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.

• This article details testing information in the context of postnatal presentations. For prenatal presentations, see Presentation: Fetus with raised nuchal translucency.
• 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 of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suit the needs of your patient or family according to the key features. Consider the following:
  • 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. In some instances, semi-rapid analysis can be requested.
  • R453 Monogenic short stature: This should be considered if a patient’s height is more than three standard deviations (3SD) below the mean at the age of at least two years, in the absence of microcephaly and with a normal short-stature screen. Testing may also be considered where a patient’s height is 2SD to 3SD below the mean at the age of at least two years in the absence of microcephaly, though the child’s height should be 3SD below the mid-parental-height centile and testing should be discussed at a specialist multidisciplinary team meeting.
  • R452 Silver-Russell syndrome and Temple syndrome: This should be considered if clinical features are strongly indicative of Silver-Russell syndrome or Temple syndrome.
  • R27 Paediatric disorders: Consider this if there is developmental delay or intellectual disability in association with congenital malformation and/or dysmorphic features, and you would like to investigate chromosomal and single-gene causes. The test involves whole genome sequencing (WGS) of a number of different panels. 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 meets eligibility criteria 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) should proceed R14 or be undertaken in parallel if there is a strong suspicion of a chromosomal cause.
• For tests that are undertaken using WGS, including R135 and R27, you will need to:
  • complete an NHS Genomic Medicine Service test order form with details of the affected individual (proband) and their parents where available, 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); and
  • complete an NHS Genomic Medicine Service record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual 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 R453 and R28:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) 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.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• R27 is an amalgamation of more than 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• R14 is a WGS test that looks agnostically across the entire genome. Requesting it currently requires authorisation from clinical genetics services. There is a special test order form and RoD form for this test, which are available from the Exeter Genetics Laboratory.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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 (PDF, 30 pages)
• GeneReviews: Noonan syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

For patients

• Child Growth Foundation
• NHS England: Whole genome sequencing patient information leaflets
• Noonan Syndrome Association