintenance [57]. More than 70 WRN mutations have been identified that lead to the syndrome [58]. Most mutations create a truncated protein that does not function properly [57].

Werner’s syndrome patients typically lack a pubertal growth spurt but then develop normally until they reach their late 20s and early 30s. At that time, patients begin to manifest skin atrophy, graying and loss of hair, osteoporosis, poor wound healing, and pronounced hypogonadism [59]. The mechanism for POI is likely accelerated follicular atresia, but the exact mechanism is unknown. Approximately 80 % of Werner’s syndrome patients have hypogonadism. Despite the bleak prognosis, some patients are still able to become pregnant, although some literature reports increased risk of preterm delivery and miscarriage [59, 60]. Werner’s syndrome patients are also at increased risk for various malignancies and have a shortened life expectancy [57].

Fanconi’s anemia is an autosomal and X-linked disorder characterized by bone marrow failure, acute myelogenous leukemia, solid tumors, and developmental abnormalities such as short stature, developmental disability, and abnormalities of the skin, arms, head, eyes, ears, and kidneys [61, 62]. There are 13 genes involved in the disorder, and the proteins they encode are responsible for the recognition and repair of damaged DNA. The genes are inactivated in patients with Fanconi’s anemia, leading to the abnormalities mentioned above. Females with Fanconi’s anemia often have menstrual irregularities, secondary amenorrhea, increased risk of gynecologic malignancies, and premature menopause [63]. A recent publication demonstrated decreased levels of serum AMH (anti-Mullerian hormone) in all patients with the disorder—with all patients older than 25 years being diagnosed with POI [64]. Fortunately, the disorder is rare (1–5/1 million), and AMH screening at the time of diagnosis may allow fertility preservation options [61].

A spectrum of clinically important disorders, including POI, involves a dynamic trinucleotide (CGG) repeat sequence mutation in the X-linked FMR1 (fragile X mental retardation 1) gene , located near the terminal end of the long arm of the X chromosome (Xq27.3) [13]. The FMR1 gene encodes the FMRP (fragile X mental retardation protein) which is present in neurons, primordial germ cells, and granulosa cells of developing ovarian follicles [65]. The normal FMR1 gene contains approximately 30 CGC repeats. The fully expanded form of the mutation, defined by more than 200 repeats, results in fragile X syndrome (FXS)—the most common genetic cause of mental retardation—affecting 1 in 4000–8000 females [66]. The premutation is characterized by 55–200 repeats and is associated with two disorders distinct from FXS [13, 67]. One is the fragile X-associated tremor/ataxia syndrome (FXTAS) , a neurologic disorder that primarily affects males. The other is POI, affecting approximately 13–26 % of women who carry the premutation [66].

Premutation carriers have been identified in approximately 15 % of women with familial POI and 1–7 % in sporadic POI, making it one of the most well-known causes of POI [14, 15]. In the full mutation, the expanded number of repeats in the 5′ untranslated region of the gene results in hypermethylation that extends into the promoter region and silences the gene. As a result, little or no FMRP is produced. FMRP is a translational suppressor that binds to approximately 4 % of mRNA in mammalian brains and appears to suppress translation of those messages, especially in the brain. Decreased FMRP may result in overexpression of mRNAs that may lead to the characteristic fragile X phenotype [65, 66]. In the premutation, the trinucleotide repeat sequence is not methylated, the gene functions, and FMRP is produced in variable amounts [13]. It has also been suggested that the risk for POI increases with the number of repeats and is highest between 80 and 100 but decreases with more than 100 [68, 69]. Patients with the full FMR1 mutation are almost universally spared from POI [65]. The mechanism of POI in patients with the FMR1 premutation is unclear [66]. Suggested mechanisms include gain of function toxicity, due to overexpression of mRNAs, resulting in an accelerated rate of follicular atresia, but further research is needed [14, 65, 66].

Because FMR1 is located on the X chromosome, it follows the basic pattern of X-linked inheritance. Women who carry the mutation transmit it to 50 % of their offspring and men who carry the mutation transmit it to all their daughters and none of their sons. The pattern of inheritance is further complicated by the meiotic instability of the repeat sequence, which tends to expand when passed from the mother to her progeny, increasing the risk for FXS and associated disorders with each generation, a phenomenon known as “anticipation” [66]. The risk for expansion increases with the number of repeats, and expansions do not typically occur until the number of repeats reaches 40–50 [13, 66]. When the premutation repeat sequence is transmitted from fathers to daughters, it remains relatively stable—rarely expanding to the full mutation [13]. This may be because large repeat sequences are highly unstable in developing sperm and only smaller premutations can be transmitted.

The FMR2 gene (fragile X mental retardation 2) is located near the FMR1 gene and has also been associated with mental retardation and POI [5, 15]. Microdeletions in this gene, which is also X-linked, are associated with 1.5 % of cases of POI [70]. Additional research is necessary to elucidate the function of the FMR2 product as well as the mechanisms leading to POI in affected patients.

Women with the FMR1 premutation often present with signs of early reproductive aging. Their cycle lengths are shorter (secondary to a shorter follicular phase), follicle-stimulating hormone (FSH) levels are higher, and inhibin levels are lower when compared to normal women [71]. Due to the complexity of inheritance of FMR1 premutations, all carriers should be offered genetic counseling. Up to 5–10 % of women who with POI who carry the FMR1 premutation will achieve pregnancy spontaneously [72]. The only fertility treatment with proven efficacy in this group of patients remains IVF with oocyte donation [13].

The TGFβ superfamily is a large family of structurally related cell regulatory proteins that was named after its first member, TGFβ1. The family includes many ligands involved in organ specification, patterning, proliferation, and differentiation [73]. Several of these ligands have been shown to be necessary for correct folliculogenesis, and their mutations are associated with POI [14].

BMP15 (bone morphogenetic protein 15) is located on the short arm of chromosome X (Xp11.2), within a critical region for proper ovarian development and function [14, 15]. The gene encodes an oocyte-derived growth and differentiation factor, which is involved in follicular development as a critical regulator of many granulosa cell processes [74]. The main roles of BMP15 are to promote folliculogenesis, regulate granulosa cell sensitivity to FSH, prevent granulosa cell apoptosis, promote oocyte competence, and regulate ovulation quota [14]. The first mutation in human BMP15 was reported in two 46,XX Italian sisters with primary amenorrhea and ovarian dysgenesis, who inherited the trait from their hemizygous father [75]. Mutations in the BMP15 gene are inherited in an X-linked fashion and are found in 1.5–12 % of patients with POI [14]. Almost all of these mutations are missense and found in the heterozygous state [76]. The mechanism by which BMP15 variants lead to POI is unknown, but most authors favor follicle atresia [11, 76].