++
In the context of evaluation of the child with developmental
delay, detection of microcephaly holds a paramount importance. Etymologically,
microcephaly means a small head, but the term micrencephaly would
be more appropriate to designate a small brain. A high correlation between
the growth of the two structures exists. Tables of head circumference
in fetuses and from birth to adulthood have been well established.
Most investigators have defined microcephaly as
an occipitofrontal circumference (OFC) of less than 3 standard deviations
(SD) below the mean for age and sex. However, a surprising amount
of controversy exists about whether 3 SD or 2 SD below the mean
for age and sex is actually abnormal. Certainly, the broader definition
of 2 SD below the mean includes some persons with a normal brain
who have a small head. Study of the head size of healthy school-aged
children will detect a few persons with head measurements of less
than –2 SD, because the definition is based on a normal
distribution. In this group, however, persons with measurements
of less than –3 SD are extremely unusual, and therefore
an OFC of that size usually indicates a pathologic abnormality of
brain growth. Small head size that is proportionate to chest size
and length in infants and to height in older children suggests proportionate
small body size. However, in a child who is physically or neurologically
abnormal, proportionate smallness should not be assumed. In addition,
an individual whose height and OFC are both 3 SD below the mean usually
has a generalized abnormality of growth affecting both the brain
and linear growth rate and should be evaluated for a broad pattern
of malformation. Because small head size can be a familial trait
or a normal familial developmental pattern (as in macrocephaly), the
OFC of the parents and siblings should be recorded and compared
with the head measurement of the propositus.
++
Microcephaly is a descriptive term that does not
refer to a particular etiology and covers a wide range of heterogeneous
cases caused by multiple mechanisms.5 Most malformed
brains are small. However, microcephaly is a relatively common finding
in a large number of constitutional and acquired conditions. Many
of the common autosomal chromosome syndromes have prenatal microcephaly
as one feature of their recognizable pattern, and most have postnatal
microcephaly as a finding (see Chapters 174 and 176). Interruption of neuronal production
or secondary destruction and/or faulty migration, caused
by intrinsic or extrinsic factors, may cause microcephaly.
++
A child with disproportionately small head at birth is said to
have primary or congenital microcephaly, and
a child with normal birth OFC, whose head circumference falls below normal
percentiles after birth, has secondary or postnatal
microcephaly.
++
Some authors prefer to classify microcephaly as isolated or pure/nonsyndromic, and associated or syndromic. Isolated
or pure/nonsyndromic microcephaly was described in the
1950s in adults with mental retardation and called microcephalia
vera. The inheritance of so-called microcephalia vera is
most often autosomal recessive, whereas autosomal dominant and X-linked
transmission have also been recorded. Recently, 6 different genetic
loci for primary nonsyndromic microcephaly have been identified;
four of them have had their particular gene identified (eg, microcephalin).
Associated or syndromic microcephaly may be part of a distinct pattern
of malformation (genetic, acquired, or of unknown origin).
++
Figure 185-2 presents a diagnostic approach
to the child with microcephaly. This approach is designed to supplement
the approach to DD/MR. The initial step in evaluating a
child with microcephaly is to obtain the newborn head size and as
many measurements on the OFC chart as possible. Congenital microcephaly
implies an intrauterine onset of the abnormality of brain growth
and has a different set of causes than does microcephaly
with postnatal onset. The head measurement is then compared with
linear growth and weight to determine whether the head size is disproportionately
small for the body or if the subject has an overall pattern of growth
deficiency. The head size can also be compared with chest size in
infancy, because these two measurements are similar during the initial
months after birth. Proportionate head circumference, chest size,
and length in an otherwise normal individual with mild microcephaly
would imply overall small size and not an abnormality of brain growth.
++
A complete pre- and perinatal history together with an extensive
family pedigree (three-generation), including consanguinity, and
measurements of parents’ head sizes constitute an essential
second step. Physical examination, including a careful search for
dysmorphic features or structural defects, should follow to determine
whether the child may have a malformation syndrome. Signs of prenatal
abnormalities, such as frontal bone recession or absence of flexion
creases on the fingers, are especially important. A thorough neurologic examination
should be performed to ascertain the presence of any abnormal finding,
such as alteration of tone and reflexes, and presence of abnormal
movements, posture, gait, and behavior. The presence of seizures
should be carefully documented. In the presence of the aforementioned
findings and features, the small head almost certainly indicates
an abnormal brain. A complete ophthalmologic evaluation with pupillary
dilation is mandatory in all children with an abnormal head size,
because the detection of chorioretinitis, optic nerve hypoplasia,
optic atrophy, cataracts, retinal folds, or macular abnormalities
may lead to a specific diagnosis or suggest a pathologic process.
++
Historical and physical/neurologic findings determine
laboratory evaluation of the child with microcephaly (Fig.
185-2). If the child is dysmorphic or has multiple malformations and
does not fit a recognizable syndrome, a karyotype should be performed;
in case of normal results, other possible pathways are illustrated
in the algorithm. If the child does fit a recognizable syndrome
(eg, Smith-Lemli-Opitz), then the most appropriate tests to define
that syndrome should be undertaken. If the child shows no major/minor
anomalies but has a history of seizures, an accurate waking/sleep
electroencephalogram (possibly with videopolygraphy) and neuroimaging
should be carried out. Neuroimaging is also recommended in the child
with pre- or postnatal microcephaly, with no specific diagnosis,
in search of possible intracranial calcifications or structural
defects. A metabolic screening is performed whenever signs of metabolic
disorders are present. Appropriate microbiologic cultures and titers
are suggested in the infant with signs of intrauterine infection
syndromes or with no obvious diagnosis. eTable
185.2 outlines the recognizable causes and common syndromes
of microcephaly.
++
Without a specific diagnosis to explain the alteration or abnormality
in brain growth, ultimate mental development cannot be predicted accurately.
If the infant has an OFC of less than 3 SD below the mean and has
abnormal neurologic signs, however, the probability of developmental
retardation is high. With milder degree of decreased head size and
no specific diagnosis, one must be cautious in predicting cognitive
ability.
++
Genetic counseling regarding the risk of recurrence in a situation
of undiagnosed sporadic microcephaly is not clear-cut. A child with
severe nonsyndromic microcephaly whose parents are not consanguineous
and who is the only affected person in the family may represent
sporadic microcephaly caused by an autosomal or X-linked gene, or
the child may have abnormal head size because of an unrecognized
environmental cause. Without a specific physical or biochemical
marker, these possibilities cannot be separated. Therefore, empirical
recurrence risk figures must be used in this situation.
+++
Laboratory and Radiographic Evaluation
++
The information gleaned from the history and physical exam alone
can help in determining a diagnosis in a number of cases or in postulating
a provisional diagnosis for appropriate testing (Fig.
185-2). For example, a patient presenting with DD, severe MR,
absent speech, epileptic seizures, microbrachycephaly, ataxia, and jerky
arm movements is likely to have Angelman syndrome. The priority
testing, then, would be methylation analysis, molecular cytogenetics
evaluation for Angelman syndrome (15q11 microdeletion) (see Chapters 173 and 174)
and an EEG for the exact definition of the seizures and movement
disorder. Test results would thus
guide the therapy modality; the first choice in this case would
most likely be drug treatment. In another example, a floppy infant
with no progress in motor functions, little or no reaction to environmental
stimuli, characteristic minor anomalies, and epileptic seizures should
undergo a metabolic workup, searching for a peroxisomal disorder
(eg, Zellweger syndrome); EEG and brain MRI would be the second-line
investigation. Another illustrative case would be a child with “coarse
facies,” macrocephaly, liver and spleen enlargement, deafness, DD,
behavioral problems, and poor motor performance, who could have
a lysosomal storage disorder; appropriate biochemical studies should be
the first step toward the diagnosis. A child with distinct craniofacial
features, large or late-closing anterior fontanel, generalized hypotonia, noncompaction
cardiomyopathy, seizures, and developmental delay is likely to have
the del 1p36 syndrome. Subtelomeric analysis with at least two region-specific
fluorescence in situ hybridization (FISH) probes or high-resolution comparative
genomic hybridization (CGH) array are the most appropriate laboratory
investigations for confirmation of diagnosis. Last, a girl with
apparently normal psychomotor development during the first 6 to
18 months of life, followed by developmental stagnation and then
by rapid regression in language and motor skills, with loss of purposeful
hand use, and postnatal deceleration of head growth, is likely to
have Rett syndrome. Molecular testing of the MECP2 gene
is the most rational approach toward confirmation of the diagnosis
(see Fig. 185-2).
++
When to order cytogenetic studies and what particular test to
perform in the evaluation of the child with DD can be an ongoing
quandary. Reduced family resemblance may be one of the most sensitive
indicators for the presence of chromosomal abnormalities. Minor anomalies
observed in the infant or child but not seen in relatives may signal
the necessity for cytogenetic evaluation (see Chapter 173).
Most individuals with chromosome syndromes have patterns of minor
anomalies and characteristic phenotypic findings often allowing
for clinical recognition (eg, Down syndrome, Wolf-Hirschhorn syndrome).
Conversely, it is worth noting that a number of MR patients thought to
be nonsyndromic on physical examination were later found to demonstrate
aneuploidy or fragile X. Thus, chromosome analysis or CGH and DNA
for fragile X testing should always be considered (as recommended
by the ACMG and the Child Neurology Society) with the highest yield
in those with dysmorphic signs.
++
In recent years the advances in technology in molecular cytogenetics
have been remarkable. CGH microarray detects deletions and duplications
with much more accuracy than the standard karyotyping of the past
including high resolution banding (see Chapter 173). Currently most clinical geneticists recommend CGH microarray
as the first-line test in the evaluation of the child with DD/MR
who has no obvious diagnosis and in whom a chromosome study is being
considered. However, in a child with the clinical signs of Down
syndrome or trisomy 18, standard cytogenetics would still be the
initial step; in the child with velocardiofacial syndrome or the
characteristic presentation of Prader-Willi syndrome, targeted FISH
would be the first option in testing.
++
Interestingly, there is no known association between chromosome
abnormalities and the level of MR. Although chromosome studies are
performed less often on individuals with mild MR, individuals with
moderate MR show no greater positive rate of chromosomal abnormalities
than do those with profound MR.
++
Little is reported in the literature on the value of the EEG
in MR patients, but a recent study by Battaglia et al. found that
the diagnostic yield of EEG investigations was relatively high (8.3%).2,6 An
EEG (waking and sleeping) polygraphy, together with an accurate
clinical history of epileptic seizures, could allow the clinician
to narrow the diagnosis as a definite epileptic syndrome. Other
specific clinical presentations could justify an EEG exam, such as
significant language impairment (Landau-Kleffner syndrome), Angelman
syndrome, inv dup(15) syndrome, Wolf-Hirschhorn syndrome, and neuronal
ceroid lipofuscinosis with both infantile and late-infantile onset.
In all these conditions, the EEG may prove to be very helpful for
diagnostic purposes and treatment.
++
It has been reported that neuroimaging can detect cerebral anomalies
in 9% to 60% of individuals with MR. Many of these
abnormalities are descriptive findings (agenesis or hypoplasia of the
corpus callosum, ventricular enlargement) and have yet to add significantly
to our knowledge of the causes of MR. However, when coupled with
ongoing improvement in our knowledge surrounding the diverse brain
malformation syndromes and sequences, the use of neuroimaging can
undoubtedly complement the diagnostic process of the individual
with MR.7
++
In several syndromes and conditions, (Prader-Willi, Angelman,
Williams, velocardiofacial, fragile X), the recognizable physical
and behavioral phenotype evolves over time; observation of these changes through
systematic clinical follow-up can guide confirmation of a diagnosis (increasing
the number of diagnoses by 5–20%), selection of
a differential diagnosis, or elimination of a diagnosis. Serial
clinical evaluations represent an important approach to the patient
with MR with the potential to eventually lead to a definite diagnosis
or even the characterization of a novel syndrome.
+++
Treatment and Management
++
As with diagnosis, the first charge in the treatment and management
of patients with MR is to recognize the individuality of each patient’s condition,
environment, and prognosis. A few disorders associated with MR,
such as phenylketonuria and hypothyroidism, can be treated with
well-established regimens. Smith-Lemli-Opitz syndrome is an example
of a malformation syndrome with DD/MR in which drug treatments
are available (supplemental cholesterol) that may improve outcome.
There remain a large number of conditions in which little can be
done using standard pharmacological treatments, but clinical trials
are being carried out in specific conditions (eg, statins for the learning
disability of NF1). It is axiomatic that each patient has the inherent
right to receive not just the ordinary care given to any child but
also the extraordinary care necessary to the patient’s well-being,
as prescribed by his or her singular situation.
++
Early intervention is key to a productive treatment plan. Intellectually
disabled patients should receive a thorough “functional
evaluation,” accomplished by an appropriate professional
at the earliest possible juncture. Whenever possible, enrollment
in a rehabilitation program, personalized to the individual’s function
level, should occur. School placement at the appropriate time is
considered mandatory. Vocational training, particularly when the child’s
overall level of function allows for progression toward independent
or semi-independent adult living, should be introduced in secondary
school.
++
Beyond health surveillance and treatment, listening to the family’s
primary concerns and addressing such concerns whenever possible are
helpful. Referral to parent support groups or arrangement of a meeting
with other parents of individuals with the same condition may be
quite beneficial.
++
Prediction of chance of recurrence of the condition depends on
the diagnosis. Genetic counseling referral is always indicated in
the pediatric setting for the family who asks questions about diagnosis
or recurrence risk. In the primary care practice or medical home,
the pediatric clinician can anticipate such concerns and ask the
parents (or child if appropriate) if they are interested in such
a referral. Genetic consultation is now available in most medical centers
in North America, Europe, Japan, Australia, and other parts of the
world.