IllnessHypogonadism, female hypergonadotropic; differential diagnosis A

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.

The FSHR polymorphism p.Asn680Ser may be relevant with regard to dose calculation prior to ovarian stimulation and is therefore reported if explicitly requested. doi: 10.1007/s00129-021-04785-6

• Allelic: 46XX sex reversal 4 (NR5A1)
• Allelic: 46XY sex reversal 3 (NR5A1)
• Allelic: Adrenocortical insufficiency (NR5A1)
• Allelic: Aromatase excess syndrome (CYP19A1)
• Allelic: Blepharophimosis, epicanthus inversus + ptosis, type 1 + 2 (FOXL2)
• Allelic: Leukoencephalopathy with vanishing white matter (EIF2B2)
• Allelic: Leukoencephalopathy with vanishing white matter (EIF2B4)
• Allelic: Leukoencephalopathy with vanishing white matter (EIF2B5)
• Allelic: Spermatogenic failure 32 (SOHLH1)
• Allelic: Spermatogenic failure 52 (C14orf39)
• Allelic: Spermatogenic failure 8 (NR5A1)
• 17,20-lyase deficiency, isolated (CYP17A1)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• Allelic: Spermatogenic failure 15 (SYCE1)
• Aromatase deficiency (CYP19A1)
• Autoimmune polyendocrinopathy syndrome type I, with/-out reversible metaphyseal dysplasia (AIRE)
• Galactosemia (GALT)
• Ovarian dysgenesis 1 (FSHR)
• Ovarian dysgenesis 2 (BMP15)
• Ovarian dysgenesis 3 (PSMC3IP)
• Ovarian dysgenesis 4 (MCM9)
• Ovarian dysgenesis 5 (SOHLH1)
• Ovarian hyperstimulation syndrome (FSHR)
• Ovarian response to FSH stimulation (FSHR)
• Ovarioleukodystrophy (EIF2B2)
• Ovarioleukodystrophy (EIF2B4)
• Ovarioleukodystrophy (EIF2B5)
• Premature ovarian failure 1 (FMR1, 55-200 CCG repeats)
• Premature ovarian failure 12 (SYCE1)
• 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)