Presentation: Patient with possible premature ovarian insufficiency

A 25-year-old female is referred to the endocrine clinic by her GP because of increasingly infrequent periods and high follicle-stimulating hormone (FSH) levels.

Indications for genomic testing in patients with possible premature ovarian insufficiency (POI) are:

• four consecutive months of unexplained amenorrhoea (primary or secondary);
• elevated serum FSH of over 30IU/L on two separate occasions at least six weeks apart;
• symptom onset under 30 years; and
• exclusion of non-genetic causes, including presence of thyroid and adrenal (21-hydroxylase) auto-antibodies.

Turner syndrome may be suspected at different ages due to various phenotypic features, including:

• short stature;
• micrognathia;
• widened carrying angle;
• low hairline;
• webbed neck;
• widely spaced nipples;
• high arched palate;
• nail dysplasia;
• scoliosis;
• high blood pressure;
• autoimmune hypothyroidism; and
• horseshoe kidney.

Fragile X syndrome may be suspected if there is a learning difficulty, family history of the disease or unexplained ataxia with onset in adulthood.

Autoimmune polyendocrinopathy syndrome types 1 and 2 are usually associated with other autoimmune problems (such as mucocutaneous candidiasis, hypoparathyroidism, Addison disease, hypothyroidism, type 1 diabetes and pernicious anaemia).

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If a patient meets the test directory criteria for POI, select:
  • R402 Premature ovarian insufficiency: this includes karyotype testing and short tandem repeat (STR) testing for the gene associated with Fragile X syndrome.
• If you suspect Turner syndrome, select:
  • R26 Likely common aneuploidy: this should be selected if you want to focus your investigations on the common aneuploidies (it tests for trisomy 13, trisomy 18, trisomy 21 and Turner syndrome);
  • R265 Chromosomal mosaicism – karyotype: this may be considered if the clinical picture is strongly suggestive of Turner Syndrome but R26 is negative (it involves karyotyping an extended number of cells in order to identify mosaicism); and
  • R137 Congenital heart disease – microarray: this should be selected if you are investigating a chromosomal cause for congenital heart disease (it will identify Turner syndrome as well as other chromosomal causes). You may wish to consult Presentation: Infant or child with congenital heart disease.
• If you suspect Fragile X syndrome, select:
  • R53 Fragile X: this involves FMR1 STR testing.
• If you suspect autoimmune polyendocrine syndrome type 1, select:
  • R155 Autoimmune polyendocrine syndrome: this involves AIRE single gene testing.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• R265 may only be requested following discussion with a clinical genetics team or your local genomics laboratory.
• If the tests outlined above return negative results, whole exome sequencing could identify rare variants in genes associated with POI (for example FSHR, GDF9, BMP15, FIGLA, NOBOX, LHCGR, SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, TP63, NR5A1, STAR, BMP15 and GDF9); however, this is currently not supported within the NHS for POI diagnosis.
• The majority of these tests are DNA based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• NHS Health A to Z: Turner syndrome

For patients

• Daisy Network (a charity for women with POI)
• Fragile X Society
• National Organization for Rare Disorders: Turner syndrome
• NHS Health A to Z: Turner syndrome
• Turner Syndrome Support Society