Details of Disease

Disease Name

Kallmann syndrome

Olfacto-genital pathological sequence; hypogonadotropic hypogonadism with anosmia; hypogonadism with anosmia; Kallman syndrome; Kallman's syndrome; congenital hypogonadotropic hypogonadism with anosmia; familial hypogonadism with anosmia

Definition

Kallmann syndrome (KS) is a developmental genetic disorder characterized by the association of congenital hypogonadotropic hypogonadism (CHH) due to gonadotropin-releasing hormone (GnRH) deficiency, and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs).

Disease Hierarchy

DIS6SVEE: Syndromic disease

DIS8JSKR: Hypogonadotropic hypogonadism

DISO3HDG: Kallmann syndrome

Disease Identifiers

MONDO ID

MONDO_0018800

MESH ID

D017436

UMLS CUI

C0162809

MedGen ID

102469

Orphanet ID

478

SNOMED CT ID

93559003

General Information of Disease (ID: DISO3HDG)

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 44 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
WDR11	OT5CY5UR	Supportive	Autosomal dominant	[1]
SEMA3E	OTD4S36H	Limited	Autosomal dominant	[17]
ANOS1	OTZJT4KN	Supportive	Autosomal dominant	[18]
CCDC141	OTQ9HA3I	Supportive	Autosomal dominant	[19]
CHD7	OTHNIZWZ	Supportive	Autosomal dominant	[20]
DCC	OT2C1SHW	Supportive	Autosomal dominant	[21]
DUSP6	OT4H6RKW	Supportive	Autosomal dominant	[7]
FEZF1	OTRX4NOT	Supportive	Autosomal dominant	[22]
FGF17	OTAQSFZ2	Supportive	Autosomal dominant	[7]
FGF8	OTFU0IUW	Supportive	Autosomal dominant	[3]
FGFR1	OT4GLCXW	Supportive	Autosomal dominant	[4]
FLRT3	OT3XMZU3	Supportive	Autosomal dominant	[7]
HESX1	OT5E2Z4G	Supportive	Autosomal dominant	[23]
HS6ST1	OTABV7D2	Supportive	Autosomal dominant	[24]
IL17RD	OTKD9XST	Supportive	Autosomal dominant	[7]
NDNF	OTCDL9PG	Supportive	Autosomal dominant	[25]
PROK2	OT70IFEZ	Supportive	Autosomal dominant	[5]
PROKR2	OT51C69M	Supportive	Autosomal dominant	[5]
SEMA3A	OTQJSV7W	Supportive	Autosomal dominant	[6]
SOX10	OTF25ULQ	Supportive	Autosomal dominant	[26]
SPRY4	OT2VK9N0	Supportive	Autosomal dominant	[7]
TACR3	OT7Q68XE	Supportive	Autosomal dominant	[7]
NSMF	OTLTA24A	moderate	Biomarker	[12]
PRKAR2A	OTZ7P17Z	moderate	Genetic Variation	[27]
SERPINA4	OTBK0GG7	moderate	Genetic Variation	[28]
ARNT2	OTAQD3YV	Strong	GermlineCausalMutation	[29]
CSHL1	OTQKU2F5	Strong	Biomarker	[30]
EBF2	OTFWZE51	Strong	Genetic Variation	[31]
EMX1	OT7NG5MJ	Strong	Genetic Variation	[1]
EMX2	OT0V8OYK	Strong	Genetic Variation	[32]
GHRH	OT94U6MO	Strong	Biomarker	[33]
IHH	OT1DWGXC	Strong	Genetic Variation	[34]
NDN	OTYBYJ82	Strong	Genetic Variation	[35]
OTX2	OTTV05B1	Strong	GermlineCausalMutation	[15]
PALM2AKAP2	OTI618VF	Strong	Biomarker	[36]
PLXNA1	OTN0BING	Strong	Biomarker	[37]
PROP1	OT8GF6N8	Strong	Genetic Variation	[38]
SCEL	OT46SDNQ	Strong	Biomarker	[39]
SEMA7A	OT0ZJK64	Strong	Genetic Variation	[40]
SHOX	OTE0YZJO	Strong	Genetic Variation	[41]
SIX3	OTP5E3VU	Strong	Biomarker	[42]
SOX3	OT1CRCOB	Strong	GermlineCausalMutation	[15]
TCF12	OTZVONNU	Strong	Autosomal recessive	[43]
TSHZ1	OTYQ9ECW	Strong	Altered Expression	[44]
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⏷ Show the Full List of 44 DOT(s)

This Disease Is Related to 16 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
GNRHR	TT8R70G	Limited	Biomarker	[2]
FGF8	TTIUF3J	Supportive	Autosomal dominant	[3]
FGFR1	TTRLW2X	Supportive	Autosomal dominant	[4]
PROKR2	TTM67AX	Supportive	Autosomal dominant	[5]
SEMA3A	TTVKD3S	Supportive	Autosomal dominant	[6]
TACR3	TTBPGLU	Supportive	Autosomal dominant	[7]
GNRH1	TT0ID4A	moderate	Genetic Variation	[8]
ANK1	TTKFPMH	Strong	Genetic Variation	[9]
FGF8	TTIUF3J	Strong	Biomarker	[10]
KISS1	TTU2O6T	Strong	Biomarker	[11]
KISS1R	TT3KBZY	Strong	Biomarker	[12]
NR0B1	TTTK36V	Strong	Genetic Variation	[13]
SEMA3A	TTVKD3S	Strong	Genetic Variation	[14]
SOX2	TTCNOT6	Strong	GermlineCausalMutation	[15]
STS	TTHM0R1	Strong	Genetic Variation	[16]
TACR3	TTBPGLU	Strong	GermlineCausalMutation	[7]
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⏷ Show the Full List of 16 DTT(s)

References

1	WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2010 Oct 8;87(4):465-79. doi: 10.1016/j.ajhg.2010.08.018.
2	Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate.Biomed Res Int. 2015;2015:649698. doi: 10.1155/2015/649698. Epub 2015 Jun 25.
3	Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008 Aug;118(8):2822-31. doi: 10.1172/JCI34538.
4	Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007 Feb;117(2):457-63. doi: 10.1172/JCI29884. Epub 2007 Jan 18.
5	Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008 Oct;93(10):4113-8. doi: 10.1210/jc.2008-0958. Epub 2008 Aug 5.
6	SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum Reprod. 2012 May;27(5):1460-5. doi: 10.1093/humrep/des022. Epub 2012 Mar 12.
7	Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
8	Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration.J Neurosci. 2020 Jan 8;40(2):311-326. doi: 10.1523/JNEUROSCI.1977-19.2019. Epub 2019 Nov 25.
9	A de novo interstitial deletion of 8p11.2 including ANK1 identified in a patient with spherocytosis, psychomotor developmental delay, and distinctive facial features.Gene. 2012 Sep 10;506(1):146-9. doi: 10.1016/j.gene.2012.06.086. Epub 2012 Jul 4.
10	TET1 regulates fibroblast growth factor 8 transcription in gonadotropin releasing hormone neurons.PLoS One. 2019 Jul 30;14(7):e0220530. doi: 10.1371/journal.pone.0220530. eCollection 2019.
11	Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene.Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10714-9. doi: 10.1073/pnas.0704114104. Epub 2007 Jun 11.
12	Genetic diagnosis of idiopathic hypogonadotrophic hypogonadism: a new point mutation in the KAL2 gene.Hormones (Athens). 2014 Apr-Jun;13(2):280-5. doi: 10.1007/BF03401342.
13	Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization.Clin Endocrinol (Oxf). 2001 Aug;55(2):163-74. doi: 10.1046/j.1365-2265.2001.01277.x.
14	Sema3a plays a role in the pathogenesis of CHARGE syndrome.Hum Mol Genet. 2018 Apr 15;27(8):1343-1352. doi: 10.1093/hmg/ddy045.
15	New insights into septo-optic dysplasia.Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2014;35(1):123-7.
16	Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome.Cytogenet Genome Res. 2017;151(1):1-4. doi: 10.1159/000458469. Epub 2017 Mar 3.
17	Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
18	A fertile male patient with Kallmann syndrome and two missense mutations in the KAL1 gene. Fertil Steril. 2011 Apr;95(5):1789.e3-6. doi: 10.1016/j.fertnstert.2010.11.045. Epub 2010 Dec 18.
19	CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab. 2017 Jun 1;102(6):1816-1825. doi: 10.1210/jc.2016-3391.
20	Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2008 Oct;83(4):511-9. doi: 10.1016/j.ajhg.2008.09.005. Epub 2008 Oct 2.
21	DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. Hum Mol Genet. 2018 Jan 15;27(2):359-372. doi: 10.1093/hmg/ddx408.
22	Mutations in FEZF1 cause Kallmann syndrome. Am J Hum Genet. 2014 Sep 4;95(3):326-31. doi: 10.1016/j.ajhg.2014.08.006.
23	Identification of HESX1 mutations in Kallmann syndrome. Fertil Steril. 2013 Jun;99(7):1831-7. doi: 10.1016/j.fertnstert.2013.01.149. Epub 2013 Mar 1.
24	Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11524-9. doi: 10.1073/pnas.1102284108. Epub 2011 Jun 23.
25	Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism. Am J Hum Genet. 2020 Jan 2;106(1):58-70. doi: 10.1016/j.ajhg.2019.12.003. Epub 2019 Dec 26.
26	Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet. 2013 May 2;92(5):707-24. doi: 10.1016/j.ajhg.2013.03.024.
27	The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis.Physiol Rev. 2018 Apr 1;98(2):1055-1082. doi: 10.1152/physrev.00012.2017.
28	Mutation analysis of the KAL gene in female patients with gonadotropin-releasing hormone deficiency.Yonsei Med J. 2004 Feb 29;45(1):107-12. doi: 10.3349/ymj.2004.45.1.107.
29	ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain. 2013 Oct;136(Pt 10):3096-105. doi: 10.1093/brain/awt218. Epub 2013 Sep 10.
30	A novel missense mutation in the mouse growth hormone gene causes semidominant dwarfism, hyperghrelinemia, and obesity.Endocrinology. 2004 May;145(5):2531-41. doi: 10.1210/en.2003-1125. Epub 2004 Jan 15.
31	Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients.J Endocrinol. 2005 Dec;187(3):361-8. doi: 10.1677/joe.1.06103.
32	Mutation analysis of the EMX2 gene in Kallmann's syndrome.Fertil Steril. 1999 Nov;72(5):910-4. doi: 10.1016/s0015-0282(99)00376-3.
33	GH, but not GHRH, plays a role in the development of experimental autoimmune encephalomyelitis.Endocrinology. 2011 Oct;152(10):3803-10. doi: 10.1210/en.2011-1317. Epub 2011 Aug 16.
34	Clinical Case Seminar. Peculiar prolactinomas in patients with pituitary developmental gene mutations: from an adult endocrinologist perspective.Hormones (Athens). 2012 Apr-Jun;11(2):189-98. doi: 10.14310/horm.2002.1346.
35	Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism.Eur J Endocrinol. 2011 Jul;165(1):145-50. doi: 10.1530/EJE-11-0199. Epub 2011 May 4.
36	The breakpoint identified in a balanced de novo translocation t(7;9)(p14.1;q31.3) disrupts the A-kinase (PRKA) anchor protein 2 gene (AKAP2) on chromosome 9 in a patient with Kallmann syndrome and bone anomalies.Int J Mol Med. 2007 Mar;19(3):429-35.
37	Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism.Clin Genet. 2019 Feb;95(2):320-324. doi: 10.1111/cge.13482. Epub 2018 Dec 26.
38	Mutations of the GnRH receptor gene: a new cause of autosomal-recessive hypogonadotropic hypogonadism.Arch Med Res. 1999 Nov-Dec;30(6):481-5. doi: 10.1016/s0188-4409(99)00072-7.
39	Identification of ROBO1/2 and SCEL as candidate genes in Kallmann syndrome with emerging bioinformatic analysis.Endocrine. 2020 Jan;67(1):224-232. doi: 10.1007/s12020-019-02010-y. Epub 2019 Jul 19.
40	A novel heterozygous intron mutation in SEMA7A causing kallmann syndrome in a female.Gynecol Endocrinol. 2020 Mar;36(3):218-221. doi: 10.1080/09513590.2019.1680624. Epub 2019 Oct 25.
41	Short stature in a mother and daughter caused by familial der(X)t(X;X)(p22.1-3;q26).Am J Med Genet. 2001 Jul 22;102(1):81-5. doi: 10.1002/1096-8628(20010722)102:1<81::aid-ajmg1375>3.0.co;2-v.
42	Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration.Mol Neurobiol. 2018 Nov;55(11):8709-8727. doi: 10.1007/s12035-018-1013-0. Epub 2018 Mar 27.
43	TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci. Hum Mol Genet. 2020 Aug 11;29(14):2435-2450. doi: 10.1093/hmg/ddaa120.
44	TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.J Clin Invest. 2014 Mar;124(3):1214-27. doi: 10.1172/JCI72466.