Premature ovarian failure (POI)

Clinically, POI is defined by hypergonadotropic hypogonadism in women under 40 years. Presentations span primary amenorrhoea with delayed pubertal development to secondary amenorrhoea in previously cycling adult women, and onset has been reported as early as adolescence in syndromic forms such as fragile X-associated POI.

Both syndromic and nonsyndromic forms are clinically recognised: nonsyndromic POI manifests as isolated 46,XX ovarian dysgenesis or adult-onset ovarian failure without extragonadal involvement, whereas syndromic forms arise as one feature of broader Mendelian disorders accompanied by neurosensory, autoimmune, dysmorphic, or metabolic manifestations in additional organ systems. Long-term sequelae of oestrogen deficiency include reduced bone mineral density, increased cardiovascular morbidity, neurocognitive impairment, and sexual dysfunction, all of which are recognised across the genetic spectrum of POI.

The estimated prevalence of POI in women under 40 years of the general population varies from approximately 1% in older studies to 3.5% in recent publications. In dedicated genetic studies, a monogenic aetiology is identifiable in up to 29.3% of POI cases.

A large number of genes have been associated with POI. This panel examines 18 causative genes. Clinically relevant germline genes on the panel include FIGLA, NOBOX, BMP15, FOXL2 and NR5A1. The remaining tested genes act across folliculogenesis, oocyte-derived signalling, gonadotropin signalling, meiosis and DNA-damage repair. Pathogenic variants converge on premature depletion or dysfunction of the ovarian primordial follicle pool, producing hypergonadotropic hypogonadism.

The genetic conditions associated with POI follow heterogeneous inheritance patterns. X-linked inheritance applies to DIAPH2 and BMP15. Autosomal recessive inheritance applies to genes acting in meiosis and DNA-damage repair (MCM9, STAG3, SYCE1, PSMC3IP) and gonadotropin receptor defects (FSHR, LHCGR). Autosomal dominant inheritance, generally through haploinsufficiency, applies to NOBOX, FOXL2, NR5A1, GDF9 and FIGLA. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis rests on biochemical evidence of hypergonadotropic hypogonadism. Updated consensus criteria require only a single follicle-stimulating hormone (FSH) value above 25 IU/L with low oestradiol and with irregular or absent menses, meeting the criteria of establishes the clinical diagnosis.

Main differential diagnoses include:

• Turner syndrome (45,X) and other X-chromosome abnormalities: primary amenorrhoea with hypergonadotropic hypogonadism; identified by karyotype.
• -associated POI: FMR1 premutation carriers as most common single-gene cause.
• Autoimmune polyglandular syndrome type 1: ovarian dysfunction with candidiasis, hypoparathyroidism and/or adrenal insufficiency; AIRE.
• : sensorineural hearing loss with ovarian dysfunction in a 46,XX individual; CLPP, LARS2, HARS2 and others.
• Blepharophimosis, ptosis and epicanthus inversus syndrome type I: eyelid malformation with syndromic POI; FOXL2.

and others.

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