Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis
Introduction
Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental conditions characterized by social and communication deficits, accompanied by repetitive and stereotyped behaviors, insistence on sameness and sensory issues, with onset generally prior to three years of age (American Psychiatric Association, 2013). Despite many advances in our understanding of the neurobiological and developmental processes underlying ASD, our knowledge remains limited and its translational impact into the clinics is still insufficient (State and Levitt, P., 2011, Chugani, 2012, Freitas et al., 2012). Furthermore, autistic subjects vary widely in clinical features, developmental trajectory, degree of severity and treatment response. This complexity is raising an intensive search to identify biological markers and specific endophenotypes able to aid clinicians in reaching earlier diagnoses and in predicting clinical prognosis as well as treatment response (Walsh et al., 2011). A biomarker can be defined as a biological variable associated with the disease of interest across and within individuals, measurable directly in a given patient or in his/her biomaterials using sensitive and reliable quantitative procedures. The concept of endophenotype goes one step beyond and has specific relevance in autism research. This term, introduced by Gottesman and Shields (1973), designates a heritable, familial, and trait-dependent biomarker, an internal construct that “cannot be observed from the outside with unaided eyes”, but can fill the gap between clinical symptoms and the underlying genes (Gottesman and Gould, 2003).
Macrocephaly (i.e., cranial circumference >97th percentile) represents one of the endophenotypes most consistently encountered in a subgroup encompassing 14%–34% of autistic patients (Courchesne et al., 2001, Aylward et al., 2002, Dementieva et al., 2005, Dissanayake et al., 2006, Sacco et al., 2007, Sacco et al., 2010). It is also familial and heritable, with first-degree relatives of macrocephalic probands displaying significantly larger head sizes compared to first-degree relatives of normo- or microcephalic autistic individuals (Sacco et al., 2007, Sacco et al., 2010). Our understanding of the link between autistic disorder and macrocephaly is still very limited. Neonates later developing autism and macrocephaly apparently display normal head circumferences at birth (Dissanayake et al., 2006, Sacco et al., 2007). Head growth rates begin accelerating during the first year of life, continue approximately until 4 years of age, and then slow down undergoing a premature arrest; no significant difference in head circumference is thus present between patients and controls at adolescence (Courchesne et al., 2001), at least in most cases. Neuroimaging studies have shown several years ago that enlarged brain volumes as responsible for macrocephaly in autism (Woodhouse et al., 1996, Lainhart et al., 1997). However, some studies describe a generalized enlargement of frontal, temporal and parietal lobes, involving both gray and white matter (Sparks et al., 2002); others find overgrowth mainly limited to the frontal lobes and to cortical gray matter, accompanied by an enlargement of the superficial white matter immediately adjacent to the gray matter (Redcay and Courchesne, 2005); still others report increased brain volume due to excessive cerebral white matter only (Hazlett et al., 2005). Altogether, despite significant heterogeneity, these findings have generally been interpreted as reflecting increased neurite sprouting and/or reduced pruning, resulting in a local overabundance of neuropil (Carper et al., 2002, Herbert et al., 2003). This phenomenon would seemingly result in cortical surface area overgrowth (Hazlett et al., 2011) directly yielding macrocephaly, although the neocortex in ASD actually displays complex and region-specific increases in surface area and cortical thickness (Ecker et al., 2010, Hazlett et al., 2011). Neurobiological mechanisms hypothesized to possibly underlie excessive neural growth in autism include several growth factors, hormones, and neurotransmitters, but direct experimental evidence is generally lacking.
Descriptions of the clinical correlates of head circumference in autism are also inconsistent. Some studies have reported higher levels of functioning (Aylward et al., 2002, Courchesne and Pierce, 2005, McCaffery and Deutsch, 2005, Sacco et al., 2007) among macrocephalic patients and have found that children with relatively larger head circumference have higher non-verbal abilities. Conversely, other studies have described no correlation between cranial circumference and specific abilities or cognitive functions (Gillberg and de Souza, 2002, Deutsch and Joseph, 2003). Moreover, larger brain volumes are not unique to ASD and have been reported in a subgroup of children with developmental language disorder (Hardan et al., 2007), as well as in multiple dysmorphic and metabolic syndromes, including Weaver, Sotos, Macrocephaly Capillary Malformations, Phosphatase and Tensin Homolog (PTEN)-related disorders (Tsatsanis et al., 2003).
In light of current interest in the creation of multi-biomarker panels for ASD, we undertook a systematic review of all studies assessing head circumference and total brain volume in autism. We then defined the cumulative percentage of ASD patients with macrocephaly and with enhanced total brain volume according to structural MRI, and perform a series of meta-analyses providing an overall estimate of the effect size and statistical significance for the association between macrocephaly and brain overgrowth with autism.
Section snippets
Literature search
Publications suitable for inclusion in the present study were found applying a strategy similar to the one we recently used to systematically review and meta-analyze publications addressing another well-known ASD biomarker, elevated serotonin blood levels (Gabriele et al., 2014): an initial search protocol was defined a priori, then followed by reiterative modifications aimed at progressively maximizing search efficiency by yielding increased numbers of pertinent studies. Our research involved
Study characteristics
The Literature search yielded a total of 261 and 391 valid records for head circumference and for TBV, respectively. Applying our exclusion criteria, 28 studies were selected for review and meta-analysis of head circumference (Fig. 1). These 28 papers, listed in Table 1, were published between 1994 and 2014; 15 studies were conducted in the United States, 12 were from Europe, and 1 from Israel. Autistic sample sizes varied widely, ranging from 15 to 1889 individuals. Similarly, the age of
Discussion
We performed a systematic review of studies measuring head circumference and TBV in autistic and control samples. Data from selected studies were then meta-analyzed, yielding results expressed as (a) global mean odds ratios and (b) overall percentage of ASD patients displaying macrocephaly and excessive TBV. The procedure employed here to systematically detect published papers on head circumference and total brain volume in autism, measured by structural MRI, was broad-based and thorough. Our
Contributors
RS collected the data and performed all statistical analyses; SG collected the data; AP conceived the study design and drafted the manuscript
Financial disclosure
The Authors have no conflict of interest, financial or otherwise, related directly or indirectly to the submitted work.
Acknowledgments
This work was supported by the Italian Ministry for University, Scientific Research and Technology (PRIN n.2006058195 and n.2008BACT54_002), the Italian Ministry of Health (RFPS-2007-5-640174, RF-2011-02350537, RF-2011-02350537 and CCM program 2012, progetto NIDA), the Fondazione Gaetano e Mafalda Luce (Milan, Italy), Autism Aid ONLUS (Naples, Italy), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), and the European Union (Innovative Medicines Initiative Joint
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