Presentation: Patient aged 18 with delayed puberty
Hypogonadism is a condition in which the testes or ovaries produce little or no sex hormones. Hypogonadotropic hypogonadism is a type of hypogonadism that is caused by problems with the pituitary gland or hypothalamus. Affected individuals typically present with puberty delayed beyond the age of 18 with low or inappropriately normal luteinising hormone (LH) and follicle stimulating hormone (FSH) levels. There is an identifiable genetic cause for 50%–60% of cases.
Example clinical scenario
An 18-year-old male presents with lack of signs of puberty. He has 3ml testes and his sense of smell is apparently normal. One of his sisters, who is 16 years old, has primary amenorrhea; his other sister went through a normal puberty. His parents are first cousins.
When to consider genomic testing
- Genomic testing should be considered in patients with absent or incomplete puberty with low LH and/or FSH levels in the context of low testosterone or oestradiol, with or without anosmia, with no detectable cause.
- Testing should be targeted to those in whom a genetic diagnosis will guide management for the proband or family.
- The number of genes associated with hypogonadotropic hypogonadism has significantly increased over the last few years.
- Note that digenic or oligogenic cause is well described in hypogonadotropic hypogonadism and this, as well as variable low penetrance, can mask family history.
What do you need to do?
- Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
- For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
- To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
- For patients who meet the testing criteria, select the below.
- R148 Hypogonadotropic hypogonadism idiopathic. This currently comprises the genes ANOS1, CHD7, FGF8, FGFR1, FSHB, GNRH1, GNRHR, IL17RD, KISS1R, KLB, LEP, LEPR, LHB, NDNF, PLXNA3, PROK2, PROKR2, SEMA3F, SOX10, TAC3, TAC3R and WDR11. It involves small gene panel sequencing and multiplex ligation-dependent probe amplification (MLPA) or equivalent.
- The tests in this panel do not include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and record of discussion forms.
- The majority of tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at four degrees Celsius until it can be posted to the genomic laboratory.
- Information about patient eligibility and test indications was 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.
Resources
For clinicians
- NHS England: National Genomic Test Directory
For patients
- Kallmann Syndrome & Congenital Hypogonadotropic Hypogonadism
- Kallmann syndrome: Delayed or absent puberty (patient’s personal blog)
- What is Hypogonadotropic Hypogonadism and Kallmann syndrome? (patient video, three minutes 56 seconds)