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Developmental Delay
Causes and Investigation
Introduction and definitions
This article provides a systematic approach to the Developmental Delay can be divided
causes of developmental delay and the impor- into:
tance of its rigorous investigation. It particularly Global developmental delay
highlights practical aspects relevant to adult neu- delay in two or more domains
rological practice. (often delayed in all domains)
Delayed development most commonly follows
the usual pattern of development where skills are Specific developmental delay
acquired more slowly (e.g. Downs syndrome). (e.g. Motor or Speech & Language)
Less commonly, skill acquisition can be disor- delay in a single domain
dered (e.g. autism). Delay is a misnomer chil-
Angharad V Walters
is a Specialist Registrar in
dren with developmental problems rarely catch The focus of this article is
Paediatric Neurology at up, and will usually have continuing difficulties Global Developmental Delay.
Addenbrookes Hospital, with learning later in life.
Cambridge. She studied Developmental delay is common, affecting 1- Causes of Global Developmental Delay
Physiology and Medicine at
Bristol University. She is training
3% of the population.1 Developmental delay is Global developmental delay can be the present-
in paediatric Neurodisability and defined as significant delay (more than two stan- ing feature of a huge number of neurodevelop-
has a particular interest in dard deviations below the mean) in one or more mental disorders (from learning disability to neu-
learning disability and behaviour. of the following developmental domains:2 romuscular disorders). It is not possible to pro-
m Gross motor vide an exhaustive list; Table 1 gives an approach
Correspondence to:
Email: angharadvw@doctors.org.uk m Vision & Fine motor to aetiology.
m Hearing, Speech & Language Careful evaluation and investigation can reveal
m Social, Emotional & Behavioural a cause in 50-70% of cases.4,1 This leaves a large
Developmental delay is a descriptive term used for minority where the cause is not determined. It is
children whose difficulties are apparent earlier in still useful to investigate globally delayed devel-
childhood where a cause is not yet established. It opment whatever the age of the child (occasion-
does not imply a particular organic or syndromic ally older children with significant disability may
cause, and the term does not appear in ICD-10.3 not have been investigated adequately).

TABLE 1: Causes of global developmental delay (adapted from Forsyth and Newton 20075).

Category Comments

Genetic or Syndromic Easily identified syndromes e.g. Downs syndrome

Identified in ~ 20% of those without Genetic causes that are less obvious in early childhood e.g. Fragile X, Velo-cardio-facial syndrome
neurological signs, dysmorphic features (22q11 deletion), Angelmans, Sotos, Rett's, maternal Phenylketonuria, Mucopolysaccharidoses,
or a family history Duchenne Muscular Dystrophy, Tuberous Sclerosis, Neurofibromatosis Type 1, and subtelomeric
deletions
Metabolic Nationwide universal neonatal screening for Phenylketonuria (PKU) and Medium-chain acyl-Co A
Identified in ~1% of those without Dehydrogenase deficiency (MCAD).
neurological signs, dysmorphic features e.g. Urea Cycle disorders.
or a family history
Endocrine There is universal neonatal screening for congenital hypothyroidism
Traumatic Acquired brain injury
Environmental Causes Children require their basic needs for food, clothes, warmth, love and stimulation to be met to develop
normally.
Children in neglectful, abusive, fearful, under stimulated environments may not show normal development.
This can be a contributory factor co-existing with other pathology and where the childs needs are
outside the parents capacity to provide for them.
Cerebral Malformations e.g. Neuronal Migration Disorders
Cerebral Palsy and Developmental Motor difficulties can prejudice development in general
Coordination Disorder (Dyspraxia)
Infections Perinatal e.g. Rubella, CMV, HIV
Neonatal meningitis
Toxins Fetal: Maternal alcohol or drugs in pregnancy
Childhood: Lead toxicity

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agreed recipe for the investigation of global

Why is finding a cause important? Investigation of Global Developmental developmental delay and there is much varia-
Establishing a cause has many benefits for the Delay tion in practice. Historically, there has been
child and family and improves overall quality Thorough history and examination are vital to patchy introduction of tests as they became
of life:4 produce a formulation of the childs problem available. This means it is well worth reviewing
m The family gains understanding of the and target investigations appropriately.4,6 The what investigations have actually been done.
condition, including prognostic diagnosis may occasionally be immediately A scheme illustrating the investigations con-
information obvious from history and examination. More sidered for global developmental delay is
m Lessens parental blame often time is needed to review clinical fea- shown in Figure 1. You should expect the first
m Ameliorates or prevents co-morbidity by tures, case notes, prior investigations and to line investigations to have been done, and rel-
identifying factors likely to cause consult the literature, dysmorphology and neu- evant second line investigations depending on
secondary disability that are rogenetic databases.4 clinical circumstances.
potentially preventable e.g. Transfer of a patient into your clinic from
surveillance of other systems such as paediatric services is a good opportunity to Practicalities:
vision and hearing review the diagnostic process. Most investiga- The approach to performing investigations is
m Appropriate genetic counselling about tions are likely to have been performed early influenced by:
recurrence risk for future children and the in the childs life; medical advances especially m identifying treatable conditions
wider family in genetic investigations and neuroimaging m identifying prevalent serious conditions
m Accessing more support (e.g. within techniques may allow further diagnostic possi- (e.g. Creatinine Kinase for Duchenne
education services and specific bilities now. Clinical geneticists are an invalu- Muscular Dystrophy)
syndrome support groups) able source of diagnostic acumen and sugges- m economic considerations (inexpensive,
m To address concerns about possible causes tions for further suitable investigations. easy to perform tests for less common
e.g. events during pregnancy or delivery1 The evidence base for investigation of devel- disorders, e.g. Fragile X)
m Potential treatment for a few opmental delay is poor and published work is m the practicalities of performing the
conditions mainly consensus opinion.2 There is no one investigations on young children

Figure 1: A scheme illustrating the investigations First Line Figure 1 Notes:

considered for global developmental delay (adapted from Chromosomes MECP2 = gene for Retts
Fragile X VLCFA = Very Long Chain Fatty Acids are for
McDonald et al 20062 and A guide to investigation of Peroxisomal disorders (e.g. Adrenoleukodystrophy)
children with developmental delay in East Anglia 2005)1. U&E GAGs = Glycosaminoglycans are for
Creatinine Kinase Mucopolysaccharidoses (e.g. MPS type III Sanfilippo)
Thyroid Function WC enzymes = White cell enzymes. These and
FBC oligosaccharides are tests for lysosomal storage
disorders (e.g. GM1 Gangliosidosis).
Ferritin Transferrins are for congenital disorders of
Vision and Hearing assessments glycosylation (CDG) e.g. type 1a
7-dehydrocholesterol is for Smith-Lemli-Opitz
Paired CSF and plasma lactate are to investigate
mitochondrial disorders where there are concerns
about growth, multisystem involvement, visual and
hearing impairments, and abnormal MRI brain.1
Second Line

Metabolic Neuroimaging EEG Genetics

Family History Abnormal Head Size Seizures Dysmorphism
Consanguinity Seizures Speech Regression Abnormal Growth
Regression Neurological signs Sensory Impairment
Organomegaly Cranial nerve abnormalities Unusual Behaviours
Coarse Features Cerebral palsy Family History
Seizures Neurocutaneous signs
Abnormal Head Size Dysmorphic facies
Episodic decompensation Arthrogryposis
Congenital Ataxia Severe visual impairment
Sensory impairment Including Optic atrophy
Glue Ear Nystagmus

Blood Urine MRI Consider Consider

Lactate (+/- CSF Lactate) Organic Acids CT for bones, 24hr EEG Telomeres
Ammonia GAGs calcification Microarrays
Amino Acids Oligosaccharides Myotonic Dystrophy
Lead Angelmans
VLCFA Prader-Willi
Acyl Carnitines MECP2
Biotinidase
Homocysteine
Transferrins
WC enzymes
7-Dehydrocholesterol

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Simple blood tests can be achieved Metabolic Other Investigations

without too much difficulty. Individual Inborn Errors of Metabolism (IEM) All children with global developmental delay
MRI brain may require a general anaes- are a rare cause of global developmental should have Visual and Audiology assessments
thetic. This may have been delayed if the delay (~1%). However, they can present with early on. An Ophthalmology opinion should
child was approaching an age (~ 5yrs or non-specific developmental delay and some be sought if there are concerns about visual
developmental equivalent) where they are amenable to treatment. Metabolic investi- function, abnormal appearance of the eyes or
could manage an MRI without an anaes- gations are targeted and selective (there is no when looking for clues to the underlying diag-
thetic. such thing as a metabolic screen). Useful nosis.
If an anaesthetic is planned, considera- metabolic investigations and the clinical cir- A TORCH screen for congenital infection is
tion should be given to whether other cumstances in which they are considered are performed in children with Intrauterine
invasive investigations can be done outlined in Figure 1.1,2 Growth Retardation (IUGR), microcephaly, or
under the same anaesthetic e.g. blood Biotinidase deficiency uncommonly pres- sensory impairments. PCR for infective organ-
tests, lumbar puncture, and skin or mus- ents with global developmental delay without isms can be performed retrospectively on the
cle biopsy. other features, but early diagnosis and treat- blood spots taken for the neonatal screening
ment improves outcome. This is not a universal programme, even many years later.
Genetics first line investigation in many parts of the UK, Radiographs are performed primarily for
Chromosome analysis yields the highest num- but some authors argue that it should be.2 Many suspected skeletal dysplasia, or lead toxicity.
ber of abnormalities when investigating global countries screen for this disorder as part of uni- Subtle skeletal dysplasia can be difficult to
developmental delay, even where there are no versal neonatal screening; the UK does not. diagnose on radiographs performed when
clinical features of a genetic problem.2 most of the skeleton is not yet ossified and
Chromosomes and Fragile X testing are first Biochemistry may need to be repeated at a later date.
line investigations if history and examination CK
do not reveal an obvious aetiology. Fragile X is Boys with Duchenne Muscular Dystrophy can Conclusions
the commonest cause of inherited learning present with delay in more than one domain m Global developmental delay is a common
disability, but remains a rare disorder. Its dys- of their development (e.g. language and motor problem in paediatric practice and has a
morphisms are difficult to recognise clinically delay); therefore Creatinine Kinase (CK) is wide aetiology.
in younger children and girls. measured as a first line investigation in boys m Selective investigations are useful in deter-
Subtelomeric rearrangements are karyotyp- with global developmental delay. CK measure- mining the cause, but the cornerstone of the
ically invisible and are traditionally looked for ment is considered in girls with severe global diagnostic process is careful clinical exami-
where the karyotype is normal but a genetic (and especially motor) developmental delay. nation.
abnormality is still suspected. Specific tests for m Finding a cause confers many medical and
sub-microscopic microdeletions (e.g. for Renal, Bone social benefits for the child and family.
Williams or Velo-cardio-facial syndrome) can Electrolytes and Urea are first line investiga- m Recent technological advances, especially
be requested when clinical index of suspicion tions, and Calcium measurement can assist in in Genetics and Neuroimaging, make it
is high.1 the diagnosis of Velo-cardio-facial and Williams important to review the need for repeat or
The new advances in Microarray technolo- syndromes, and pseudohypoparathyroidism. updated investigations.
gy offer up to 15% more diagnoses than con- m The transfer of a patient to your practice
ventional karyotyping for global developmen- TFT from paediatrics is an opportunity to review
tal delay. They are cost-effective and, although Thyroid Function tests are easy to perform and the diagnosis (or lack of one), and to evalu-
not yet used routinely, are likely to be adopted have historically been part of investigations for ate the need for further investigation. l
widely in the future.7 developmental delay. TSH is measured as part
of universal neonatal screening. In addition,
Neuroimaging many chromosomal abnormalities are associat-
Cranial MRI in young children (5-6yrs) ed with an increased and ongoing risk of
requires day case admission to hospital for hypothyroidism (e.g. Turners, Velo-cardio-facial REFERENCES
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