Alternative titles; symbols
ORPHA: 432, 478; DO: 0090083;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p11.23 | Hypogonadotropic hypogonadism 2 with or without anosmia | 147950 | Autosomal dominant | 3 | FGFR1 | 136350 |
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-2 with or without anosmia (HH2) is caused by heterozygous mutation in the gene encoding fibroblast growth factor receptor-1 (FGFR1; 136350) on chromosome 8p11, sometimes in association with mutation in other genes, e.g., FGF8 (600483) and GNRHR (138850).
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'
Although HH was initially considered to be a monogenic disorder, the presence of marked locus heterogeneity, incomplete penetrance within pedigrees, and variable expressivity of pathogenic alleles, together with evidence for mutations in multiple genes in some affected individuals, resulted in a conceptual shift from monogenicity to an oligogenic framework in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction (Sykiotis et al., 2010).
Genetic Heterogeneity of Hypogonadotropic Hypogonadism with or without Anosmia
Other forms of autosomal hypogonadotropic hypogonadism with or without anosmia include HH3 (244200), caused by mutation in the PROKR2 gene (607123); HH4 (610628), caused by mutation in the PROK2 gene (607002); HH5 (612370), caused by mutation in the CHD7 gene (608892); HH6 (612702), caused by mutation in the FGF8 gene (600483); HH7 (146110), caused by mutation in the GNRHR gene (138850); HH8 (614837), caused by mutation in the KISS1R gene (604161); HH9 (614838), caused by mutation in the NELF gene (608137); HH10 (614839), caused by mutation in the TAC3 gene (162330); HH11 (614840), caused by mutation in the TACR3 gene (162332); HH12 (614841), caused by mutation in the GNRH1 gene (152760); HH13 (614842), caused by mutation in the KISS1 gene (603286); HH14 (614858), caused by mutation in the WDR11 gene (606417); HH15 (614880), caused by mutation in the HS6ST1 gene (604846); HH16 (614897), caused by mutation in the SEMA3A gene (603961); HH17 (615266), caused by mutation in the SPRY4 gene (607984); HH18 (615267), caused by mutation in the IL17RD gene (606807); HH19 (615269), caused by mutation in the DUSP6 gene (602748); HH20 (615270), caused by mutation in the FGF17 gene (603725); HH21 (615271), caused by mutation in the FLRT3 gene (604808); HH22 (616030), caused by mutation in the FEZF1 gene (613301); HH23 (228300), caused by mutation in the LHB gene (152780); HH24 (229070), caused by mutation in the FSHB gene (136530); HH25 (618841), caused by mutation in the NDNF gene (616506); and HH26 (619718), caused by mutation in the TCF12 gene.
There is also an X-linked form of the disorder (HH1; 308700), caused by mutation in the KAL1 gene (300836).
There is evidence that mutation in 2 or more of these genes can work in combination (oligogenicity) to produce GnRH-deficient conditions (summary by Chan, 2011). Sykiotis et al. (2010), for example, demonstrated that of patients with an identifiable coding sequence mutation in 1 of 8 genes responsible for isolated GnRH deficiency, 11% carried mutations in at least one other of these genes as well.
Reviews
Valdes-Socin et al. (2014) reviewed the reproductive, neurodevelopmental, and genetic aspects of hypogonadotropic hypogonadism in human pathology.
Young et al. (2019) reviewed the genetics, diagnosis, and clinical management of patients with congenital hypogonadotropic hypogonadism.
In some cases of hypogonadotropic hypogonadism and anosmia, midline cranial anomalies (cleft lip, cleft palate and imperfect fusion) are present. In a large kindred with a high rate of consanguinity, Rosen (1965) found 5 cases of hypogonadism, 3 of anosmia, and 6 of midline cranial anomalies. Both males and females were affected; 2 persons had 2 defects and 2 others showed all 3.
Tagatz et al. (1970) described 3 unrelated females with hypogonadotropic hypogonadism and anosmia. No relative was affected and the parents in each case were unrelated. Induction of ovulation with resulting normal term pregnancy was achieved in 2 of the patients with exogenous gonadotropins. Hintz et al. (1968) may have described the same or a related disorder.
Merriam et al. (1977) reported the instructive case of a father with cryptorchidism, hypogonadism, and hyposmia who was rendered fertile by treatment with chorionic gonadotropin and had 3 children. One of the 3, a son, also had the triad mentioned. A brother and sister were apparently normal.
Soules and Hammond (1980) reported the fully studied case of a female.
In a study of 23 patients, Lieblich et al. (1982) found subtle abnormalities of hypothalamic-pituitary function, although hypogonadism was the only endocrine deficit evident clinically. Some relatives had only anosmia or had hypogonadotropic hypogonadism with normal sense of smell.
Among 18 probands with anosmia and hypogonadotropic hypogonadism studied at the National Institutes of Health, White et al. (1983) found that 7 had affected relatives and 3 had consanguineous parents. Both sexes were equally affected and parents were phenotypically normal. Cleft lip and palate occurred in both eugonadal and hypogonadal persons with anosmia. Segregation analysis was consistent with autosomal recessive inheritance with variable expression. They suggested that association of unilateral renal agenesis, mental retardation, and hypotelorism (e.g., families reported by Turner et al., 1974 and Wegenke et al., 1975) may indicate a distinct X-linked or male-limited autosomal dominant form (see 308700).
Evain-Brion et al. (1982) suspected hypogonadotropic hypogonadism in 3 male newborns on the basis of a very small penis, cryptorchidism, and a family history of Kallmann syndrome in 1 and isolated anosmia in the other 2. The diagnosis was confirmed in early infancy by lack of the postnatal rise of LH and testosterone and a blunted response to LHRH and HCG stimulation. In 1 case the mother had anosmia, primary amenorrhea, low gonadotropin and lack of response to LHRH; she had been successfully treated with HMG and HCG to induce ovulation (Gorins et al., 1977). In the second case, 'the father was hyposmic with normal gonadal function, and his grandmother had been anosmic.' In the third case, although the parents were normal, a maternal uncle had cryptorchidism with anosmia.
Klein et al. (1987) described the association of Kallmann syndrome with choanal atresia. The Kallmann syndrome occurred in an aunt and niece; the niece also had choanal atresia as did her newborn child. The olfactory capacity and gonadal or hormonal status of the infant could not be determined at her age. Klein et al. (1987) suggested that this may be further evidence that Kallmann syndrome represents the least severe form of the holoprosencephaly-hypopituitarism complex, a group of developmental field defects.
Kallmann syndrome associated with congenital heart disease may be a distinct entity. Cortez et al. (1993) described the case of a 17-year-old boy with Kallmann syndrome and a complex congenital heart malformation. He also had neurosensory hearing loss and mental retardation. They noted that 7 previously reported patients with Kallmann syndrome and cardiac abnormalities were short with heights more than 2 standard deviations below the mean for age, lacked a family history of Kallmann syndrome, and were mentally retarded.
Levy and Knudtzon (1993) reported a family in which 2 sisters, aged 13 and 19 years, had hypogonadotropic hypogonadism and anosmia. In addition, they had bilateral vesicoureteral reflux and unilateral hearing loss. One of the girls had unilateral coloboma of the optic nerve. The father had no clinical signs of either hypogonadism or anosmia. However, he had unilateral hearing loss and duplication of the left ureter and died suddenly at the age of 40 from myocardial infarction and undiagnosed coarctation of the aorta. The mother was normal. Levy and Knudtzon (1993) postulated dominant inheritance in this family.
The European Recombinant Human LH Study Group (1998) evaluated the efficacy of recombinant human luteinizing hormone (rhLH; see 152780) for supporting human recombinant follicle-stimulating hormone (rhFSH)-induced follicular development in hypogonadotropic hypogonadal women (WHO group I anovulation). Thirty-eight patients were randomized to receive rhLH (0, 25, 75, or 225 IU per day) in addition to a fixed dose of rhFSH (150 IU per day). RhLH was found to promote dose-related increases in estradiol (E2) and androstenedione secretion by rhFSH-induced follicles, increase ovarian sensitivity to FSH, and enhance the ability of these follicles to luteinize when exposed to human chorionic gonadotropin (CG; see 118850). A daily dose of 75 IU rhLH was effective in the majority of women in promoting optimal follicular development and maximal endometrial growth. The authors concluded that a minority of patients may require up to 225 IU per day and that rhLH given subcutaneously at a dose up to 225 IU per day was not immunogenic and was well tolerated.
Young et al. (1999) measured the serum anti-mullerian hormone (AMH; 600957) levels in 20 normal men, aged 20 to 60 years, 12 patients with congenital hypogonadotropic hypogonadism (CHH), aged 19 to 30 years, and 18 patients with acquired hypogonadotropic hypogonadism (AHH), aged 19 to 65 years, either untreated or during testosterone (T) or human CG therapy. Mean serum AMH levels in normal adult men were low (20 +/- 4.9 pmol/L). In untreated CHH patients, mean serum AMH levels were significantly higher than in normal men (292 +/- 86 pmol/L; p less than 0.001) and were similar to those previously reported in prepubertal boys. In men with AHH, mean serum AMH levels were also significantly increased (107 +/- 50 pmol/L; p less than 0.01) when compared with healthy men, but were less than in men with CHH. In addition, in 10 patients treated for prostate cancer, a modest but significant increase of serum AMH (from 11.4 +/- 5.7 pmol/L to 49 +/- 9.9 pmol/L; p less than 0.01) was observed 12 months after suppression of the gonadal axis with the GNRH agonist Triptorelin (3.75 mg IM once a month). Plasma T and serum AMH levels were measured at baseline and at 3 and 6 months in 10 HH patients (6 CHH and 4 AHH) treated with human CG (1,500 IU/twice weekly for 6 months) and in 8 HH patients (4 CHH and 4 AHH) treated with T (T enanthate, 250 mg/3 weeks for 6 months). Human CG treatment induced an increase of plasma T (from 1.0 +/- 0.7 to 11 +/- 2.4 and 19 +/- 4.8 nmol/L, at 3 and 6 months, respectively) associated with a dramatic decrease of serum AMH (from 314 +/- 93 to 56 +/- 30 and 17 +/- 4.3 pmol/L). The similar increase in plasma T levels (from 1.4 +/- 1.0 to 15.6 +/- 4.2 and 23 +/- 6.2 ng/ml) obtained with exogenous T induced a lesser decrease of serum AMH (from 221 +/- 107 to 114 +/- 50 and 66 +/- 17 pmol/L). The authors concluded that (1) high plasma AMH levels in CHH patients are related to the absence of pubertal maturation of Sertoli cells; (2) high AMH levels in AHH and its increase after Triptorelin-induced gonadotropin deficiency suggested that the suppression of AMH is a reversible phenomenon; and (3) inhibition of AMH production by Sertoli cells is induced by intratesticular T.
To test the hypothesis that follicle-stimulating hormone (FSH; see 136530) might be responsible for AMH upregulation in the absence of androgen inhibition, Young et al. (2005) administered recombinant human FSH to 8 male patients aged 18 to 31 years with untreated congenital hypogonadotropic hypogonadism. Although LH and T did not vary, AMH and inhibin B (see 147290) levels gradually increased after 20 days of FSH administration. However, in contrast to FSH alone, combined FSH plus CG stimulation of the testis dramatically suppressed the secretion of AMH and induced a modest but significant reduction of circulating inhibin B levels. The authors concluded that FSH stimulates AMH production in the testis when it is at a prepubertal stage.
Gasztonyi et al. (2000) described 3 unrelated women with hypogonadotropic hypogonadism and anosmia. Absence of olfactory bulbs and tracts and different degrees of asymmetric dysplasia of olfactory sulci were demonstrated by MRI. The father of 1 patient and the maternal aunt of another had anosmia, making autosomal dominant inheritance likely. The last patient had Kallmann syndrome and femur-fibula-ulna syndrome (228200) as a sporadic occurrence in her family.
Clinical Variability
Dean et al. (1990) suggested autosomal dominant inheritance with variable expression as the basis for aggregation of isolated hypogonadotropic hypogonadism in the family that they studied. A brother and sister had been most fully studied. Limited examination was performed on 2 aunts and the son of one of the aunts. The sister presented at age 17 with primary amenorrhea. She did not have anosmia. Ovulation was subsequently induced by pulsatile infusion of gonadotropin-releasing hormone (GNRH1; 152760). The brother presented at age 21 with delayed puberty. He likewise denied anosmia. Both testes were small but were in the scrotum. One paternal aunt had primary amenorrhea and an adopted son, whereas another paternal aunt had menarche at age 23, following which she had 5 or 6 menstrual periods. Six years after her last period, she became pregnant and delivered an apparently normal male infant. In the subsequent 21 years she did not menstruate. The son had immature genitalia and an unbroken voice at age 16 but refused examinations. The father of the brother and sister had died from thromboembolism and was not available for study.
Pitteloud et al. (2002) examined historical, clinical, biochemical, histologic, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. They hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome, 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, Kallmann syndrome represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Mean gonadotropin levels and the finding of apulsatile LH secretion based on frequent sampling (80% vs 55%; p less than 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The authors concluded that use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism (219050), and microphallus), biochemical markers of testicular growth and differentiation (inhibin B, mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. The authors further concluded viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.
Bhagavath et al. (2006) studied 315 probands with HH, 185 of whom had previously been studied by Bhagavath et al. (2005); the 315 probands included 258 males and 57 females, and 20 (6.3%) of the probands had 1 or more affected relatives. Of patients in whom information was available, 67 (31.5%) of 213 males and 12 (27.9%) of 43 females were anosmic, and 124 (62%) of 200 males and 16 (45.7%) of 35 females had complete HH. In the 20 HH families, 3 (15%) demonstrated vertical transmission, whereas 2 (5%) had only affected males inherited through presumptive carrier females, suggesting X-linked recessive inheritance. In 10 of the families, including both families that appeared to be X-linked recessive, affected individuals had anosmia (Kallmann syndrome). Bhagavath et al. (2006) noted that in contrast to previous reports of cryptorchidism being more common in Kallmann syndrome than in normosmic HH, cryptorchidism was present in 5 to 6% of both normosmic and hyposmic/anosmic HH patients in their cohort; however, in keeping with previous findings (Pitteloud et al., 2002), cryptorchidism was 4 times more common in cases of complete HH (16%) than in cases of incomplete HH (4%). Additional anomalies included visual abnormalities in 8 (2.5%) of 315 patients, neurologic abnormalities in 7 (2.2%), and renal agenesis in 1 (0.3%).
In a review, Young et al. (2019) noted that, in many cases, infertility in patients with HH can be successfully treated.
Hockaday (1966) described 2 cases. In the second case, the father was found to have 'complete anosmia on testing.' Thus, this may have been an autosomal dominant form of the disorder.
On the basis of cases in which the father of affected individuals showed anosmia, Santen and Paulsen (1973) concluded that autosomal dominant inheritance is most likely.
Oligogenic Inheritance
Tornberg et al. (2011) studied a large French Canadian pedigree with several consanguineous loops, previously reported by White et al. (1983), in which affected individuals variably presented with hypogonadotropic hypogonadism, anosmia, and cleft palate. In 4 affected family members, Tornberg et al. (2011) identified homozygosity or heterozygosity for a missense mutation in the HS6ST1 gene (604846.0002; see HH15, 614880). Because of the phenotypic variability and reduced penetrance displayed in the family, the authors screened 8 additional known HH-associated genes and detected a missense mutation in FGFR1 that was also present in the 4 affected members as well as 1 unaffected individual (136350.0025). In another family in which a man with anosmic HH and his unaffected brother both carried a missense mutation in HS6ST1 (604846.0001), screening revealed an additional missense mutation in the NELF gene (608137.0001; see HH9, 614838) in the proband. Tornberg et al. (2011) concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction.
In the large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate, previously reported by White et al. (1983) and in which Tornberg et al. (2011) had identified mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes, Miraoui et al. (2013) identified additional mutations in 2 more genes in the FGF network, FGF17 (603725.0001) and FLRT3 (604808.0001 and 604808.0002). In 4 more unrelated probands with anosmic HH, Miraoui et al. (2013) identified heterozygosity for missense mutations in FGFR1 (e.g., 136350.0026) as well as heterozygosity for 4 other genes in the FGF network: IL17RD (606807.0002), SPRY4 (607984.0002), DUSP6 (602748.0002), and FLRT3 (604808.0003). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital hypogonadotropic hypogonadism (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
In a man with Kallmann syndrome, Bergstrom et al. (1987) found a consistent extra small marker chromosome, seemingly derived from chromosome group D or G, with satellites at each end.
Best et al. (1990) described a balanced de novo translocation (7;12)(q22;q24) in an individual with Kallmann syndrome.
In a male patient with hypogonadotropic hypogonadism and cleft lip and palate, Kim et al. (2005) identified a balanced reciprocal translocation, t(7;8)(p12.3;p11.2). Positional cloning of the breakpoints revealed that the translocation disrupts the FGFR1 gene between exons 2 and 3 and predicts a novel fusion gene product.
Of 59 Kallmann syndrome patients analyzed by Oliveira et al. (2001), 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 (300836) were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). Oliveira et al. (2001) concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes.
Dode et al. (2003) took advantage of overlapping interstitial deletions at 8p12-p11 in 2 individuals who were affected by different contiguous gene syndromes that both included Kallmann syndrome. The gene encoding fibroblast growth factor receptor-1 (FGFR1; 136350) was in the critical interval. By determining the nucleotide sequence of the 18 coding exons and splice sites of FGFR1 in 129 unrelated individuals with Kallmann syndrome (91 males and 38 females), they detected heterozygous mutations in 4 familial cases and 8 sporadic cases (see, e.g., 136350.0002-136350.0006). In addition, they found that 1 individual, who was born to consanguineous parents and was affected by Kallmann syndrome with cleft palate, agenesis of the corpus callosum, unilateral hearing loss, and fusion of the fourth and fifth metacarpal bones, was homozygous with respect to a deleterious missense mutation (136350.0007). Moreover, cleft palate or lip and selective tooth agenesis, 2 anomalies that are occasionally associated with Kallmann syndrome (White et al., 1983; Hardelin, 2001) and were present in 5 individuals with mutations in FGFR1, can now be ascribed to this disease. In 1 family with an FGFR1 mutation, bimanual synkinesia was identified, indicating that it can occur in autosomal Kallmann syndrome, although it had previously been considered to be specific to the X-linked form of the disorder. The results of these studies suggested that olfactory bulb development in humans is crucially sensitive to reduced dosage of FGFR1.
Sato et al. (2004) studied 25 male and 3 female Japanese individuals, aged 10 to 53 years, with Kallmann syndrome. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. The authors found 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. The 2 males with FGFR1 mutations had hypogonadotropic hypogonadism and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and selective tooth agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction.
Pitteloud et al. (2006) examined the FGFR1 gene in 7 unrelated patients with normosmic IHH and identified heterozygous mutations in 3 individuals. An 18-year-old female diagnosed with partial IHH and her brother, who had Kallmann syndrome, were found to have a heterozygous missense mutation in the FGFR1 gene (136350.0013); their father, who was also heterozygous for the mutation, had congenital anosmia. In a 25-year-old Hispanic male with normosmic IHH and unilateral cryptorchidism who also had 2 congenitally missing teeth, Pitteloud et al. (2006) identified complex heterozygosity for 2 mutations of the FGFR1 gene on the same allele (136350.0014). The patient's mother, who was also heterozygous for the mutations, had congenital anosmia and normal puberty. In 2 brothers with normosmic IHH, 1 of whom also had cleft lip and palate and 3 missing teeth, Pitteloud et al. (2006) identified heterozygosity for a nonsense mutation in the FGFR1 gene (136350.0015). The sibs' father, who was also heterozygous for the mutation, reported having delayed puberty. Structural and biochemical analysis of the mutations revealed that all resulted in receptor loss of function. Noting the mixed pedigrees caused by mutation in FGFR1, Pitteloud et al. (2006) suggested that Kallmann syndrome and normosmic IHH are part of the same spectrum of disease.
In a 16-year-old female with cleft lip and palate who presented with anosmia, irregular menstrual periods, and agenesis of 2 teeth, Riley et al. (2007) identified a nonsense mutation in the FGFR1 gene (136350.0018). Her father, who also carried the mutation, had isolated cleft lip and palate and a normal sense of smell and was fertile. The mutation was not found in the unaffected mother or brother; a deceased paternal great aunt was also reported to have cleft lip.
Raivio et al. (2009) sequenced the FGFR1 gene in 134 patients with normosmic IHH and identified heterozygous loss-of-function mutations in 9 (7%). Screening of 5 more HH-associated genes in the 9 mutation-positive patients revealed additional mutations in 5 patients, including mutations in the GNRHR (138850), PROKR2 (607123), and FGF8 (600483) genes.
Villanueva et al. (2015) studied 7 probands with mutations in the FGFR1 gene (see, e.g., 136350.0026) who exhibited HH as well as split hand/foot malformations (SHFM). In 6 families that were screened for mutation in 4 to 6 known HH-associated genes, the probands were heterozygous for FGFR1 mutations and exhibited SHFM limited to one or both feet. Other features exhibited by affected individuals included dental anomalies and cleft lip and/or palate. In 2 of these families, Incomplete penetrance was demonstrated by unaffected female carriers, and in 3 of the families, parental mutation status was not reported. In a consanguineous Turkish family, screened for mutation in 13 known HH-associated genes, the proband was homozygous for an FGFR1 missense mutation and had SHFM involving both hands and both feet as well as absent septum pellucidum and hypoplastic anterior corpus callosum on MRI. His unaffected parents and an anosmic sister were heterozygous for the mutation; in addition, 3 sibs with reportedly severe skeletal anomalies had died as neonates.
Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females
Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, all of whom completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency.
Associations Pending Confirmation
From a cohort of 104 probands with KS or HH, Salian-Mehta et al. (2014) identified 4 patients, 2 with KS and 2 with HH, who were negative for mutation in 14 known KS- or HH-associated genes but who had heterozygous mutations in the AXL gene (109135), including 3 missense mutations and 1 splice site mutation. Segregation was not reported in 3 of the families; in case 1, the mutation was also present in the proband's unaffected father. The 3 missense variants were found in public variant databases. In vitro functional analysis showed no abnormally spliced products or difference in splicing efficiency with the splicing mutation compared to wildtype AXL, and the missense mutations did not alter Gas6 (600441) ligand binding. However, in GT1-7 and GnRH neuronal cells expressing 2 of the missense mutations (S202C or Q361P), defective ligand-dependent receptor processing and aberrant neuronal migration were observed, and the Q361P mutant also showed defective ligand-independent chemotaxis. The authors suggested that the probands' phenotypes might result from concomitant mutations in other genes.
By whole-exome sequencing of 133 patients with hypogonadotropic hypogonadism with or without anosmia, Bouilly et al. (2018) identified 7 patients from 6 families with heterozygous variants in the DCC gene (601614), occurring alone in 3 families, and in combination with heterozygous or homozygous variants in 1 or more HH-associated genes in 3 families. The designations for 2 of the families, as well as for 2 of the probands, were discrepant between Figure 4 and the case summaries. Familial segregation was not reported for 2 of the families. Unaffected carriers were present in 3 families, and in 1 family, the proband's mother, who did not carry a DCC mutation, had delayed puberty, whereas mutation status was unknown for the proband's unaffected father. Immunofluorescence analysis of immortalized GnRH neurons demonstrated that the identified DCC variants significantly impaired cytoskeletal and membrane rearrangement involved in cell protrusion formation, consistent with impairment of GnRH neuron migration. The authors suggested that the incomplete penetrance and variable expressivity observed both within and across families with HH might be explained by oligogenic inheritance or by the presence of mutations in unknown HH loci.
In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. (2000) identified compound heterozygosity for mutations in the GNRHR gene: Q106R (138850.0001) on one allele and R262Q (138850.0002) on the other. The apparently unaffected parents were heterozygous for the mutations. The older sister conceived 3 times on pulsatile GnRH and twice on exogenous gonadotropin therapy, but suffered recurrent pregnancy loss; an embryo/trophoblast toxic factor was identified. The younger sister was treated with exogenous gonadotropins and gave birth to 3 children, with 1 singleton and 1 twin pregnancy. Pitteloud et al. (2007) reexamined the family studied by Seminara et al. (2000) and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter who had undergone normal puberty was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene; and her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene. In another family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, Pitteloud et al. (2007) identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his sister. Heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (608137.0002), was identified in the proband, his mother, and his brother. The mother and both sibs of the proband had normal puberty and a normal sense of smell by formal testing. Pitteloud et al. (2007) concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency.
Salenave et al. (2008) studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 (300836) and 18 in FGFR1, but none had additional mutations in PROK2 (607002) or PROKR2 (607123) genes. Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete congenital hypogonadotropic hypogonadism. The fathers of 3 unrelated men with KS, who also carried the respective FGFR1 mutations, had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent and testicular volume was smaller in HH subjects with KAL1 mutations than in subjects with FGFR1 mutations. The mean basal plasma FSH (see 136530) level, serum inhibin B (see 147290) level, basal LH (see 152780) plasma level, and GnRH-stimulated LH plasma level were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 complete HH subjects with KAL1 mutations and 7 subjects with FGFR1 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. Salenave et al. (2008) concluded that men with KS and documented KAL1 mutations have a more severe reproductive phenotype than men with FGFR1 mutations, which are associated with a broad spectrum of phenotypes, ranging from complete HH to normality.
Sykiotis et al. (2010) analyzed 8 known HH-associated genes, including KAL1, FGFR1, PROKR2, PROK2, FGF8, GNRHR, KISS1R, and NELF, in 397 well-phenotyped HH patients, of whom 44 women and 155 men had anosmia/hyposmia, and 52 women and 146 men were normosmic. Compared to 179 controls tested, HH patients were significantly more likely to harbor rare protein-altering variants (22% vs 10%; p = 0.001). A single variant allele was identified in 68 (17%) of the patients, and oligogenicity was found as frequently as homozygosity or compound heterozygosity in this cohort: 10 (2.5%) of the patients had rare variants in both alleles of a single gene, and 10 (2.5%) had variants in 2 or more alleles of different genes. Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%; no oligogenicity was detected among the controls (p less than 0.05), even though deleterious alleles were present. In the 10 oligogenic pedigrees, 3 of which were new and 7 of which had previously been reported (Pitteloud et al., 2007; Falardeau et al., 2008; Cole et al., 2008; Raivio et al., 2009; Chan et al., 2009), the higher the number of affected genes and alleles that an individual harbored, the more likely he or she was to have HH as opposed to a milder or partial phenotype, such as delayed puberty, isolated anosmia, or isolated cleft lip/palate. Sykiotis et al. (2010) concluded that GnRH deficiency should be considered to be an oligogenic disorder, and noted that the fact that no rare protein-altering variants were found in the majority (78%) of patients indicated that the 8 genes sequenced accounted for only a fraction of the genetic etiology of the disease.
To assess oligogenicity in hypogonadotropic hypogonadism, Miraoui et al. (2013) analyzed 350 HH probands of European descent for mutation in 17 HH-associated genes. Mutations were identified in 124 (35%) of the probands, and 24 (19%) of the mutation-positive probands carried at least 2 mutant alleles from different genes. Miraoui et al. (2013) noted that 23 of the 24 oligogenic cases involved at least 1 gene associated with the fibroblast growth factor (FGF) network (see 601513).
Dode et al. (2006) stated that loss-of-function mutations in the KAL1 (300836) and FGFR1 genes account for approximately 20% of all cases of Kallmann syndrome and that mutations in the PROKR2 and PROK2 genes account for an additional 10%.
Gurbuz et al. (2012) reviewed all causative mutations detected in multiplex families with normosmic hypogonadotropic hypogonadism over a 7-year period in Turkey. Mutations that segregated with disease were identified in 17 (77.2%) of 22 families studied, including mutations of the GNRHR gene in 7 (31.8%) of the families, TACR3 in 6 (27.2%), KISSR in 2 (9%), TAC3 in 1 (4.5%), and KISS1 in 1 (4.5%). Inheritance was autosomal recessive in all 17 families.
In a family with Kallmann syndrome inherited presumably as an autosomal recessive, Dornan et al. (1980) excluded close linkage with HLA.
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