Developmental Delay – Causes and Investigation (PDF)

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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. Down’s 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.
Addenbrooke’s 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:                     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. Down’s 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), Angelman’s, Soto’s, Rett's, maternal Phenylketonuria, Mucopolysaccharidoses,
   or a family history                              Duchenne Muscular Dystrophy, Tuberous Sclerosis, Neurofibromatosis Type 1, and subtelomeric
   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
                                                  • 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 child’s 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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                                                                                                                               PA E D I AT R I C N E U R O L O G Y

                                                                                                         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 child’s 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 child’s 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 Rett’s
                                                                   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                                                                                                                               Angelman’s
  VLCFA                                                                                                                              Prader-Willi
  Acyl Carnitines                                                                                                                    MECP2
  WC enzymes

                                                                                                               ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010          > 33

      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.
William’s 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. Turner’s, Velo-cardio-facial    REFERENCES
sedation or general anaesthesia. It is a second      syndromes). Thyroid function tests are worth
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stances outlined in Figure 1, in addition to         clinical diagnosis of hypothyroidism is more dif- on1/03/10
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performed in the first two years of life before                                                              R. Investigation of global developmental delay. Arch Dis
                                                                                                             Child 2006;91:701–5.
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                                                                                                             University Press, 2007.
ment varies widely between studies (9-80%).8         dence that children with developmental prob-
                                                                                                          6. Maw, A. Paediatric Neurology – History and
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the reported abnormalities are in children           general child population;9 interpretation of            Rehabilitation 2009;9(5):34-6.
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