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 include:
  • 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, cardiac 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).
  • Wider 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.
  • Temple syndrome: Neonatal features of this condition include generalised hypotonia, poor feeding, IUGR and small hands and feet.
    • See Presentation: Clinical suspicion of Silver-Russell syndrome. (Temple and Silver-Russell syndromes are tested for together.)
• 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 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 suits the needs of your patient or family.
  • If you suspect a common trisomy (such as trisomy 21, 18 or 13):
    • R26 Likely common aneuploidy: This is 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: This is a genome-wide microarray. Where possible, the chromosomal disorder suspected should be specified on the test request form.
  • If you suspect Prader-Willi syndrome:
    • R48 Prader-Willi syndrome: Uses methylation and multiplex ligation-dependent probe amplification (MLPA) or equivalent analysis
  • If you suspect SMA:
    • R70 Spinal muscular atrophy type 1 diagnostic test: SMN1 multiplex ligation-dependent probe amplification (MLPA) or equivalent to assess SMN1 gene dosage. This test should be performed first as most individuals with SMA have deletions of both copies of the SMN1 gene.
    • R71 Spinal muscular atrophy type 1 rare variant testing: SMN1 gene testing. This test is for individuals with a clinical diagnosis of SMA where only one copy of the SMN1 gene is deleted. The test looks for a sequence variant on the other allele.
  • If you suspect congenital myotonic dystrophy type 1:
    • R72 Myotonic dystrophy type 1: This uses short tandem repeat (STR) testing to look at the number of CTG repeats in the DMPK gene, with larger expansions being associated with neonatal onset.
  • If you suspect Temple syndrome:
    • R452 Silver Russell Syndrome and Temple Syndrome: This typically uses a methylation-sensitive MLPA assay that includes probes for the chromosome 7 and chromosome 11 loci associated with Silver-Russell syndrome (not typically associated with neonatal hypotonia) as well as chromosome 14 associated with Temple syndrome.
  • If you suspect a likely central cause:
    • R69 Hypotonic infant: This test uses whole genome sequencing (WGS) to investigate single gene variants. It is a multi-panel test focusing on genes associated with syndromic, metabolic, muscular and neuromuscular disorders.
  • If you suspect a broader multi-system condition due to the presence of congenital anomalies and/or dysmorphic features alongside hypotonia:
    • 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 can request both R69 and R27, where eligibility criteria are met as they contain a different combination of panels.
  • 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 Acutely unwell children with a likely monogenic disorder: Rapid WGS agnostically across the genome. Please note that myotonic dystrophy, SMA, Prader-Willi syndrome and Temple syndrome are not tested for within this R-code and will need to be requested separately.
• 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 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 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 RoD form for support); and
  • submit parental samples alongside the child’s sample 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, R28, R48, R70, R71, R72 and R452:
  • 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.
• 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.
• 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.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing 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 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

• Cleveland Clinic: Hypotonia in Babies (Hypotonia information)