OBJECTIVES: The goals were to identify and to classify causes and growth patterns of acquired (or progressive) microcephaly and to look for hypothesized correlations between causes, growth patterns, and developmental quotient/IQ.
METHODS: Fifty-one children (24 boys), 0.7 to 11.3 years of age, with early occipitofrontal circumference measurements above and later ones below the second percentile (SD: −2.03) were studied through retrospective note and growth chart review, with formal assessments of developmental quotient or IQ (n = 34).
RESULTS: Causes were classifiable into 5 groups as follows: idiopathic, familial, syndromic, symptomatic, and mixed. Four patterns of head growth were identified, as follows: type A, initial decrease from the normal range to below the second percentile, followed by growth below and parallel to the second percentile; type B, continued decrease away from the second percentile; type C, decrease below the normal range, with partial later recovery; type D, insufficient data. For 12 children, there were accompanying decreases in weight percentiles and for 5 of these in height percentiles as well. Infants with lower head circumference z scores at the end of the study also had lower z scores for final weight and final length. There was no correlation between causal group and growth pattern. Developmental quotient/IQ values were mostly <100 and did not correlate with head circumference z score, cause, or pattern.
CONCLUSIONS: The classification of causal groups and growth patterns should aid clinical management. Neither cause nor pattern predicted outcomes. The associations with poor weight gain and body growth deserve further study.
Acquired (also known as progressive) microcephaly is a condition in which a child's head circumference is within the normal range at birth and for an undefined period thereafter but then does not increase as fast as normal and, as a result, crosses percentiles to below the second percentile. In our experience, this is a relatively common form of microcephaly. Although there is extensive literature on microcephaly, there is little on this subtype. Recognized causes include acquired brain damage as well as Rett syndrome, Angelman syndrome, Down syndrome, and other rarer syndromes, but these account for a minority of cases.1,2 There are also differing head growth patterns for children with microcephaly, which have not been studied. As a result, there is no currently available information to give to most families whose children show acquired microcephaly.
To help remedy this, we conducted an observational study in which we attempted to classify the patterns and, where possible, the causes of acquired microcephaly. Although this was an exploratory study, we also hypothesized that there would be a link between the cause and pattern, so that more-severe lesional causes would be associated with more-severe failure of growth, and that more-severe head growth failure would be associated with lower developmental quotient (DQ)/IQ scores.
This was a retrospective study of children referred to 1 pediatric neurology clinic during a 10-year period, from a local population of ∼500000. Measurements were taken by examining health care professionals in routine clinic settings, including neonatal discharge examinations by doctors in training grades, outpatient measurements, and community measurements by health visitors or other nursing professionals. For all cases without a symptomatic cause (see below for definition), the head growth pattern was the cause of referral, with or without concern regarding early closure of the anterior fontanelle.
Acquired microcephaly was defined on the basis of birth or early head circumference measurements above the second percentile and later measurements below it. The second percentile corresponds to −2.03 SDs below the mean or a z score of −2.03. Percentile charts and growth data were the most recent available for British children.3 These are based on United Kingdom cross-sectional reference data and apply from birth to 16 to 18 years of age.
The cause was derived from standard clinical diagnostic assessments, including measurements of head sizes in the immediate family, and investigations that were individualized for each child. Children with unexplained developmental delay or mental retardation underwent a minimum of karyotyping, fragile X status determination, thyroid function testing, and measurements of levels of amino acids, glycosaminoglycans, and creatine kinase (for boys). The growth pattern was identified from visual inspection of the percentile charts.
Children were invited to undergo neuropsychological testing with either the Bayley Scales of Infant Development,4 the Wechsler Preschool and Primary Scales of Intelligence-Revised,5 or the Wechsler Intelligence Scale for Children,6 as appropriate for their age group. All scores are presented as either IQ or DQ, to facilitate comparisons across different scales (mean score: 100; SD: 15). DQ/IQ of <70 was classified as developmental delay/mental retardation.
Many of the rest of the data are presented as descriptive statistics. Paired t tests were used to compare the initial head circumference z scores with those at the end of the study. Mean differences with 95% confidence intervals were calculated. Differences were checked for normality through plotting of a histogram. All paired differences were compared in this way. Differences between causes of acquired microcephaly were compared through analysis of variance, after residuals were checked for normality. Where significant differences were indicated, the Scheffé posthoc test was applied. An arbitrary level of 5% statistical significance (2-tailed) was assumed. In accordance with standard statistical practice, we report exact P values. Data were analyzed by using SPSS 10.0 (SPSS, Chicago, IL). The study was approved by the South Sheffield local research ethics committee.
Fifty-one children (24 boys and 27 girls) were identified (median age: 4.5 years [range: 0.7–11.3 years]). Two children were born preterm (33 and 35 weeks), and the rest were born at term. Initial and final measurements were taken at medians of 0.03 and 4.49 years of age, respectively. Forty-nine children had 1 to 6 measurements above the second percentile at ages ranging from 2 weeks to 3 years, before they developed microcephaly. Two children with normal measurements at birth alone had initial z scores of −0.55 and −1.25.
Causes were divided initially into multiple subgroups, but a final review allowed these to be simplified into 5 groups, defined as follows: (1) idiopathic, that is, no cause could be recognized from the history, examination, or investigations, and there were no other abnormal findings; (2) familial, that is, a parent and/or sibling had a head circumference at or below the second percentile; (3) syndromic, that is, with associated anomalies; (4) symptomatic, that is, following a pathogenic event; or (5) mixed, that is, ≥2 of the aforementioned. In the idiopathic group, 6 children were in otherwise normal condition and so did not undergo any investigations apart from brain MRI in 1 case, which showed reduced white matter volume with gliosis. Two children, with IQs of 63 and 71, underwent the investigations listed above, with normal results; the first also underwent brain MRI, with normal results.
In the familial group (n = 12), affected relatives were as follows: mother and brother (including 2 sibling pairs), n = 4; mother alone, n = 4; brother alone, n = 2; sister alone, n = 1; mother and sister, n = 1. The phenotypes of other affected family members were not recorded in more detail because they were not included in the study. In most cases, microcephaly was recognized only when family measurements were taken after the index case had been identified.
In the syndromic group (n = 13), 4 patients had recognized syndromes (Rett syndrome, n = 2; Gomez-Lopez-Hernandez syndrome, n = 1; chromosome 9q34.3 microdeletion, n = 1). The latter 2 children were allocated to this group before the syndrome was identified. The other 9 children were allocated to this group because they had dysmorphic features and/or congenital anomalies. One also had sickle cell anemia. Because of referral selection, no child with Down syndrome was included in the study.
In the symptomatic group (n = 15), individual causes were as follows: prenatal: Epstein-Barr virus infection with white matter signal changes on MRI scans; trauma; maternal drug abuse; white matter gliosis; perinatal: neonatal encephalopathy (n = 7),7 periventricular leukomalacia/preterm birth; postnatal: intracranial hemorrhage, hypernatremic dehydration, global failure to thrive. The latter patient was the only child for whom weight and length parameters decreased before head growth.
In the mixed group, all cases had a familial component (2 mothers and 1 sister). Two patients had syndromic features, and 1 had diplegia associated with bacterial vaginitis in pregnancy, several episodes of threatened preterm labor, and white matter signal changes on T2-weighted MRI scans.
Visual observations of the patterns led to classification into 4 groups (Fig 1). In type A (n = 30), an initial decrease from the normal range to below the second percentile was followed by steady growth below and parallel to the second percentile. In type B (n = 12), there was a continued decrease away from the second percentile. In type C (n = 4), after a decrease below the normal range, there was partial later recovery, with persisting microcephaly. In type D (n = 5), there were insufficient data, usually because of young age. For 7 children, there was an accompanying decrease in the weight percentile, although not in the length percentile; for another 5 children, there were decreases in both weight and length percentiles (Table 1).
Table 1 gives more details according to cause. The mean initial head circumference z score in the familial group seemed lower than those in the other groups, but this difference was not significant (P = .11). The final head circumference z scores in all groups were much closer together, with no obvious difference (P = .83). There was no obvious difference between the groups regarding the age at which the head circumference decreased below the second percentile. Brain MRI was not performed for the entire group, particularly younger children who would have required a general anesthetic, because this investigation was not considered ethically acceptable if the children did not show abnormal clinical findings. With this limitation, there was some correlation between MRI results and cause groupings, in that children with symptomatic causes usually had abnormal MRI results, whereas those with familial causes had normal MRI findings. White matter changes consisted of reduced volume and/or periventricular gliosis. Other changes consisted of lesional or malformative findings.
Table 2 gives more details according to the patterns of head growth. All patterns could be seen with all causes, but more patients with pattern B had a symptomatic cause than did those with pattern A (6 of 12 patients vs 8 of 30 patients). Patients with pattern B had significantly lower z scores (P ≤ .0001) than did the other patients at the end of study.
Children with higher z scores at baseline had higher z scores at the end of the study (mean difference: 2.96 [95% confidence interval: 2.66–3.26]; P < .0001). Head circumference z scores did not differ between boys and girls at the beginning of the study (P = .28) but did differ at the end of the study (boys, mean: −3.24; girls, mean: −3.81; P = .036). There was no relationship between the final head circumference z score and the age at which it was measured (P = .61). Twelve of the 51 children also showed abnormal growth patterns for weight and height. The reduction in weight percentile usually coincided with that of the head percentile. Children with lower head circumference z scores at the end of the study also had lower z scores for both final weight (P = .05) and final length (P = .038).
Ten of the 15 children in the symptomatic group had cerebral palsy (Gross Motor Function Classification Scale level I, n = 3; level II, n = 1; level III, n = 1; level IV, n = 1; level V, n = 5), as did 1 child each in the familial (level III) and syndromic (level IV) groups. Thirty-four families agreed to further assessment of DQs or IQs. For those children, the median DQ/IQ was 63. Only 3 (9%) of 34 children had a score of ≥100. The idiopathic group had the highest median score, that is, 83, and the syndromic group the lowest, that is, 45 (Table 1). Children with pattern A had a higher median score than did those with pattern B (Table 2). The numbers of children in those groups was too small for us to make meaningful statistical comparisons. The presence or absence of associated growth abnormalities had no effect on these scores. There was no correlation between DQ/IQ and the simultaneously measured head circumference z score (P = .4).
This is the first attempt to study acquired, or progressive, microcephaly systematically.2 One major reason was to provide better information to parents whose children developed the condition. We also hoped that this would be a useful diagnostic aid for clinicians, because acquired microcephaly was the presenting complaint for all children except those in the symptomatic group, for whom it mostly followed their pathogenic event. The latter group also could be distinguished clinically by the presence of other neurologic signs, such as cerebral palsy. This group corresponds to “acquired” or “secondary” microcephaly; both are ambiguous terms because they are used both to distinguish symptomatic from primary or genetic microcephaly and to distinguish early-onset from late-onset brain growth failure. Our study has suggested that many late-onset cases are likely to have a genetic basis. As in studies of microcephaly as a whole, there are a variety of recognized causes.1,2 Attempts to classify these have not led to an accepted international method. Our classification for this group has the advantages of practicality and simplicity.
In terms of cause, relatively few cases were in the idiopathic group. We had not expected so many cases to be familial. This could suggest “familial microcephaly,” rather similar to familial macrocephaly, but the strong maternal link suggests a different genetic influence. We had very limited power to show significant differences, and we cannot confirm whether this group also had smaller initial head circumferences, compared with the other groups. The available MRI data suggested that this group did not have structural abnormalities. In the syndromic group, there were many different phenotypes, mostly unrecognized, some possibly with a genetic origin. In congenital microcephaly, similar difficulties in classifying likely syndromic cases have occurred.7 However, there were very few cases in the overlapping/mixed group. No cases of Down syndrome were included, because such children attend a different clinical service and usually present with other problems. Interestingly, no child had suture synostosis, which rarely presents with acquired microcephaly. Gomez syndrome is the association of parietal alopecia, cerebellar rhombencephalosynapsis, and suture synostosis; although our patient had acquired microcephaly, she did not have synostosis.8 This suggests that, in this syndrome, the head growth pattern might have been ascribed incorrectly to synostosis. Finally, cerebral palsy seemed more prevalent in the symptomatic group, which likely reflects the underlying causes.
This is also the first attempt to classify the growth patterns in acquired microcephaly. Our classification is simple and practical. The majority of cases fit pattern A. To our surprise, however, there was no obvious correlation between the cause and the pattern. We had hypothesized that pattern B, with more-severe failure of growth, would be associated only with symptomatic causes but, although pattern B was seen more commonly in that group, it occurred in other groups too. As expected, the final z scores for children with pattern B were lower than those for children with pattern A, reflecting the more-severe growth failure of the former. Pattern C also was not clearly related to cause. Postnatal head growth is ascribed traditionally to development of the white matter and myelination in early childhood and skull bone growth in late childhood and adolescence. In younger children, the head circumference correlates closely with brain volume. This implies that acquired microcephaly is mainly attributable to a failure of white matter growth. The MRI data, for a limited number of our patients, supported this suggestion to some extent, because many patients did show abnormal white matter volume or signal. Many patients did not, however, and we did not perform volumetric analyses in a systematic way. It has been suggested that prenatal microcephaly reflects reduced numbers of neurons, whereas acquired microcephaly reflects decreased numbers of dendritic and synaptic connections.9 Pattern A (which, for example, is typical among girls with Rett syndrome) suggests that different processes may control early and later periods of postnatal brain growth as well.
It was also unexpected that so many patients demonstrated a decrease in weight percentile starting at the same time as the decrease in head percentile, mostly without an accompanying decrease in length percentile. This could not have been attributable to energy deprivation, in which failure to thrive in weight generally precedes a decrease in length, and head growth is the last to be affected. This association has not been recognized previously, but we are unable to suggest an explanation at present. This group deserves further study.
The DQ/IQ values of children with acquired microcephaly were generally below average, with approximately one half being in the lower part of the normal range (ie, 70–100) and the rest being <70. We found no correlation with head size. This parallels the results for congenital microcephaly, in which there is lower than average IQ but no clear correlation with size.10 Similarly, for NICU survivors, there was no close correlation between developmental performance and absolute or corrected head size.11 We could not identify any predictive factors, but our ability to do so was limited by small numbers. Although head circumference measurements were obtained in a nonstandardized way, previous studies showed good reproducibility of such measurements between observers.12
The proportions in each causal group may differ in a population study, because this study was limited by being retrospective and selective. We had data for an additional 7 children but, because we could no longer contact the patients, our ethics committee denied us permission to use the data. This exclusion made no difference regarding the proportions in each group or our conclusions.
Our study was intended to examine the pattern in which head size is within normal limits at birth and falls below those limits later. The median head size was already below average at the start, however, which indicates a probable prenatal origin in most cases, and the final values correlated with the initial values. Acquired microcephaly is thus a somewhat artificial construct that is based solely on a specific clinical presentation. The definition also excluded children whose head circumference declined across the percentiles but ended up above the second percentile, which can occur in some children, for example, approximately one half of those with Down syndrome.13 We chose to use the second percentile because it is close to −2 SD and data are available in clinics with standard growth charts, whereas others have argued that −2.5 or −3 SD is more appropriate, especially for genetic studies.7 For those with pattern B, this will be affected by the age of measurement.
The small sample size (N = 51 at baseline) meant that statistical analyses were limited. It was not sensible to carry out complex statistical modeling, and we focused on comparing group means. The statistical power to compare groups was limited, especially in comparisons of the causes of acquired microcephaly. Unfortunately, it will be difficult to study the questions raised in this group further in the United Kingdom, because head size is no longer measured routinely during infancy.
This, the first study of acquired microcephaly, has resulted in a simple classification of causal groups and growth patterns, which should aid clinical management. Many cases are likely to have a genetic origin, and there seems to be a maternal influence in the familial group. Neither the causal group nor the growth pattern predicted DQ/IQ. The associations with poor weight gain and body growth deserve further study.
This work was supported by the Sheffield Children's Hospital Charity.
We thank the families who participated, Dr Barbara Steele for help in gathering and analyzing data, Dr Jerry Wales for transforming the growth data into z scores, and Vanda Cupit for secretarial support.
- Accepted January 12, 2009.
- Address correspondence to Peter Stuart Baxter, MD, Ryegate Centre, Sheffield Children's NHS Foundation Trust, Tapton Crescent Road, Sheffield S10 5DD, England. E-mail:
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject:
Microcephaly can be congenital or acquired. There is a large variety of causes. Head circumference does not correlate directly with IQ.
What This Study Adds:
This study of acquired microcephaly adds 5 causal groupings, 4 growth patterns, and an association with failure to thrive. One half of subjects had DQs/IQs between 70 and 100 and the other half <70, but no predictive factors were identified.
- ↵Seaver LH, Holden KR. Acquired microcephaly: etiologies and associations. Proc Greenwood Genet Center.2003;22 :23– 26
- ↵Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med. 1998;17 (4):407– 429
- ↵Bayley N. Bayley Scales of Infant Development (BSID-II). 2nd ed. Lutz, FL: Psychological Assessment Resources; 1993
- ↵Wechsler D. Wechsler Preschool and Primary Scales of Intelligence-Revised (WPPSI-R). San Antonio, TX: Psychological Corp; 1989
- ↵Wechsler D. Wechsler Intelligence Scale for Children (WISC-IV). 4th ed. San Antonio, TX: Psychological Corp; 2003
- ↵Bartram JL, Rigby AS, Baxter PS. The “Lasso-o” tape: stretchability and observer variability in head circumference measurement. Arch Dis Child.2005;90 (8):820– 821
- Copyright © 2009 by the American Academy of Pediatrics