IllnessHypogonadism, hypogonadotropic; differential diagnosis

NGS +

[Sanger]

Hypogonadotropic hypogonadism (HH) is either due to low concentrations of sexual steroids (oestrogen, progesterone) or gonadotropins (FSH, LH) with hypothalamic or pituitary causes. The majority of cases is diagnosed in men; women usually have primary amenorrhoea, which is often not genetic. HH can occur congenitally or later, and is usually diagnosed definitively at the age of 18 years. The detection rate is significantly higher in congenital HH (35-60%) than in late puberty as an expression of later manifested forms of HH that cannot be clinically distinguished. Statements on penetrance rates and expressivity must be made on the basis of genes or mutations. An inconspicuous genetic finding certainly does not mean that the suspected clinical diagnosis is excluded.

Reference: https://www.nature.com/articles/nrendo.2015.112

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520594/

• Allelic: CHARGE syndrome (CHD7)
• Allelic: Encephalocraniocutaneous lipomatosis, somatic mosaic (FGFR1)
• Allelic: Encephalocraniocutaneous lipomatosis; Hartsfield syndrome; Jackson-Weiss syndrome (FGFR1)
• Allelic: Fascioscapulohumeral muscular dystrophy 2, digenic (SMCHD1)
• Allelic: Hartsfield syndrome (FGFR1)
• Allelic: Holoprosencephaly 9 (GLI2)
• Allelic: Jackson-Weiss syndrome (FGFR1)
• Allelic: Laurence-Moon syndrome (PNPLA6)
• Allelic: Microphthalmia, syndromic 3 (SOX2)
• Allelic: Obesity, susceptibility to, BMIQ12 (PCSK1)
• Allelic: Obesity, susceptibility to, BMIQ14 (FTO)
• Allelic: Oliver-McFarlane syndrome (PNPLA6)
• Allelic: Osteoglophonic dysplasia (FGFR1)
• Allelic: Osteoglophonic dysplasia; Pfeiffer syndrome; Trigonocephaly 1 (FGFR1)
• Allelic: PCWH syndrome (SOX10)
• Allelic: Pfeiffer syndrome (FGFR1)
• Allelic: Precocious puberty, central, 1 (KISS1R)
• Allelic: Septooptic dysplasia (HESX1)
• Allelic: Spastic paraplegia 39, AR (PNPLA6)
• Allelic: Treacher Collins syndrome 3 (POLRR1C)
• Allelic: Trigonocephaly 1 (FGFR1)
• Allelic: Wiedemann-Rautenstrauch syndrome (POLR3A)
• 46XY sex reversal 2, dosage-sensitive (NR0B1)
• Adrenal hypoplasia, congenital (NR0B1)
• Allelic: Blood group, John-Milton-Hagen system (SEMA7A)
• Allelic: Luteinizing hormone resistance, female (LHCGR)
• Allelic: Precocious puberty, male (LHCGR)
• Alopecia, neurologic defects + endocrinopathy syndrome (RBM28)
• Bardet-Biedl syndrome genes (Rp, obesity, kidney dysfunction, hypogonadism...)
• Bosma arhinia microphthalmia syndrome (SMCHD1)
• Boucher-Neuhauser syndrome (PNPLA6)
• CHARGE syndrome (SEMA3E)
• Cerebellar ataxia + hypogonadotropic hypogonadism (RNF216)
• Congenital hypogonadotropic hypogonadism (KLB)
• Congenital hypogonadotropic hypogonadism [MONDO:0015770] (CCDC141)
• Craniosynostosis 3 (TCF12)
• Culler-Jones syndrome (GLI2)
• Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Growth hormone deficiency with pituitary anomalies (HESX1)
• Growth retardation, developmental delay, facial dysmorphism (FTO)
• Hemochromatosis (HFE)
• Hemochromatosis, type 2B (HAMP)
• Hemochromatosis, type 3 (TFR2)
• Hemochromatosis, type 4 (SLC40A1)
• Histiocytosis-lymphadenopathy plus syndrome (SLC29A3)
• Hypogonadotropic hypogonadism 1 with/-out anosmia; Kallmann syndrome 1 (ANOS1)
• Hypogonadotropic hypogonadism 10 with/-out anosmia (TAC3)
• Hypogonadotropic hypogonadism 11 with/-out anosmia (TACR3)
• Hypogonadotropic hypogonadism 12 with/-out anosmia (GNRH1)
• Hypogonadotropic hypogonadism 13 with/-out anosmia (KISS1)
• Hypogonadotropic hypogonadism 14 with/-out anosmia (WDR11)
• Hypogonadotropic hypogonadism 15 with/-out anosmia (HS6ST1)
• Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
• Hypogonadotropic hypogonadism 17 with/-out anosmia (SPRY4)
• Hypogonadotropic hypogonadism 18 with/-out anosmia (IL17RD)
• Hypogonadotropic hypogonadism 19 with/_out anosmia (DUSP6)
• Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Hypogonadotropic hypogonadism 20 with/-out anosmia (FGF17)
• Hypogonadotropic hypogonadism 21 with anosmia (FLRT3)
• Hypogonadotropic hypogonadism 22, with/-out anosmia (FEZF1)
• Hypogonadotropic hypogonadism 23 with/-out anosmia (LHB)
• Hypogonadotropic hypogonadism 24 without anosmia (FSHB)
• Hypogonadotropic hypogonadism 25 with anosmia (NDNF)
• Hypogonadotropic hypogonadism 3 with/-out anosmia (PROKR2)
• Hypogonadotropic hypogonadism 4 with/-out anosmia (PROK2)
• Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
• Hypogonadotropic hypogonadism 6 with/-out anosmia (FGF8)
• Hypogonadotropic hypogonadism 7 without anosmia (GNRHR)
• Hypogonadotropic hypogonadism 8 with/-out anosmia (KISS1R)
• Hypogonadotropic hypogonadism 9 with/_out anosmia (NSMF)
• Hypogonadotropic hypogonadism without anosmia; normosmic IHH [panelapp] (CCDC141)
• Hypogonadotropic hypogonadism, delayed puberty, primary ovary insufficiency [panelapp] (IGSF10)
• Intellectual developmental disorder + hypogonadotropic hypogonadism (CPE)
• Isolated GnRH deficiency [genereviews] (AXL)
• Isolated GnRH deficiency [genereviews] (SRA1)
• Leukodystrophy, hypomyelinating, 11 (POLR1C)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia and/or hypogon. hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia and/or hypogon. hypogonadism (POL3RB)
• Leydig cell hypoplasia with hypergonadotropic hypogonadism (LHCGR)
• Martsolf syndrome 1 (RAB3GAP2)
• Martsolf syndrome 2 (RAB3GAB1)
• Mental retardation, XL, syndromic 15 [Cabezas type] (CUL4B)
• Obesity with impaired prohormone processing (PCSK1)
• Obesity, morbid, due to leptin deficiency (LEP)
• Obesity, morbid, due to leptin receptor deficiency (LEPR)
• Optic nerve hypoplasia + abnormalities of the central nervous system (SOX2)
• PCWH syndrome (SOX10)
• Perrault syndrome 3 (CLPP)
• Pituitary hormone deficiency, combined, 1 (POUF1)
• Pituitary hormone deficiency, combined, 2 (PROP1)
• Pituitary hormone deficiency, combined, 3 (LHX3)
• Pituitary hormone deficiency, combined, 4 (LHX4)
• Pituitary hormone deficiency, combined, 5 (HESX1)
• Prader-Willi syndrome (NDN, SIM1, SNRPN)
• Spinocerebellar ataxia, AR 16 (STUB1)
• Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
• Waardenburg syndrome, type 4C (SOX10)
• Warburg micro syndrome 1 (RAB3GAP1)
• Warburg micro syndrome 2 (RAB3GAP2)
• Woodhouse-Sakati syndrome (DCAF17)