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WHO 1 Anovulation
Hypogonadotrophic hypogonadism (HH) might result from combined pituitary hormonal deficiencies (CPHD) or from isolated gonadotropin-releasing hormone (Gn-RH), follicle-stimulating hormone (FSH), or luteinizing hormone (LH) deficiencies. For an extensive review, see Larson, Nokoff, and Meeks (1).
Among 195 individuals with combined pituitary hormonal deficiency, 13% were found to have mutations in one of five genes sequenced (POU1F1, PROP1, LHX3, LHX4, and HESX1). The yield was much higher for familial cases at 52%. Estimates of the prevalence of mutations in PROP1 among patients with CPHD vary widely based on geography (due to founder effects) and presence or absence of family history. Turkish patients with CPHD had sequencing of PROP1, POU1F1, LHX3, and HESX1 with mutations identified in 31% of patients. PROP1 encodes a transcription factor critical for development of most lineages of anterior pituitary cells. POU1F1 (formerly PIT1) is a transcription factor expressed in the subset of anterior pituitary cells that will secrete GH, TSH, and prolactin. Biallelic mutations in the gene cause deficiencies in these hormones. HESX1 mutations are discussed below in conjunction with septo optic dysplasia (1).
LHX3 and LHX4 mutations are rare causes of CPHD. The genes encode transcription factors critical for developing Rathke’s pouch. Heterozygous mutations in LHX4 can cause CPHD with a structurally abnormal pituitary gland, sella turcica, and cerebellum in some cases. A wide range of phenotypes have been noted, including individuals with only subtle subclinical hormone deficiencies. Biallelic mutations in LHX3 result in CPHD with abnormal pituitary imaging and cervical spine anomalies. A syndrome of CPHD and hearing loss has also been described (1).
Sequence variants, deletions, and duplications of SOX3, a transcription factor, are associated with CPHD, pituitary imaging abnormalities, and other CNS morphological anomalies. SOX3 is on the X chromosome, and manifestations are largely seen in males. A family with isolated GH deficiency in conjunction with intellectual disability due to SOX3 mutation has been reported (1).
Deficiency of LH and FSH or HH, usually results from deficient action of hypothalamic Gn-RH. The association of anosmia with HH is known as Kallmann syndrome (KS). Abnormal development of the olfactory bulb impairs migration of the embryonic precursors of GnRH-secreting cells to the hypothala-mus, resulting in the common association between anosmia and HH (2). There is a continuous spectrum of olfactory phenotypes among individuals with HH, and thus, we will often refer to HH/KS as a group rather than separately (1).
The first gene linked with KS, KAL1, resides on the X chromosome and encodes a secreted extracellular glycoprotein necessary for olfactory neuron axonal pathfinding (3). Fibroblast growth factor and prokineticin signaling are critical for olfactory bulb development and GnRH-secreting cell migration. Mutations in FGFR1, FGF8, PROK2, and PROKR2 disrupt those signaling mechanisms and have been identified in patients with HH/KS (4–6). Compared to other etiologies of HH/KS, patients with KAL1 mutations are more likely to have very small testicular volume, complete absence of puberty, renal anomalies, and bimanual synkinesia (mirroring of the movements of one hand with the other). Patients with FGF8 and FGFR1 mutations are more likely to have cleft palate, dental anomalies, and syndactyly (1).
CHARGE syndrome is an acronym conveying the association of ocular coloboma, congenital heart defects, choanal atresia, growth restriction, intellectual disability, genital abnormalities, and ear abnormalities. Heterozygous mutations in the gene CHD7 cause CHARGE (7). The protein encoded by CHD7 is a chromatin modifier that regulates gene transcription and is expressed in the developing pituitary as well as other tissues. HH/KS represents the milder end of the phenotypic spectrum resulting from CHD7 mutations in comparison to the more severe CHARGE phenotype (8). Compared to patients with other gene mutations causing HH/KS, those with CHD7 mutations are more likely to have hearing loss (1).
Along with the aforementioned genes that are critical during embryogenesis of the olfactory bulb and hypothalamus, biallelic mutations within the genes encoding Gn-RH itself (GNRH1) and the Gn-RH receptor (GNRHR) can cause HH (9,10). Kisspeptin signaling is necessary for normal hypothalamic Gn-RH release and biallelic mutations in the gene encoding kisspeptin (KISS1) and the kisspeptin receptor (KISS1R) also result in HH (11,12). An additional signaling mechanism is now known to be necessary for normal Gn-RH release with mutations in the genes encoding neurokinin B (also known as tachykinin 3) and its receptor (TAC3 and TACR3) identified in families with recessively inherited HH/KS (1).
Complicating genetic counseling for HH/KS is the identification of patients with complex inheritance patterns. Digenic inheritance has been described in multiple families. Also, HH/KS appears to be a partially sex-limited phenotype: males with HH/KS outnumber females by a factor of about four. A small portion of the male predominance in HH/KS stems from the X-linked inheritance of KAL1 mutations. The fact that males may have physical exam findings apparent at birth (micropenis and undescended testes) could account for some ascertainment bias, but that alone also cannot account for such a wide disparity (1).
In HH/KS, the estimated prevalence of mutations in each gene depends on the specific phenotype in question. Generally speaking, genes with the highest prevalence of mutations are FGFR1, KAL1, PROKR2, GNRHR, and CHD7 (13). None of these genes account for more than 10% of cases, and therefore, HH/KS is a phenotype usually more appropriate for panel testing rather than individual gene testing. In addition to those noted above, mutations in the genes encoding FEZF1, NR0B1, NSMF, WDR11, SEMA3A, HS6ST, SOX10, FGF17, IL17RD, SPRY4, DUSP6, and FLRT3 constitute rare causes of HH/ KS. In the cases of some genes, it is not apparent whether mutations are sufficient to cause HH/KS in the absence of a second affected gene (1).
WHO 2 and PCOS
Because PCOS clusters within families, the syndrome is at least partially genetically determined. Earlier studies of the genetics of PCOS suggested an autosomal dominant mode of inheritance, but the recruitment of large families with multiple affected women likely biased these studies. Nowadays, PCOS is generally looked upon as being a complex polygenic disease that may involve the subtle interaction of environmental factors, susceptibility, and protective genomic variants (14).
The evidence for a common genetic background is derived from numerous studies either family or population based, candidate gene studies, and more recently, from genome-wide association studies (GWAS).
Two studies assessed the heritability of PCOS in twins by comparing the degree of concordance between mono- and dizygotic twin pairs. Both studies indicated that at least 50%–70% of the syndrome is attributable to genetic factors. Moreover, both studies showed that there is also evidence that these genetic factors do interact with unique environmental factors. Finally, they also showed that phenomena generally associated with the syndrome, that is, BMI, insulin resistance, and androgen levels, are genetically determined (15,16).
Evidence for the role of genetics in PCOS includes a well-documented familial clustering of PCOS with sisters more likely to be affected with signs and symptoms of the disorder, and first-degree relatives having higher rates of metabolic abnormalities including insulin resistance, decreased beta cell function, dyslipidemia, and MetS (17). Female as well as male siblings do exhibit higher levels of androgens. Moreover, the incidence of PCOS and PCOS characteristics is increased in sisters of affected probands within families (18,19).
Population-based studies have tested a large number of functional candidate genes for association or linkage with PCOS phenotypes, mostly ending with negative findings. However, a lack of universally accepted diagnostic criteria makes comparison of such studies problematic. A further problem is that the candidate gene approach relies upon some prior understanding of pathogenesis to determine the candidacy of the gene chosen with more than 20,000 genes to choose from within the human genome. Moreover, controversies and lack of consensus about how to define the syndrome hamper genetic research in this area. Finally, although more than 200 candidate genes have been studied up till now, the small sample size of most studies renders them underpowered, resulting in inconsistent results that, in most instances, have not been replicated in different independent samples (14). Genes or genetic variants that have been identified and replicated to a certain extent are FSH-R, TGF-β family members, insulin receptor and insulin signaling, WNT signaling (transcription factor 7 like 2 [TCG7L2]), fat and obesity-associated gene (FTO), and genetic variants in sex hormone binding globulin (SHBG) (20).
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