Kallmann Syndrome and Hypogonadotropic Hypogonadism
Inheritance pattern
Autosomal recessive, autosomal dominant, X-linked
Clinical features
Kallmann syndrome (KS) is a developmental genetic disorder characterized by delayed or absent puberty and impaired sense of smell and it belongs to isolated gonadotropin-releasing hormone deficiencies. Deficient hypothalamic gonadotropin-releasing hormone (GnRH) secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.
Incidence of Kallmann syndrome was estimated to be 1:30,000 in males and 1:125,000 in females in Finland with the male-to-female ratio of nearly 4:1 1.
Patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism may not experience puberty or may experience incomplete puberty and have symptoms associated with hypogonadism. For men, these symptoms include decreased libido, erectile dysfunction, decreased muscle strength, and diminished aggressiveness and drive 2, 3. For women, symptoms include amenorrhea and dyspareunia. Family members of patients with idiopathic hypogonadotropic hypogonadism may have a history of delayed, although otherwise normal, puberty 2, 3.
The impaired olfactory function in Kallmann syndrome can be either hyposmia or complete anosmia 2, 3. Most individuals with impaired sense of smell are otherwise asymptomatic. Isolated gonadotropine deficiency is associated with a normal sense of smell (“normosmic”) in approximately 40% of affected individuals and with an impaired sense of smell (Kallmann syndrome) in approximately 60% of affected cases 2, 3.
Laboratory findings of Kallmann syndrome and hypogonadotropic hypogonadism include reduced levels of testosterone in males and estradiol in females, as well as very low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone). Levels of other anterior pituitary hormones are typically normal.
Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance |
---|---|---|---|
ABCB11 | 603201 | progressive familial intrahepatic cholestasis type 2; benign recurrent intrahepatic cholestasis type 2 | AR |
ABCB4 | 171060 | gallbladder disease type 1; progressive familial intrahepatic cholestasis type 3; Cholestasis, intrahepatic, of pregnancy, 3 | AD, AR |
ABCC2 | 601107 | Dubin-Johnson syndrome | AR |
ACTN4 | 604638 | Glomerulosclerosis, focal segmental, 1 | AD |
ACVR2B | 602730 | Heterotaxy, visceral, 4, autosomal | |
AGPS | 603051 | rhizomelic chondrodysplasia punctata type 3 | AR |
AHI1 | 608894 | Joubert syndrome 3 | AR |
AIPL1 | 604392 | Leber congenital amaurosis 4 | AD, AR |
AKR1D1 | 604741 | Bile acid synthesis defect, congenital, 2 | AR |
ALDOB | 612724 | hereditary fructose intolerance | AR |
ALG8 | 608103 | congenital disorder of glycosylation type 1h | AD, AR |
ALPL | 171760 | adult hypophosphatasia; infantile hypophosphatasia; childhood-onset hypophosphatasia | AD, AR |
ANKH | 605145 | Chondrocalcinosis 2; Craniometaphyseal dysplasia | AD |
ANKS6 | 615370 | nephronophthisis 16 | AR |
ANO5 | 608662 | gnathodiaphyseal dysplasia; limb-girdle muscular dystrophy type 2L | AD, AR |
ANOS1 | 300836 | Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) | XLR |
AP2S1 | 602242 | Hypocalciuric hypercalcemia, familial, type III | AD |
ARHGAP31 | 610911 | Adams-Oliver syndrome 1 | AD |
ARHGDIA | 601925 | Nephrotic syndrome, type 8 | AR |
ARL13B | 608922 | Joubert syndrome 8 | AR |
ARL6 | 608845 | Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 | AR, DiR |
ARMC4 | 615408 | primary ciliary dyskinesia, 23 | AR |
ARSL | 300180 | Chondrodysplasia punctata, X-linked recessive | XLR |
ATP6V0A4 | 605239 | distal renal tubular acidosis | AR |
ATP6V1B1 | 192132 | Renal tubular acidosis with deafness | AR |
ATP8B1 | 602397 | Cholestasis, intrahepatic, of pregnancy, 1; Cholestasis, Progressive Familial Intrahepatic, 1; Cholestasis, Benign Recurrent Intrahepatic, 1 | AD, AR |
ATR | 601215 | Seckel syndrome 1; ?Cutaneous telangiectasia and cancer syndrome, familial | AD, AR |
B9D1 | 614144 | Meckel Syndrome, Type 9 | AR |
B9D2 | 611951 | Meckel syndrome 10 | AR |
BBS1 | 209901 | Bardet-Biedl syndrome type 1 | AR, DiR |
BBS10 | 610148 | Bardet-Biedl syndrome type 10 | AR |
BBS12 | 610683 | Bardet-Biedl syndrome type 12 | AR |
BBS2 | 606151 | Bardet-Biedl syndrome type 2; retinitis pigmentosa type 74 | AR |
BBS4 | 600374 | Bardet-Biedl syndrome 4 | AR |
BBS5 | 603650 | Bardet-Biedl syndrome 5 | AR |
BBS7 | 607590 | Bardet-Biedl syndrome type 7 | AR |
BBS9 | 607968 | Bardet-Biedl syndrome type 9 | AR |
BCS1L | 603647 | Mitochondrial complex III deficiency, nuclear type 1; Leigh syndrome; Bjornstad syndrome; GRACILE syndrome | AR, M |
BICC1 | 614295 | Renal dysplasia, cystic, susceptibility to | AD |
BMP1 | 112264 | osteogenesis imperfecta type 13 | AR |
BMPR1B | 603248 | Brachydactyly type A2; Chondrodysplasia, Acromesomelic, With Genital Anomalies | AD, AR |
BSND | 606412 | Bartter Syndrome type 4A | AR |
C8orf37 | 614477 | Cone-rod dystrophy 16; Bardet-Biedl syndrome type 21 | AR |
CA2 | 611492 | Osteopetrosis, autosomal recessive 3, with renal tubular acidosis | AR |
CABP4 | 608965 | Night blindness, congenital stationary (incomplete), 2B, autosomal recessive | AR |
CANT1 | 613165 | Desbuquois dysplasia type 1 | AR |
CASP10 | 601762 | Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer | AD |
CASR | 601199 | Hypocalciuric hypercalcemia, type I; Hyperparathyroidism, neonatal; Hypocalcemia, autosomal dominant, with Bartter syndrome; Epilepsy idiopathic generalized, susceptibility to, 8 | AD, AR |
CC2D2A | 612013 | COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 | AR |
CCDC103 | 614677 | Ciliary dyskinesia, primary, 17 | AR |
CCDC114 | 615038 | Ciliary dyskinesia, primary, 20 | AR |
CCDC151 | 615956 | primary Ciliary dyskinesia type 30 | AR |
CCDC28B | 610162 | Bardet-Biedl syndrome type 1 | AR, DiR |
CCDC39 | 613798 | Ciliary dyskinesia, primary, 14 | |
CCDC40 | 613799 | Ciliary dyskinesia, primary, 15 | |
CCDC65 | 611088 | Ciliary dyskinesia, primary, 27 | AR |
CCNO | 607752 | primary ciliary dyskinesia type 29 | AR |
CD2AP | 604241 | Glomerulosclerosis, focal segmental, 3 | |
CDKN1C | 600856 | Beckwith-Wiedemann syndrome; IMAGE syndrome | AD |
CENPF | 600236 | Stromme syndrome | AR |
CENPJ | 609279 | primary microcephaly 6; Seckel syndrome 4 | AR |
CEP152 | 613529 | Seckel syndrome 5; primary microcephaly 9 | AR |
CEP164 | 614848 | nephronophthisis 15 | AR |
CEP290 | 610142 | Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 | AR |
CEP41 | 610523 | Joubert syndrome 15 | AR |
CEP63 | 614724 | Seckel syndrome 6 | AR |
CFAP298 | 615494 | primary ciliary dyskinesia type 26 | AR |
CFAP53 | 614759 | Heterotaxy, visceral, 6, autosomal recessive | AR |
CFC1 | 605194 | Heterotaxy, visceral, 2, autosomal | AD |
CFTR | 602421 | hereditary pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens | AD, AR |
CHD7 | 608892 | CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia | AD |
CHSY1 | 608183 | AR | |
CILK1 | 612325 | AD, AR | |
CLCN5 | 300008 | Dent disease; Hypophosphatemic rickets; Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis; Nephrolithiasis, type I | XLR |
CLCNKA | 602024 | Bartter syndrome, type 4b, digenic | DiR |
CLCNKB | 602023 | Bartter syndrome, type 3; Bartter syndrome, type 4b, digenic | AR, DiR |
CLDN16 | 603959 | renal hypomagnesemia type 3 | AR |
CLDN19 | 610036 | Hypomagnesemia 5, renal, with ocular involvement | AR |
CNGA3 | 600053 | Achromatopsia type 2 | AR |
COL10A1 | 120110 | METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE | AD |
COL4A1 | 120130 | porencephaly 1; Brain small vessel disease with or without ocular anomalies; Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps; Hemorrhage, intracerebral, susceptibility to | AD |
COL4A3 | 120070 | Alport syndrome 3, AD; benign familial hematuria benign familial; Alport syndrome, AR | AD, AR |
COL4A4 | 120131 | benign familial hematuria benign familial; Alport syndrome, AR | AD, AR |
COL4A5 | 303630 | Alport syndrome | XLD |
COL9A3 | 120270 | multiple epiphyseal dysplasia type 3 | AD |
COMP | 600310 | Epiphyseal Dysplasia, Multiple, 1; Pseudoachondroplasia | AD |
COQ2 | 609825 | Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 | AD, AR |
COQ6 | 614647 | Coenzyme Q10 deficiency, primary, 6 | AR |
COQ8B | 615567 | Nephrotic syndrome, type 9 | AR |
COQ9 | 612837 | Coenzyme Q10 deficiency, primary, 5 | AR |
CPLANE1 | 614571 | oral-facial-digital syndrome 6; Joubert syndrome 17 | AR |
CRB1 | 604210 | pigmented paravenous chorioretinal atrophy; retinitis pigmentosa type 12; Leber congenital amaurosis type 8 | AD, AR |
CRELD1 | 607170 | Atrioventricular septal defect, partial, with heterotaxy syndrome | AD |
CRTAP | 605497 | osteogenesis imperfecta type 7 | AR |
CRX | 602225 | Cone-rod retinal dystrophy-2; Leber congenital amaurosis 7 | AD |
CSPP1 | 611654 | Joubert syndrome 21 | AR |
CTNS | 606272 | ocular nonnephropathic cystinosis; cystinosis; late-onset juvenile or adolescent nephropathic cystinosis | AR |
CUBN | 602997 | megaloblastic anemia 1 | AR |
CUL3 | 603136 | Pseudohypoaldosteronism, type IIE | AD |
CYP7B1 | 603711 | spastic paraplegia 5A | AR |
DDR2 | 191311 | Spondylometaepiphyseal dysplasia, short limb-hand type | AD, AR |
DGKE | 601440 | Nephrotic syndrome, type 7 | AR |
DGUOK | 601465 | mitochondrial DNA depletion syndrome 3 | AR |
DHCR7 | 602858 | Smith-Lemli-Opitz syndrome | AR |
DMP1 | 600980 | Hypophosphatemic Rickets, Autosomal Recessive, 1 | AR |
DNAAF1 | 613190 | Ciliary dyskinesia, primary, 13 | AR |
DNAAF2 | 612517 | Ciliary dyskinesia, primary, 10 | |
DNAAF3 | 614566 | Ciliary dyskinesia, primary, 2 | AR |
DNAAF4 | 608706 | Ciliary dyskinesia, primary, 25 | AD, AR |
DNAAF5 | 614864 | Ciliary dyskinesia, primary, 18 | AR |
DNAH11 | 603339 | primary ciliary dyskinesia type 7, with or without situs inversus | AR |
DNAH5 | 603335 | primary ciliary dyskinesia type 3, with or without situs inversus | |
DNAI1 | 604366 | primary ciliary dyskinesia type 1, with or without situs inversus | AR |
DNAI2 | 605483 | primary ciliary dyskinesia type 9, with or without situs inversus | |
DNAL1 | 610062 | Ciliary dyskinesia, primary, 16 | AR |
DRC1 | 615288 | primary ciliary dyskinesia, 21 | AR |
DUSP6 | 602748 | Hypogonadotropic hypogonadism 19 with or without anosmia | AD |
DYM | 607461 | Dyggve-Melchior-Clausen disease | AR |
DYNC2H1 | 603297 | short-rib thoracic dysplasia-3 with or without polydactyly | AR, DiR |
DYNC2I1 | 615462 | Short-rib thoracic dysplasia 8 with or without polydactyly | AR |
DYNC2I2 | 613363 | Short-rib thoracic dysplasia 11 with or without polydactyly | AR |
EBP | 300205 | MEND syndrome; Chondrodysplasia punctata, X-linked dominant | XLD, XLR |
EIF2AK3 | 604032 | Wolcott-Rallison syndrome | AR |
ENPP1 | 173335 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Arterial calcification, generalized, of infancy, 1; OBESITY; Hypophosphatemic rickets, autosomal recessive, 2; Cole disease | AD, AR |
ESCO2 | 609353 | Roberts syndrome | AR |
EVC | 604831 | Weyers acrofacial dysostosis; Ellis-van Creveld syndrome | AD, AR |
EVC2 | 607261 | Weyers acrofacial dysostosis; Ellis-van Creveld syndrome | AD, AR |
FAH | 613871 | tyrosinemia type 1 | AR |
FAS | 134637 | Autoimmune lymphoproliferative syndrome | AD |
FASLG | 134638 | Lung Cancer; Autoimmune lymphoproliferative syndrome | AD |
FEZF1 | 613301 | AR | |
FGF17 | 603725 | Hypogonadotropic hypogonadism 20 with or without anosmia | AD |
FGF23 | 605380 | Hypophosphatemic rickets, autosomal dominant | AD, AR |
FGF8 | 600483 | hypogonadotropic hypogonadism 6 with or without anosmia | AD |
FGFR1 | 136350 | Craniofacial-skeletal-dermatologic dysplasia; Jackson-Weiss syndrome; hypogonadotropic hypogonadism-2 with or without anosmia; Osteoglophonic dysplasia; Hartsfield syndrome | AD |
FKBP10 | 607063 | Bruck syndrome 1; osteogenesis imperfecta type 11 | AR |
FLNB | 603381 | Atelosteogenesis, type i; Atelosteogenesis, type iii; Boomerang dysplasia; Larsen syndrome; Spondylocarpotarsal synostosis syndrome | AD, AR |
FLRT3 | 604808 | AD | |
FSHB | 136530 | AR | |
FXYD2 | 601814 | Hypomagnesemia-2, renal | AD |
GDF1 | 602880 | Right atrial isomerism; Transposition of the great arteries, dextro-looped 3 | AD, AR |
GDF5 | 601146 | Brachydactyly type A2; Brachydactyly type C; Grebe type chondrodysplasia; Hunter-Thompson type of acromesomelic dysplasia; Du Pan syndrome; multiple synostoses syndrome type 2; susceptibility to osteoarthritis type 5; brachydactyly type A1; proximal symphalangism type 1B | AD, AR |
GFM1 | 606639 | Combined oxidative phosphorylation deficiency 1 | AR |
GHR | 600946 | familial hypercholesterolemia; Laron syndrome; Increased responsiveness to growth hormone | AD, AR |
GLA | 300644 | Fabry disease; Fabry disease, atypical cardiac variant | XL |
GLI2 | 165230 | holoprosencephaly 9; Culler-Jones syndrome | AD |
GLI3 | 165240 | Pallister-Hall syndrome; Polydactyly, postaxial, types A1 and B; Preaxial polydactyly type IV; Greig cephalopolysyndactyly syndrome | AD |
GLIS2 | 608539 | nephronophthisis 7 | |
GNA11 | 139313 | Hypocalciuric hypercalcemia, familial, type ii; Hypocalcemia, autosomal dominant 2 | AD |
GNAS | 139320 | Pseudohypoparathyroidism Ia; Osseous heteroplasia, progressive; McCune-Albright syndrome, somatic, mosaic; ACTH-independent macronodular adrenal hyperplasia; Pseudohypoparathyroidism type Ib; Pseudohypoparathyroidism Ic; Pseudopseudohypoparathyroidism | AD |
GNPAT | 602744 | rhizomelic chondrodysplasia punctata type 2 | AR |
GNRH1 | 152760 | hypogonadotropic hypogonadism 12 with or without anosmia | AR |
GNRHR | 138850 | hypogonadotropic hypogonadism 7 with or without anosmia | AR |
GUCY2D | 600179 | Leber congenital amaurosis type 1; cone-rod dystrophy type 6 | AD, AR |
HAMP | 606464 | Hemochromatosis, type 2B | AR |
HESX1 | 601802 | Septooptic dysplasia | AD, AR |
HEXA | 606869 | Tay-Sachs disease/ GM2-gangliosidosis | AR |
HFE | 613609 | Alzheimer Disease; hepatoerythropoietic porphyria; variegate porphyria; hemochromatosis type 1; susceptibility to microvascular complications of diabetes type 7; Transferrin serum level QTL2 | AD, AR |
HNF1B | 189907 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic | AD |
HNF4A | 600281 | MODY type 1; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young | AD |
HS6ST1 | 604846 | hypogonadotropic hypogonadism 15 with or without anosmia | AD |
HSD11B2 | 614232 | apparent mineralocorticoid excess | AR |
HSD3B7 | 607764 | Bile acid synthesis defect, congenital, 1 | AR |
HSPG2 | 142461 | Silverman-Handmaker type of dyssegmental dysplasia; Schwartz-Jampel syndrome | AR |
HYDIN | 610812 | primary ciliary dyskinesia type 5 | AR |
HYLS1 | 610693 | Hydrolethalus syndrome | AR |
IFITM5 | 614757 | osteogenesis imperfecta type 5 | AD |
IFT122 | 606045 | Cranioectodermal dysplasia 1 | AR |
IFT140 | 614620 | Mainzer-Saldino syndrome; retinitis pigmentosa type 80 | AR |
IFT172 | 607386 | Short-rib thoracic dysplasia 10 with or without polydactyly | AR |
IFT27 | 615870 | Bardet-Biedl syndrome 19 | AR |
IFT43 | 614068 | Cranioectodermal dysplasia 3 | AR |
IFT80 | 611177 | AR | |
IL17RD | 606807 | Hypogonadotropic hypogonadism type 18 with or without anosmia | AD, AR, DiD |
IMPDH1 | 146690 | Retinitis pigmentosa 10; Leber congenital amaurosis 11 | AD |
INF2 | 610982 | Focal Segmental Glomerulosclerosis 5; intermediate type E Charcot-Marie-Tooth | AD |
INPP5E | 613037 | Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis | AR |
INPPL1 | 600829 | Opsismodysplasia | AR |
INVS | 243305 | nephronophthisis 2 | AR |
IQCB1 | 609237 | Senior-Loken syndrome 5 | AR |
ITGA3 | 605025 | Congenital interstitial lung disease with nephrotic syndrome and epidermolysis bullosa | AR |
JAG1 | 601920 | Alagille syndrome; Tetralogy of Fallot | AD |
KCNJ1 | 600359 | Bartter syndrome, type 2 | AR |
KCNJ10 | 602208 | autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance | AR |
KCNJ13 | 603208 | AD, AR | |
KCNJ5 | 600734 | Long QT syndrome 13 | AD |
KIF7 | 611254 | Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 | AR |
KISS1 | 603286 | hypogonadotropic hypogonadism 13 with or without anosmia | AR |
KISS1R | 604161 | Precocious puberty, central, 1; hypogonadotropic hypogonadism 8 with or without anosmia | AD, AR |
KLHL3 | 605775 | Pseudohypoaldosteronism, type IID | AD, AR |
LAMB2 | 150325 | Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalities | AR |
LBR | 600024 | Pelger-Huet anomaly; Greenberg skeletal dysplasia | AD, AR |
LCA5 | 611408 | Leber congenital amaurosis type 5 | AR |
LCT | 603202 | AR | |
LEFTY2 | 601877 | ||
LEP | 164160 | Leptin deficiency | AR |
LEPR | 601007 | Morbid obesity due to leptin receptor deficiency | AR |
LHB | 152780 | Hypogonadotropic hypogonadism 23 with or without anosmia | AR |
LHX3 | 600577 | Pituitary hormone deficiency, combined, 3 | AR |
LHX4 | 602146 | Pituitary hormone deficiency, combined, 4 | AD |
LIFR | 151443 | Stuve-Wiedemann syndrome | AR |
LMX1B | 602575 | Nail-patella syndrome | AD |
LRAT | 604863 | Leber congenital amaurosis 14 | AR |
LRP5 | 603506 | Hyperostosis Corticalis Generalisata, Benign Form Of Worth, With Torus Palatinus; OSTEOPOROSIS; Osteoporosis-pseudoglioma syndrome; Exudative vitreoretinopathy 4; Bone Mineral Density Quantitative Trait Locus 1; autosomal dominant osteopetrosis type 1; van Buchem disease, type 2 | AD, AR |
LRRC6 | 614930 | Ciliary dyskinesia, primary, 19 | AR |
LZTFL1 | 606568 | Bardet-Biedl syndrome 17 | AR |
MAGI2 | 606382 | nephrotic syndrome type 15 | AR |
MATN3 | 602109 | Epiphyseal dysplasia, multiple, 5 | AD, AR |
MCEE | 608419 | Methylmalonyl-coa epimerase deficiency | AR |
MERTK | 604705 | Retinitis pigmentosa 38 | AR |
MKKS | 604896 | McKusick-Kaufman syndrome; Bardet-Biedl syndrome type 6 | AR |
MKS1 | 609883 | Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 | AR |
MMAA | 607481 | methylmalonic aciduria (MMA) of the cblA complementation type | AR |
MMAB | 607568 | methylmalonic aciduria (MMA) of the cblB complementation type | AR |
MMADHC | 611935 | methylmalonic aciduria (MMA) of the cblD complementation type | AR |
MMP13 | 600108 | Metaphyseal dysplasia, Spahr type; Spondyloepimetaphyseal dysplasia, Missouri type | AD, AR |
MMP21 | 608416 | Heterotaxy, visceral, 7, autosomal | AR |
MMP9 | 120361 | Metaphyseal anadysplasia 2 | |
MMUT | 609058 | complete deficiency of methylmalonyl-CoA mutase | AR |
MPV17 | 137960 | mitochondrial DNA depletion syndrome type 6 | AR |
MYH9 | 160775 | Fechtner syndrome; Macrothrombocytopenia and progressive sensorineural deafness; May-Hegglin anomaly; Sebastian syndrome; deafness type 17 | AD |
MYO7A | 276903 | Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 | AD, AR |
NBAS | 608025 | Short stature, optic nerve atrophy, and Pelger-Huet anomaly; Infantile liver failure syndrome type 2 | AR |
NEK1 | 604588 | Short-rib thoracic dysplasia 6 with or without polydactyly | AD, AR, DiR |
NEK8 | 609799 | nephronophthisis 9; Renal-hepatic-pancreatic dysplasia 2 | AR |
NEUROG3 | 604882 | Diarrhea 4, malabsorptive, congenital | AR |
NKX2-5 | 600584 | Atrial Septal Defect 7 With Or Without Atrioventricular Conduction Defects; Tetralogy of Fallot; Conotruncal Heart Malformations; Hypothyroidism, Congenital, Nongoitrous, 5; Ventricular septal defect 3; Hypoplastic left heart syndrome 2 | AD |
NKX3-2 | 602183 | Spondylo-megaepiphyseal-metaphyseal dysplasia | AR |
NME8 | 607421 | Ciliary dyskinesia, primary, 6 | AR |
NMNAT1 | 608700 | Leber congenital amaurosis 9 | AR |
NODAL | 601265 | Heterotaxy, visceral, 5, autosomal | AD |
NOG | 602991 | proximal symphalangism 1A | AD |
NOTCH2 | 600275 | Hajdu-Cheney syndrome; Alagille syndrome 2 | AD |
NPC1 | 607623 | Niemann-Pick disease type C/D | AR |
NPC2 | 601015 | Niemann-Pick disease type C2 | AR |
NPHP1 | 607100 | nephronophthisis 1; Joubert syndrome 4 | AR |
NPHP3 | 608002 | Renal-hepatic-pancreatic dysplasia 1; Meckel syndrome 7; nephronophthisis 3 | AR |
NPHP4 | 607215 | nephronophthisis 4 | AR |
NPHS1 | 602716 | nephrotic syndrome type 1 | AR |
NPHS2 | 604766 | nephrotic syndrome type 2 | AR |
NR0B1 | 300473 | 46XY sex reversal 2, dosage-sensitive; Adrenal hypoplasia, congenital, with hypogonadotropic hypogonadism | XL, XLR |
NR0B2 | 604630 | OBESITY | AD, AR |
NR3C2 | 600983 | Pseudohypoaldosteronism type I, autosomal dominant | AD |
NSDHL | 300275 | CK syndrome; CHILD syndrome | XLD, XLR |
NSMF | 608137 | hypogonadotropic hypogonadism 9 with or without anosmia | AD |
OCRL | 300535 | Dent disease type 2; Lowe oculocerebrorenal syndrome | XLR |
OFD1 | 300170 | Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 | XLD, XLR |
OTX2 | 600037 | Microphthalmia, syndromic 5; Pituitary hormone deficiency, combined, 6 | AD |
P3H1 | 610339 | osteogenesis imperfecta type 8 | AR |
PAX2 | 167409 | Papillorenal syndrome | AD |
PCSK1 | 162150 | Obesity with impaired prohormone processing | AR |
PDE6D | 602676 | Joubert syndrome 22 | AR |
PDSS2 | 610564 | Coenzyme Q10 deficiency, primary, 3 | AR |
PEX1 | 602136 | Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B | AR |
PEX10 | 602859 | peroxisome biogenesis disorder 6A (Zellweger); peroxisome biogenesis disorder 6B | AR |
PEX12 | 601758 | peroxisome biogenesis disorder type 3B; peroxisome biogenesis disorder type 3A (Zellweger) | AR |
PEX2 | 170993 | peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B | AR |
PEX26 | 608666 | peroxisome biogenesis disorder type 7A (Zellweger); peroxisome biogenesis disorder 7B | AR |
PEX5 | 600414 | peroxisome biogenesis disorder 2B (Zellweger); peroxisome biogenesis disorder 2A (Zellweger); Rhizomelic chondrodysplasia punctata, type 5 | AR |
PEX6 | 601498 | peroxisome biogenesis disorder type 4A (Zellweger); peroxisome biogenesis disorder type 4B; Heimler syndrome type 2 | AD, AR |
PEX7 | 601757 | Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) | AR |
PHEX | 300550 | X-linked dominant hypophosphatemic rickets | XLD |
PHF6 | 300414 | Borjeson-Forssman-Lehmann syndrome | XLR |
PKD1L1 | 609721 | Visceral heterotaxy type 8 | AR |
PKD2 | 173910 | polycystic kidney disease type 2 | AD |
PKHD1 | 606702 | polycystic kidney disease type 4 with or without polycystic liver disease | AR |
PLCE1 | 608414 | Nephrotic syndrome, type 3 | AR |
PLOD2 | 601865 | Bruck syndrome 2 | AR |
PMM2 | 601785 | congenital disorder of glycosylation type 1a | AR |
PNPLA6 | 603197 | Boucher-Neuhauser syndrome; spastic paraplegia 39 | AR |
POLG | 174763 | progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B | AD, AR |
POLR3B | 614366 | hypomyelinating leukodystrophy-8 | AR |
POMC | 176830 | OBESITY; Proopiomelanocortin Deficiency | AD, AR |
POU1F1 | 173110 | Pituitary hormone deficiency, combined, 1 | AD, AR |
PPARG | 601487 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 | AD, AR |
PPIB | 123841 | osteogenesis imperfecta type 9 | AR |
PRKAR1A | 188830 | Acrodysostosis 1 With Or Without Hormone Resistance; Carney complex, type 1; Myxoma, intracardiac; Pigmented nodular adrenocortical disease, primary, 1 | AD |
PROK2 | 607002 | hypogonadotropic hypogonadism 4 with or without anosmia | AD |
PROKR2 | 607123 | hypogonadotropic hypogonadism 3 with or without anosmia | AD |
PROM1 | 604365 | Stargardt disease 4; Macular dystrophy, retinal, 2; Retinitis pigmentosa 41; Cone-rod dystrophy 12 | AD, AR |
PROP1 | 601538 | Pituitary hormone deficiency, combined, 2 | AR |
PRPH2 | 179605 | Retinitis punctata albescens; Patterned dystrophy of retinal pigment epithelium (macular dystrophy); Retinitis pigmentosa 7; vitelliform macular dystrophy-3; Choriodal dystrophy, central areolar 2 | AD, AR |
PTH1R | 168468 | primary failure of tooth eruption; Metaphyseal chondrodysplasia, Murk Jansen type; Chondrodysplasia, Blomstrand type; Eiken syndrome | AD, AR |
RBBP8 | 604124 | Jawad syndrome / Microcephaly with mental retardation and digital anomalies; Seckel syndrome 2 | AR |
RD3 | 180040 | Leber congenital amaurosis 12 | AR |
RDH12 | 608830 | Leber congenital amaurosis type 13 | AD, AR |
RDH5 | 601617 | Retinitis punctata albescens | AD, AR |
RHO | 180380 | Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1; Retinitis Pigmentosa 4 | AD, AR |
RLBP1 | 180090 | Retinitis punctata albescens | AD, AR |
RMND1 | 614917 | Combined oxidative phosphorylation deficiency 11 | AR |
ROR2 | 602337 | Brachydactyly, type B1; Robinow syndrome, autosomal recessive | AD, AR |
RPE65 | 180069 | Leber congenital amaurosis type 2; retinitis pigmentosa type 20 | AD, AR |
RPGRIP1 | 605446 | Cone-rod dystrophy 13; Leber congenital amaurosis 6 | AR |
RPGRIP1L | 610937 | COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 | AR |
RRM2B | 604712 | mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 | AD, AR |
RSPH1 | 609314 | primary ciliary dyskinesia, 24 | AR |
RSPH4A | 612647 | Ciliary dyskinesia, primary, 11 | |
RSPH9 | 612648 | Ciliary dyskinesia, primary, 12 | |
RUNX2 | 600211 | Cleidocranial dysplasia | AD |
SALL1 | 602218 | Townes-Brocks syndrome | AD |
SALL4 | 607343 | Okihiro syndrome | AD |
SBDS | 607444 | Shwachman-Bodian-Diamond syndrome; Aplastic Anemia | AR |
SCARB2 | 602257 | Epilepsy, progressive myoclonic 4, with or without renal failure | AR |
SCNN1A | 600228 | Pseudohypoaldosteronism, type I | AD, AR |
SCNN1B | 600760 | Liddle syndrome; Bronchiectasis with or without elevated sweat chloride type 1; Pseudohypoaldosteronism, type I | AD, AR |
SCNN1G | 600761 | Pseudohypoaldosteronism, type I; Bronchiectasis with or without elevated sweat chloride 3 | AD, AR |
SDCCAG8 | 613524 | Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 | AR |
SEMA3A | 603961 | hypogonadotropic hypogonadism 16 with or without anosmia | AD |
SERPINA1 | 107400 | alpha-1 antitrypsin deficiency | AR |
SERPINF1 | 172860 | osteogenesis imperfecta type 6 | AR |
SERPINH1 | 600943 | Preterm premature rupture of the membranes, susceptibility to; osteogenesis imperfecta type 10 | AR |
SLC12A1 | 600839 | Bartter syndrome type 1 | AR |
SLC12A3 | 600968 | Gitelman syndrome | AR |
SLC25A13 | 603859 | Citrullinemia, Type Ii, Adult-Onset; Citrullinemia, type II, neonatal-onset | AR |
SLC25A15 | 603861 | Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome | AR |
SLC26A2 | 606718 | Diastrophic dysplasia; multiple epiphyseal dysplasia type 4; Atelosteogenesis type II; Achondrogenesis type IB | AR |
SLC26A3 | 126650 | Diarrhea 1, secretory chloride, congenital | AR |
SLC2A2 | 138160 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi-Bickel syndrome | AD, AR |
SLC34A1 | 182309 | Nephrolithiasis/osteoporosis, hypophosphatemic, 1; Fanconi renotubular syndrome 2; Hypercalcemia, infantile, 2 | AD, AR |
SLC34A3 | 609826 | Hypophosphatemic rickets with hypercalciuria | AR |
SLC35D1 | 610804 | Schneckenbecken dysplasia | AR |
SLC4A1 | 109270 | Autosomal dominant distal renal tubular acidosis; resistance to malaria; Renal tubular acidosis, distal, with hemolytic anemia; Spherocytosis, type 4 | AD, AR |
SLC4A4 | 603345 | Renal tubular acidosis, proximal, with ocular abnormalities | AR |
SLCO1B1 | 604843 | Hyperbilirubinemia, Rotor type, digenic | DiR |
SLCO1B3 | 605495 | Hyperbilirubinemia, Rotor type, digenic | DiR |
SMPD1 | 607608 | Niemann-Pick disease type A; Niemann-Pick disease type A/B | AR |
SOX10 | 602229 | PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C | AD |
SOX2 | 184429 | Microphthalmia, Syndromic 3 | AD |
SOX3 | 313430 | Mental Retardation, X-Linked, With Panhypopituitarism; Panhypopituitarism, X-linked | XL |
SOX9 | 608160 | campomelic dysplasia | AD |
SPAG1 | 603395 | Primary Ciliary dyskinesia type 28 | AR |
SPATA7 | 609868 | Leber congenital amaurosis 3 | |
SPINT2 | 605124 | AR | |
SPRY4 | 607984 | Hypogonadotropic hypogonadism 17 with or without anosmia | AD |
TAC3 | 162330 | hypogonadotropic hypogonadism 10 with or without anosmia | AR |
TACR3 | 162332 | hypogonadotropic hypogonadism 11 with or without anosmia | AR |
TBX5 | 601620 | Holt-Oram syndrome | AD |
TCTN1 | 609863 | Joubert syndrome 13 | AR |
TCTN2 | 613846 | Meckel syndrome 8; Joubert syndrome type 24 | AR |
TCTN3 | 613847 | oral-facial-digital syndrome 4; Joubert syndrome 18 | AR |
TFR2 | 604720 | hemochromatosis type 3 | AR |
TJP2 | 607709 | Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4 | AR |
TMEM138 | 614459 | Joubert syndrome 16 | AR |
TMEM216 | 613277 | Meckel Syndrome type 2; Joubert syndrome type 2 | AR |
TMEM231 | 614949 | Joubert syndrome 20; Meckel syndrome, type 11 | AR |
TMEM237 | 614423 | Joubert syndrome 14 | AR |
TMEM67 | 609884 | COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 | AR |
TNFRSF11B | 602643 | Paget disease of bone 5, juvenile-onset | AR |
TRIM32 | 602290 | limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 | AR |
TRIP11 | 604505 | Achondrogenesis, type IA | AR |
TRMU | 610230 | Deafness, Aminoglycoside-Induced; Liver Failure, Infantile, Transient | AR, M |
TRPC6 | 603652 | Glomerulosclerosis, focal segmental, 2 | AD |
TRPS1 | 604386 | trichorhinophalangeal syndrome 1 | AD |
TRPV4 | 605427 | Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc | AD |
TSC1 | 605284 | tuberous sclerosis type 1 | AD |
TSC2 | 191092 | tuberous sclerosis-2 | AD |
TTC21B | 612014 | Short-rib thoracic dysplasia 4 with or without polydactyly; nephronophthisis 12 | AD, AR |
TTC8 | 608132 | retinitis pigmentosa type 51; Bardet-Biedl syndrome type 8 | AR |
TULP1 | 602280 | Retinitis pigmentosa 14 | AR |
UGT1A1 | 191740 | Gilbert syndrome; Crigler-Najjar syndrome type I; familial transient neonatal hyperbilirubinemia; serum level of Bilirubin, QTL1; Crigler-Najjar syndrome type II | AR |
VHL | 608537 | Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 | AD, AR |
VIPAS39 | 613401 | Arthrogryposis, renal dysfunction, and cholestasis 2 | AR |
WDPCP | 613580 | Bardet-Biedl syndrome 15 | AR |
WDR11 | 606417 | hypogonadotropic hypogonadism 14 with or without anosmia | AD |
WDR19 | 608151 | Short-rib thoracic dysplasia 5 with or without polydactyly; nephronophthisis 13; Cranioectodermal dysplasia 4; Senior-Loken syndrome 8 | AR |
WDR35 | 613602 | Cranioectodermal dysplasia 2 | AR |
WDR73 | 616144 | Galloway syndrome | AR |
WNK1 | 605232 | Neuropathy, hereditary sensory and autonomic, type II; Pseudohypoaldosteronism, type IIC | AD, AR |
WNK4 | 601844 | Pseudohypoaldosteronism, type IIB | AD |
WNT5A | 164975 | Robinow syndrome, autosomal dominant | AD |
WNT7A | 601570 | Fuhrmann syndrome; Ulna and fibula, absence of, with sever limb deficiency | AR |
WT1 | 607102 | Frasier syndrome; Mesothelioma, somatic; Wilms tumor, type 1; Denys-Drash syndrome; Nephrotic syndrome, type 4; Meacham syndrome | AD |
ZIC3 | 300265 | Heterotaxy, visceral, 1, x-linked; Vacterl association, x-linked, with or without hydrocephalus | XLR |
ZMYND10 | 607070 | primary ciliary dyskinesia, 22 | AR |
ZNF423 | 604557 | nephronophthisis 14; Joubert syndrome 19 | AD, AR |
A major treatment for Kallmann syndrome is hormone replacement therapy, based on the use of testosterone in males and estradiol in females. In addition, human chorionic gonadotropin (hCG) injections in males or progestin in females can be used in order to stimulate spermatogenesis or folliculogenesis. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization may be an option.
CENTOGENE offers sequencing and deletion/duplication analysis for the Kallmann syndrome and Hypogonadotropic hypogonadism panel (genes: ANOS1, CHD7, DUSP6, FEZF1, FGF17, FGF8, FGFR1, FLRT3, FSHB, GNRH1, GNRHR, HESX1, HS6ST1, IL17RD, KISS1, KISS1R, LHB, NSMF, PROK2, PROKR2, SEMA3A, SPRY4, TAC3, TACR3, WDR11). We also offer single gene tests for each gene included in the panel.
Differential diagnosis
The differential diagnosis of Kallmann syndrome related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Amenorrhea
- Borjeson-Forssman-Lehmann syndrome
- CHARGE syndrome
- Constitutional growth delay
- Erectile dysfunction
- Follicle-stimulating hormone abnormalities
- Infertility
- Klinefelter syndrome
- LEOPARD syndrome
- Laurence-Moon-Biedl syndrome
- Luteinizing hormone deficiency
- Luteinizing hormone–releasing hormone deficiency
- Martsolf syndrome
- Prader-Willi syndrome
- Rothmund-Thomson syndrome
- Turner syndrome
- Septooptic dysplasia.
Testing strategy
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Kallmann syndrome using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Kallmann syndrome panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the Kallmann syndrome panel, we further recommend continuing the bioinformatics analysis of the data with whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
Referral reasons
The following individuals are candidates for Kallmann syndrome gene testing:
- Individuals with a family history of Kallmann syndrome and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling Kallmann syndrome
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Test utility
Sequencing, deletion/duplication of Kallmann syndrome related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with Kallmann syndrome should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Kallmann syndrome, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.