IllnessHypogonadism, female hypergonadotropic; differential diagnosis expanded

NGS +

[Sanger]

Hypergonadotropic hypogonadism is characterized by low levels of sex hormones and increased gonadotropins in females with a 46XX karyotype. In girls, puberty is delayed, and in initially inconspicuous women hypergonadotropic hypogonadism leads to primary ovarian insufficiency (POI), which is defined by development before age 40 resembling menopause. In addition to infertility, women with POI are at increased risk for a number of comorbidities, including osteoporosis as well as increased cardiovascular morbidity and mortality. The genetic disorders rarely include (a late diagnosed) 45X Turner syndrome, more commonly pre-mutations in the Fragile X Mental Retardation Type 1 (FMR1) gene in up to 15% of cases, but also monogenic syndromic or non-syndromic disorders. Two thirds of these cases remain primarily unexplained, although idiopathic hypergonadotropic hypogonadism may be associated with mutations in a variety of different genes. Using NGS approaches genetic alterations may be detected in up to 25% of cases with female hypergonadotropic hypogonadism. Therefore, a negative molecular genetic finding excludes by no means the clinical diagnosis.

References: doi: 10.1007/s12020-021-02626-z

doi: 10.1210/jendso/bvz037.

• Allelic: 17,20-lyase deficiency, isolated (CYP17A1)
• Allelic: 46XX sex reversal 4 (NR5A1)
• Allelic: 46XY sex reversal 3 (NR5A1)
• Allelic: Acromesomelic dysplasia 3 (BMPR1B)
• Allelic: Adrenocortical insufficiency (NR5A1)
• Allelic: Aromatase excess syndrome (CYP19A1)
• Allelic: Blepharophimosis, epicanthus inversus + ptosis, type 1 (FOXL2)
• Allelic: Blepharophimosis, epicanthus inversus + ptosis, type 2 (FOXL2)
• Allelic: Brachydactyly, type A1, D (BMPR1B)
• Allelic: Brachydactyly, type A2 (BMPR1B)
• Allelic: Brachydactyly, type B2 (NOG)
• Allelic: Colorectal cancer, somatic (BUB1B)
• Allelic: D-bifunctional protein deficiency (HSD17B4)
• Allelic: Fragile X syndrome (FMR1)
• Allelic: Fragile X tremor/ataxia syndrome (FMR1)
• Allelic: Galloway-Mowat syndrome 7 (NUP107)
• Allelic: Hydrops, lactic acidosis + sideroblastic anemia (LARS2)
• Allelic: Leukoencephalopathy with vanishing white matter (EIF2B2, EIF2B4, EIF2B5)
• Allelic: Mitochondrial DNA depletion syndrome 7, hepatocerebral type (TWNK)
• Allelic: Mosaic variegated aneuploidy syndrome 1 (BUB1B)
• Allelic: Multiple synostoses syndrome 1 (NOG)
• Allelic: Nephrotic syndrome, type 11 (NUP107)
• Allelic: Non-obstructive azoospermia [panelapp] (MSH4)
• Allelic: Premature chromatid separation trait (BUB1B)
• Allelic: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Allelic: Spermatogenic failure 15 (SYCE1)
• Allelic: Spermatogenic failure 32 (SOHLH1)
• Allelic: Spermatogenic failure 52 (C14orf39)
• Allelic: Spermatogenic failure 8 (NR5A1)
• Allelic: Stapes ankylosis with broad thumbs + toes (NOG)
• Allelic: Symphalangism, proximal, 1A (NOG)
• Allelic: Tarsal-carpal coalition syndrome (NOG)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• Aromatase deficiency (CYP19A1)
• Autoimmune polyendocrinopathy syndrome type I, with/-out reversible metaphyseal dysplasia (AIRE)
• Combined oxidative phosphorylation deficiency 8 (AARS2)
• Galactosemia (GALT)
• Hypogonadotropic hypogonadism 24 without anosmia (FSHB)
• Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Ovarian dysgenesis 1 (FSHR)
• Ovarian dysgenesis 2 (BMP15)
• Ovarian dysgenesis 3 (PSMC3IP)
• Ovarian dysgenesis 4 (MCM9)
• Ovarian dysgenesis 5 (SOHLH1)
• Ovarian dysgenesis 6 (NUP107)
• Ovarian hyperstimulation syndrome (FSHR)
• Ovarian response to FSH stimulation (FSHR)
• Ovarioleukodystrophy (EIF2B2, EIF2B4, EIF2B5)
• Perrault syndrome (SGO2)
• Perrault syndrome 1 (HSD17B4)
• Perrault syndrome 2 (HARS2)
• Perrault syndrome 3 (CLPP)
• Perrault syndrome 4 (LARS2)
• Perrault syndrome 5 (TWNK)
• Premature Ovarian Insufficiency [panelapp] (BMPR1B)
• Premature ovarian failure 1 (FMR1))
• Premature ovarian failure 10 (MCM8)
• Premature ovarian failure 12 (SYCE1)
• Premature ovarian failure 13 (MSH5)
• Premature ovarian failure 14 (GDF9)
• Premature ovarian failure 18 (C14orf39)
• Premature ovarian failure 2A (DIAPH2)
• Premature ovarian failure 2B (POF1B)
• Premature ovarian failure 3 (FOXL2)
• Premature ovarian failure 4 (BMP15)
• Premature ovarian failure 5 (NOBOX)
• Premature ovarian failure 6 (FIGLA)
• Premature ovarian failure 7 (NR5A1)
• Premature ovarian failure 8 (STAG3)
• Premature ovarian failure 9 (HFM1)
• Premature ovarian failure [panelapp] (BUB1B)
• Premature ovarian failure [panelapp] (DACH2)
• Premature ovarian failure [panelapp] (EIF4ENIF1)
• Premature ovarian failure [panelapp] (KHDRBS1)
• Premature ovarian failure [panelapp] (POLR2C)
• Premature ovarian failure [panelapp] (POLR3H)
• Premature ovarian failure [panelapp] (SYCP2L)
• Premature ovarian insufficiency [panelapp] (PGRMC1)
• Primary ovarian failure (MONDO:0005387] (MSH4)
• Primary ovarian insufficiency (MSH4)
• Primary ovarian insufficiency [panelapp] (NANOS3)
• Primary ovarian insufficiency [panelapp] (NOG)