Presentation: Clinical suspicion of Patau syndrome (trisomy 13)

A baby is admitted to the neonatal intensive care unit (NICU) after birth. Antenatal scans had shown intrauterine growth restriction (IUGR), an atrial septal defect and bilateral extra fingers. The parents declined prenatal amniocentesis. The baby has distinctive physical features suggestive of Patau syndrome, including close set eyes, cutis aplasia, clenched hands and unusually shaped feet with prominent heels.

Patau syndrome can present pre- and postnatally in a variety of ways.

Prenatally

• Most cases are identified at this stage. Many parents opt to have screening for Patau syndrome, and signs are typically evident on prenatal ultrasounds. For more information, see:
  • Presentation: Patient with a higher-chance first-trimester combined screening result;
  • Presentation: Fetus with raised nuchal translucency; and
  • Presentation: Patient with a higher-chance non-invasive prenatal test (NIPT) result.

Postnatally

• Neonates may present with IUGR and typical physical features. There are numerous medical complications that are more common in the context of Patau syndrome. Signs and symptoms are listed below.
  • Craniofacial features:
    • scalp anomalies, such as missing skin;
    • sloping forehead;
    • close-set eyes;
    • short, flat, or atypically shaped nose;
    • cleft palate and/or lip;
    • small jaw; and
    • ears may be small, low set, posteriorly rotated and malformed.
  • Limb anomalies:
    • clenched hands;
    • single palmar crease;
    • extra fingers and toes (polydactyly);
    • nail hypoplasia;
    • smooth, curved sole of the foot with prominent heel; and
    • club feet.
  • Cardiac anomalies (found in 80% of cases):
    • septal anomalies;
    • tetralogy of Fallot; and
    • double outlet right ventricle.
  • Respiratory symptoms:
    • breathing difficulties including apnoeas.
  • Neurological symptoms:
    • microcephaly;
    • hypotonia and feeding difficulties;
    • seizures;
    • severe developmental delay;
    • alobar holoprosencephaly; and
    • spinal anomalies.
  • Ophthalmological symptoms:
    • cataracts;
    • retinal dysplasia or detachment;
    • nystagmus;
    • optic nerve hypoplasia;
    • small or absent eyes; and
    • coloboma of the iris.
  • Gastroenterological symptoms:
    • omphalocele;
    • umbilical hernia;
    • malrotation; and
    • Meckel diverticulum.
  • Genital anomalies:
    • undescended testicles;
    • hypospadias;
    • hypertrophy of the clitoris;
    • labia minora hypoplasia; and
    • bicornuate uterus.
  • Renal symptoms:
    • polycystic kidney;
    • hydronephrosis; and
    • horseshoe kidney.
  • Other:
    • hearing loss; and
    • capillary haemangioma.

• 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.
• 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. It may be appropriate to select more than one.
  • R26 Likely common aneuploidy: This is the correct test if you are reasonably confident that the patient has Patau syndrome. The common aneuploidy (QF-PCR) test looks for the presence of trisomy 13, trisomy 18, trisomy 21 and Turner syndrome. Note that this test request indication does not include gene sequencing. If a negative result is returned, further genomic testing may be indicated. This is the fastest way to diagnose the common trisomies and sex chromosome aneuploidies.
  • R28 Congenital malformation and dysmorphism syndromes – microarray only: This test may be considered where clinical features are highly suggestive of a chromosomal cause, though not completely typical for the common trisomies or sex chromosome aneuploidies. If relating to an in-patient, urgent analysis can be requested (typically return results within two weeks). A microarray is not a requirement prior to R27 being initiated in patients with a possible monogenic cause of a syndromic paediatric disorder.
  • R27 Paediatric disorders: This testing indication throws the net much more widely, investigating chromosomal and single-gene causes of congenital malformations and dysmorphism syndromes. You might consider R27 if you are less certain of the clinical diagnosis of Patau syndrome or where R26 is negative. Ideally you would do this test as a trio with parental samples.
  • R14 Acutely unwell children with a likely monogenic disorder: This rapid agnostic test may be considered in the context of an acutely unwell infant with multiple congenital anomalies, where a diagnosis may change management. Ideally trio analysis is undertaken as this increases the diagnostic rate. As with R27, this test will investigate chromosomal and single-gene causes of congenital malformations and dysmorphism syndromes.
  • R265 Chromosomal mosaicism (karyotype): A minority of individuals with Patau syndrome have some cells with trisomy 13 and some cells with the usual two copies of chromosome 13. This is termed mosaicism. R265 can be requested when R26 is suggestive of mosaicism, or if the clinical features are highly suggestive of Patau syndrome but R26 returns a negative result.
  • R297 Possible structural chromosomal rearrangement – karyotype or targeted chromosome analysis: This should be considered if findings from microarray, whole genome sequencing (WGS) or other laboratory techniques suggest a possible Robertsonian translocation, reciprocal translocation, ring chromosome or other microscopically visible structural rearrangement.
    • Use also R297 for parents of an affected child when a karyotype from the child indicates an underlying structural chromosome change in parents is likely. In this situation parental karyotypes are essential in determining the recurrence risk, and thus reproductive options for future pregnancies.
• For tests that do not include WGS, including R26, R28, R265 and R297:
  • 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.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS 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 WGS for support in completing WGS-specific forms);
  • complete an NHS GMS 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).
• R27 is an amalgamation of over 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. There is a special test order form and RoD form for this test, which are available from the Exeter Genetics Laboratory.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing (R297) and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube). For more information, see Samples for genomic testing in rare disease.
• 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Soft UK: For professionals

For patients

• NHS England: Whole genome sequencing patient information leaflets
• Sands (support for anyone who has been affected by the death of a baby)
• Soft UK (support for families of children born with trisomy 13 or trisomy 18)
• Together for Short Lives (support for families of seriously ill children)
• Trisomy 18 Foundation