Presentation: Patient aged 18 with delayed puberty

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.

• 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. In males, ‘red flag’ clinical signs of cryptorchidism (undescended testes), micropenis or low testes volumes may also be seen.
• 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.

• 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 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 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 detects small variants and copy number variants (CNVs) by small gene panel sequencing.
• 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.

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) (YouTube, 3 minutes 56 seconds)