Presentation: Clinical suspicion of Noonan syndrome

A 12-year-old girl presents with short stature. She previously had a small atrial septal defect, which closed spontaneously in early childhood, and she has been receiving extra support since transferring to secondary school. She looks subtly different to her mother, with slightly low-set ears and mild bilateral ptosis.

Consider genomic testing for Noonan syndrome if a fetus or individual presents with a combination of some of the features listed below.

• Prenatally:
  • a raised nuchal translucency, cystic hygroma, pleural effusions and/or polyhydramnios; and
  • cardiac and/or renal anomalies, particularly pulmonary stenosis and renal pelvic dilatation.
• Neonatally:
  • feeding difficulties and poor weight gain;
  • hypertelorism, down-slanted palpebral fissures, low-set posteriorly rotated ears, short neck with excess skin folds and/or low posterior hairline;
  • cardiac anomalies, particularly pulmonary valve stenosis, branch pulmonary arch stenosis and hypertrophic cardiomyopathy; and
  • undescended testes in boys.
• Childhood:
  • short stature with relative macrocephaly;
  • similar facial features to those found in the neonatal period, except with full upper eyelids or ptosis, flattened nasal bridge with bulbous root, and a lack of expression;
  • cardiac anomalies, particularly pulmonary valve stenosis, branch pulmonary arch stenosis and hypertrophic cardiomyopathy;
  • developmental delay, mild learning difficulty or intellectual impairment; and
  • a history of unusual bleeding or easy bruising.

• 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.
• Decide which of the panels best suits the needs of your patient or family. For testing information in the context of prenatal presentations, see Fetus with raised nuchal translucency. For postnatal presentations, consider the below.
  • R135 Paediatric or syndromic cardiomyopathy: This would be suitable for children presenting with a cardiomyopathy associated with dysmorphism or other feature(s) suggestive of a syndromic cause such as Noonan syndrome (or the wider group of RASopathies). Currently, it can only be requested by clinical genetics or cardiology teams.
  • R147 Growth failure in early childhood: This can be used for children over the age of two years with a height greater than three standard deviations (3SD) below the mean.
  • R27 Paediatric disorders: Consider this if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes. The test includes microarray and a whole genome sequencing (WGS) ‘super panel’ (a panel comprised of several different constituent panels forming one large panel). You may ask for a ‘Noonan/RASopathy slice’, in which genes associated with these conditions are reviewed first and, if a pathogenic variant is identified, the remaining data scrutinised no further.
  • R14 Acutely unwell children with a likely monogenic disorder: This option may be considered if your patient’s presentation matches the description and a diagnosis would potentially change management. Both parents should be available for trio analysis, though occasional exceptions may be made. R28 Congenital malformation and dysmorphism syndromes (microarray) may also be undertaken in parallel.
• For tests that are undertaken using WGS, including R135 and R27, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for whole genome sequencing for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS, including R147:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• The majority of 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).
• R27 is a large WGS ‘super panel’, and requesting it currently requires authorisation from clinical genetics.
• R14 is a WGS test that looks agnostically across the entire genome. Requesting it currently requires authorisation from clinical genetics. There is a special test order form and RoD form for this test, which are available from the Exeter Genetics 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

• DYSCERNE Noonan Syndrome Guideline Development Group: Management of Noonan syndrome: A clinical guideline (page 29) (PDF, 30 pages)
• GeneReviews: Noonan syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Human Genome Research Institute: Noonan syndrome
• NHS England: National Genomic Test Directory

For patients

• Child Growth Foundation
• DYSCERNE Noonan Syndrome Guideline Development Group: Management of Noonan syndrome: A clinical guideline (page 29) (PDF, 30 pages)
• Noonan Syndrome Association
• NHS England: Whole genome sequencing patient information leaflets