Presentation: Hypotonic infant

A term baby is admitted at day one to the neonatal unit because she is profoundly floppy (hypotonic). There are no other dysmorphic features or congenital anomalies, and she is spontaneously ventilating in air.

Genomic testing should be considered if:

• an infant is assessed as having significant hypotonia;
• hypotonia is not attributed to an acquired cause (such as sepsis or hypoxic encephalopathy);
• the infant has additional medical problems and/or dysmorphic features;
• an older child with hypotonia is alert and interactive, in which case you should consider neuromuscular causes; or
• an older child is not alert, or has a developmental delay, in which case you should consider central causes.

Specific conditions or families of conditions that can present with hypotonia are listed below.

• Prader-Willi syndrome: Presentation in the neonatal period is of central hypotonia, lethargy and feeding difficulties requiring nasogastric supplementation due to a weak suck.
  • See Presentation: Clinical suspicion of Prader-Willi syndrome
• Congenital myotonic dystrophy: This is the most common cause of neuromuscular anomalies in newborns. Severely affected infants display central hypotonia, and often require ventilatory assistance at birth.
  • See Presentation: Neonate with suspected myotonic dystrophy type 1
• Spinal muscular atrophy (SMA): Individuals with SMA can present with progressive neuromuscular weakness (affecting proximal muscles to a greater extent than distal muscles) at any age in childhood. The most severe forms of SMA present at birth or shortly afterward.
  • See Presentation: Clinical suspicion of spinal muscular atrophy in adolescent or adult
• Inborn error of metabolism: Infants affected by this will display hypotonia with additional suggestive features such as encephalopathy, metabolic acidosis, hepatomegaly, resistant hypoglycaemia, cataracts, cardiomyopathy, unusual odours, decompensation triggered by illness or fasting, faltering growth or positive family history.

Aneuploidies

• Trisomy 21: Down syndrome is the most common aneuploidy. Features include hypotonia, up-slanting palpebral fissures, epicanthic folds and a flat facial profile, single palmar crease, sandal gap, septal defects and Hirschsprung disease.
  • See Presentation: Clinical suspicion of Down syndrome (trisomy 21)
• Trisomy 18: Edwards syndrome can present in a variety of ways, including intrauterine growth restriction and physical features such as a triangular, asymmetric face, clenched hands with over-riding fingers, and cardiac and respiratory anomalies.
  • See Presentation: Clinical suspicion of Edwards syndrome (trisomy 18)
• Trisomy 13: Alongside hypotonia, typical features of Patau syndrome include cardiac defects, microcephaly, hypotelorism, microphthalmia, cleft lip or palate, rocker-bottom feet, polycystic kidneys and a variety of other complications.
  • See Presentation: Clinical suspicion of Patau syndrome (trisomy 13)
• Chromosomal conditions (caused by copy number variants, including deletions, duplications and structural rearrangements) can also present with a variety of congenital anomalies, and sometimes with hypotonia. However, in many instances, the specific underlying genetic diagnosis for a hypotonic infant may be unclear.
  • For the acutely unwell infant, please see Presentation: Child acutely unwell in NICU or PICU

• 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.
  • If you suspect a common trisomy (13, 18 or 21):
    • R26 Likely common aneuploidy by genome-wide common aneuploidy testing (send EDTA and lithium heparin samples).
  • If you suspect a wider chromosomal disorder:
    • R28 Congenital malformation and dysmorphism syndromes (microarray only).
  • If you suspect a likely central cause:
    • • R69 – Hypotonic infant with a likely central cause. This is a multifaceted test subdivided as follows:
        • R69.1 SNRPN DNA methylation testing for Prader-Willi syndrome;
        • R69.3 Microarray to investigate copy number variants (chromosome deletions or duplications);
        • R69.4 DMPK short tandem repeat (STR) testing for congenital myotonic dystrophy; and/or
        • R69.5 Whole genome sequencing (WGS) to investigate for single gene variants.
  • If you suspect a peripheral or neuromuscular cause:
    • R70 Spinal muscular atrophy type 1 diagnostic test by SMN1 multiplex ligation-dependent probe amplification (MLPA) or equivalent to assess SMN1 gene dosage.
  • If you suspect a broader multi-system condition due to the presence of congenital anomalies and/or dysmorphic features alongside hypotonia:
    • R27 Paediatric disorders by microarray and WGS.
      • R27 is a large WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics.
  • If a neonate or child with significant hypotonia is acutely unwell, likely to have a monogenic disorder and a molecular diagnosis is likely to impact management:
    • R14 by rapid WGS agnostically across the genome.
      • R14 requests currently require authorisation from clinical genetics.
      • There is a special test order form and Record of Discussion (RoD) form for this test, which are available from the Exeter Genetics Laboratory.
  • For tests that are undertaken using WGS, including R27 and R69, 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 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).
  • For tests that do not include WGS, including R26 and R70:
    • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
    • parental samples may be needed for interpretation of the infant’s result. Parental samples can be taken alongside that of the infant, 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).
• 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 Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Sparks SE. ‘Neonatal hypotonia’. Clinical Perinatology 2015: volume 42, issue 2, pages 363–371. DOI: 10.1016/j.clp.2015.02.008

For patients

• National Institute of Neurological Disorders and Stroke: Hypotonia