Genetics of GnRH deficiency conditions

Last updated
The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism.jpg
The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

To date, at least 25 different genes have been implicated in causing gonadotropin-releasing hormone (GnRH) deficiency conditions such as Kallmann syndrome (KS) or other forms of congenital hypogonadotropic hypogonadism (CHH) through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance, and no one gene defect has been shown to be common to all cases, which makes genetic testing and inheritance prediction difficult. [1] [2]

Contents

The number of genes known to cause cases of KS/CHH is still increasing. [3] In addition, it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time. [4]

Genes

A table of known genes responsible for cases of GnRH deficiency conditions is shown below. Listed are the estimated prevalence of cases caused by the specific gene, additional associated symptoms and the form of inheritance. [4] [5] Between 35 and 45% of cases of KS/CHH have an unknown genetic cause. [6]

Prevalence (%) OMIM NameGene Locus Clinical featuresSyndromes associatedInheritance pattern
5, [4] 5-10 [7] 308700 ANOS1 (KAL1) ANOS1 Xp22.3 Anosmia. Bimanual synkinesis. Renal agenesis.x-linked
10 [4] [7] 147950 KAL2 FGFR1 8p11.23 Cleft lip and / or cleft palate. Septo-optic dysplasia. Skeletal anomomalies. Bimanual synkinesis. Hand / foot malformations such as ectrodactyly. Combined pituitary hormone deficiency. Hartsfield syndrome Autosomal dominant
6-16, [4] 5-10 [7] 146110 GNRHR GNRHR 4q13.2Autosomal recessive
6, [4] 5-10 [7] 612370 CHD7 CHD7 8q12.2 Congenital hearing loss. Semicircular canal hypoplasia. CHARGE syndrome Autosomal dominant
3-6, [4] <2 [7] 610628 KAL4 PROK2 3p13Autosomal recessive
3-6, [4] 5 [7] 244200 KAL3 PROKR2 20p12.3 Combined pituitary hormone deficiency. Morning Glory syndrome Autosomal recessive
3, [4] 2-5 [7] 615267 IL17RD IL17RD 3p14.3 Congenital hearing loss.Autosomal recessive
2, [4] 2-5 [7] 611584 SOX10 SOX10 22q13.1 Congenital hearing loss. Waardenburg syndrome Autosomal dominant
2, [4] <2 [7] 614842 KISS1 KiSS-1 1q32.1Autosomal recessive
2, [4] <2 [7] 614837 KISS1R (GPR54) GPR54 19p13.3Autosomal recessive
<2 [7] 612702 FGF8 FGF8 10q24.32 Cleft lip and / or cleft palate. Skeletal anomomolies. Bimanual synkinesis. Combined pituitary hormone deficiency.Autosomal dominant
<2, [4] 1 report [7] 615270 FGF17 FGF17 8p21.3 Dandy–Walker syndrome Autosomal dominant
<2 [4] 164260 LEP LEP 7q32.1Early onset of morbid obesity.Autosomal recessive
<2 [4] 601007 LEPR LEPR 1p31.3Early onset of morbid obesity.Autosomal recessive
<2 [4] 162150 PCSK1 PCSK1 5q15Early onset of morbid obesity.Autosomal recessive
Rare, [4] 1 report [7] [8] 616030 FEZF1 FEZF1 7q31.32Autosomal recessive
Rare, [4] 2 reports [7] [9] [10] [11] 616031 CCDC141 CCDC141 2q31.2Unknown
Rare, [4] <2 [7] 614897 SEMA3A SEMA3A 7q21.11Autosomal dominant
1 report [7] 608166 SEMA3E SEMA3E 7q21.11 CHARGE syndrome Autosomal dominant
Rare [4] 607961 SEMA7A SEMA7A 15q24.1Autosomal dominant
Rare, [4] <2 [7] 614880 HS6ST1 HS6ST1 2q14.3 Cleft lip and / or cleft palate. Skeletal anomalies.Autosomal dominant
Rare, [4] 1 report [7] 614858 WDR11 WDR11 10q26.12 Combined pituitary hormone deficiency.Autosomal dominant
Rare [4] 614838 NELF (NSMF) NELF 9q34.3Autosomal dominant
Rare [4] 617351 IGSF10 IGSF10 3q24Autosomal dominant
Rare, [4] <2 [7] 614841 GNRH1 GNRH1 8p21.2Autosomal recessive
Rare, [4] <2 [7] 614839 TAC3 TAC3 12q3Autosomal recessive
Rare, [4] 5 [7] 614840 TACR3 TACR3 4q24Autosomal recessive
Rare [4] 611744 OTUD4 OTUD4 4q31.21 Cerebellar ataxia. Gordon Holmes syndrome Autosomal recessive
Rare [4] 609948 RNF216 RNF216 7p22.1 Cerebellar ataxia. Gordon Holmes syndrome Autosomal recessive
Rare [4] 603197 PNPLA6 PNPLA6 19p13.2 Cerebellar ataxia. Gordon Holmes syndrome Autosomal recessive
1 report [7] 109135 AXL AXL 19q13.2Unknown
Rare [4] 612186 DMXL2 DMXL2 15q21.2Polyendocrine deficiencies and polyneuropathy.Autosomal recessive
Rare [4] 300473 NR0B1 (DAX1) NR0B1 Xp21.2 Adrenal hypoplasia.x-linked
1 report [7] 602748 DUSP6 DUSP6 12q21.33Autosomal dominant
1 report [7] 614366 POLR3B POLR3B 12q23.3Autosomal recessive
1 report [7] 615266 SPRY4 SPRY4 5q31.3Autosomal dominant
1 report [7] 615271 FLRT3 FLRT3 20p12.1Autosomal dominant
1 report [7] 617264 SRA1 SRA1 19q13.33Unknown
Rare [4] 601802 HESX1 HESX1 3p14.3 Septo-optic dysplasia. Combined pituitary hormone deficiency.Autosomal recessive and dominant

See also

Related Research Articles

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

X-linked adrenal hypoplasia congenita is a genetic disorder that mainly affects males. It involves many endocrine tissues in the body, especially the adrenal glands.

Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.

The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-releasing hormone (GnRH). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

Anosmin-1 is a secreted, EM associated glycoprotein found in humans and other organisms responsible for normal development, which is expressed in the brain, spinal cord and kidney. Absence or damage to the protein results in Kallmann syndrome in humans, which is characterized by loss of olfactory bulbs and GnRH secretion leading to anosmia and hypothalamic hypogonadotropic hypogonadism. Anosmin-1 is coded by the KAL-1 gene, which is found on the X chromosome. Anosmin-1 is 100 kilodaltons and is expressed on the outside of cells. Because of this and because of its contribution to normal migration of nerve cells, a role in the extracellular matrix has been postulated.

<span class="mw-page-title-main">DAX1</span> Protein-coding gene in humans

DAX1 is a nuclear receptor protein that in humans is encoded by the NR0B1 gene. The NR0B1 gene is located on the short (p) arm of the X chromosome between bands Xp21.3 and Xp21.2, from base pair 30,082,120 to base pair 30,087,136.

<span class="mw-page-title-main">GNRHR</span> Protein-coding gene in the species Homo sapiens

Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the GNRHR gene.

<span class="mw-page-title-main">FSHB</span> Protein-coding gene in the species Homo sapiens

Follitropin subunit beta also known as follicle-stimulating hormone beta subunit (FSH-B) is a protein that in humans is encoded by the FSHB gene. Alternative splicing results in two transcript variants encoding the same protein.

Progonadoliberin-2 is a protein that in humans is encoded by the GNRH2 gene.

<span class="mw-page-title-main">TSHB</span> Protein-coding gene in the species Homo sapiens

Thyroid stimulating hormone, beta also known as TSHB is a protein which in humans is encoded by the TSHB gene.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

<span class="mw-page-title-main">GnRH neuron</span>

GnRH neurons, or gonadotropin-releasing hormone expressing neurons, are the cells in the brain that control the release of reproductive hormones from the pituitary. These brain cells control reproduction by secreting GnRH into the hypophyseal portal capillary bloodstream, so are sometimes referred to as “sex neurons”. This small capillary network carries GnRH to the anterior pituitary, causing release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) into the wider bloodstream. When GnRH neurons change their pattern of release from the juvenile to the adult pattern of GnRH secretion, puberty is initiated. Failure of GnRH neurons to form the proper connections, or failure to successfully stimulate the pituitary with GnRH, means that puberty is not initiated. These disruptions to the GnRH system cause reproductive disorders like hypogonadotropic hypogonadism or Kallmann Syndrome.

<span class="mw-page-title-main">FEZF1</span> Protein-coding gene in the species Homo sapiens

FEZ family zinc finger 1 is a protein that in humans is encoded by the FEZF1 gene.

<span class="mw-page-title-main">Fertile eunuch syndrome</span> Medical condition

The fertile eunuch syndrome or Pasqualini syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis. Pasqualini and Bur published the first case of eunuchoidism with preserved spermatogenesis in 1950 in la Revista de la Asociación Médica Argentina. The hypoandrogenism with spermatogenesis syndrome included:

<span class="mw-page-title-main">Boucher-Neuhäuser syndrome</span> Medical condition

Boucher-Neuhäuser syndrome is a very rare genetic disorder which is characterized by a triad consisting of cerebellar ataxia, chorioretinal dystrophy, and hypogonadism.

References

  1. ↑ Layman L. (2013). "Clinical Testing for Kallmann Syndrome". J Clin Endocrinol Metab. 98 (5): 1860–1862. doi:10.1210/jc.2013-1624. PMC   3644595 . PMID   23650337.
  2. ↑ Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes". Front Endocrinol (Lausanne). 5 (109): 109. doi: 10.3389/fendo.2014.00109 . PMC   4088923 . PMID   25071724.
  3. ↑ Mitchell AL, Dwyer A, Pitteloud N, Quinton R (2011). "Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory". Trends Endocrinol. Metab. 22 (7): 249–58. doi:10.1016/j.tem.2011.03.002. PMID   21511493. S2CID   23578201.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Lima Amato LG, Latronico AC, Gontijo Silveira LF (2017). "Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism". Endocrinol Metab Clin North Am. 46 (2): 283–303. doi:10.1016/j.ecl.2017.01.010. PMID   28476224.
  5. ↑ Boehm U, Bouloux PM, Dattani MT, et al. (2015). "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment". Nat Rev Endocrinol. 11 (Jul 21): 547–64. doi: 10.1038/nrendo.2015.112 . hdl: 11567/821921 . PMID   26194704.
  6. ↑ Vezzoli V, Duminuco P, Bassi I, Guizzardi F, Persani L, Bonomi M (2016). "The complex genetic basis of congenital hypogonadotropic hypogonadism". Minerva Endocrinol. 41 (2): 223–39. PMID   26934720.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Balasubramanian R, Crowley WF Jr (2017). "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency". SourceGeneReviews. PMID   20301509.
  8. ↑ Kotan, LD; Hutchins, BI; Ozkan, Y; Demirel, F; Stoner, H; Cheng, PJ; Esen, I; Gurbuz, F; Bicakci, YK; Mengen, E; Yuksel, B; Wray, S; Topaloglu, AK (4 September 2014). "Mutations in FEZF1 cause Kallmann syndrome". American Journal of Human Genetics. 95 (3): 326–31. doi:10.1016/j.ajhg.2014.08.006. PMC   4157145 . PMID   25192046.
  9. ↑ Hutchins, BI; Kotan, LD; Taylor-Burds, C; Ozkan, Y; Cheng, PJ; Gurbuz, F; Tiong, JD; Mengen, E; Yuksel, B; Topaloglu, AK; Wray, S (May 2016). "CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration". Endocrinology. 157 (5): 1956–66. doi:10.1210/en.2015-1846. PMC   4870868 . PMID   27014940.
  10. ↑ Turan, I; Hutchins, BI; Hacihamdioglu, B; Kotan, LD; Gurbuz, F; Ulubay, A; Mengen, E; Yuksel, B; Wray, S; Topaloglu, AK (1 June 2017). "CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism". The Journal of Clinical Endocrinology and Metabolism. 102 (6): 1816–1825. doi:10.1210/jc.2016-3391. PMC   5470764 . PMID   28324054.
  11. ↑ Hou, Q; Wu, J; Zhao, Y; Wang, X; Jiang, F; Chen, DN; Zheng, R; Men, M; Li, JD (September 2020). "Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism". European Journal of Endocrinology. 183 (3): 245–254. doi: 10.1530/EJE-19-1018 . PMID   32520725. S2CID   219585992.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.