Investigation of early developmental impairment in children

If diagnosis is not apparent after clinical assessment consider the following first line tests:

• Chromosomal microarray
• Fragile X
• Urea & electrolytes
• Bone profile
• Liver function tests
• Thyroid function tests
• Creatine kinase
• Urate
• Full blood count
• Ferritin
• Lead (include only if history of pica)

If first line tests are normal, monitor development and clinical features and consider the need for individually tailored additional investigations or referral to specialist.

MR brain imaging is indicated if child has an abnormal head size, a rapid change in head circumference, focal neurological signs, or epilepsy.

Note: It may be possible to perform MRI brain imaging during sleep in young children <3 years at RHC which avoids the need for general anaesthetic. If a sleep scan is being considered this should be stated on the request form so that and appropriate slot can be given. If a child requires a general anaesthetic consider prior discussion with a Paediatric Neurologist as in some clinical presentations a lumbar puncture for CSF analysis may be indicated.

A referral for genetic opinion should be considered if no aetiology has been identified on first line genetic testing, and if history or examination is suggestive of underlying genetic disorder e.g. dysmorphic features, congenital anomalies, abnormal growth pattern, epilepsy, movement disorder, moderate to severe global developmental impairment, strong family history of neurogenetic disorder (other than autism), or family history suggestive of X-linked pattern of inheritance.  Possible additional genetic investigations may include specific gene testing, developmental exome sequencing, targeted gene panel testing or newer genetic technologies such as whole genome sequencing.

Referral to, or discussion with, a Paediatric Neurology specialist should be considered if there is a history of regression in skills or behaviour, epileptic seizures, movement disorder, muscle weakness, focal neurological signs without a clear cause, eye movement disorder, new onset visual or hearing impairment, or in cases where there is diagnostic uncertainty.

Referral to, or discussion with, a Paediatric specialist in Inherited Metabolic Medicine or Metabolic Biochemistry should be considered for advice on testing or metabolic test results, or if a child has unexplained EDI/intellectual disability with other features suggestive of an IEM e.g. hypotonia, coarse features, episodic illness, hepatosplenomegaly, developmental regression, poor growth / short stature, family history of IEM or parental consanguinity.

Inborn errors of metabolism (IEMs) are a rare cause of EDI but some are treatable. Additional tests should be considered if clinical features are suggestive of IEM e.g. unexplained EDI/intellectual disability, hypotonia, coarse features, episodic illness, hepatosplenomegaly, developmental regression, poor growth / short stature, family history of IEM, or parental consanguinity.

The following metabolic tests for unexplained EDI/intellectual disability with or without associated clinical features can be considered:

• Plasma Amino Acids
• Plasma Ammonia
• Plasma Lactate
• Plasma Total Homocysteine
• Serum folate
• Plasma or bloodspot Acyl Carnitine profile
• Urine Organic Acids
• Urine Glycosaminoglycans
• Urine Oligosaccharides
• Urine Creatine
• Serum Copper
• Serum Caeruloplasmin
• Plasma Biotinidase
• Plasma Very Long Chain Fatty Acids
• Plasma Lysosomal Enzymes
• Serum Desialotransferrin DST (transferrin/N-glycan profiling)

Guidance on investigations for IEM is available on the National Metabolic Biochemistry website, and the Treatable-ID web resource has published an algorithm to guide testing and additional guidance on targeted investigations for IEMs in children with unexplained developmental impairment and intellectual disability which can be accessed on the Treatable-ID website/App and referenced article (5). Additional guidance on clinical reasoning for investigations for early developmental impairment is available in the other cited references.