Introduction

Have you ever been curious about the intricate development of our brains, or how variations in human brain growth can impact a child’s journey? Macrocephaly, where the head circumference is unusually large, is one of the many variations that suggest underlying neurological conditions. This article delves into the multi-faceted relationship between macrocephaly in neurodevelopmental disorders, with a focus on its link to Autism Spectrum Disorder (ASD). The aim is to understand macrocephaly and its impact and connections to various neurodevelopmental conditions, and explain how healthcare professionals assess and manage it. It is important to understand why monitoring head growth in the early stages of life, to recognise the diverse causes of macrocephaly in these conditions, so that ongoing research can be facilitated to improve outcomes for people with neurodevelopmental disorders. 

Macrocephaly in ASD

Macrocephaly is a condition where the head circumference of an individual is significantly larger than the average size for their sex and age.¹ It is a clinical feature in a subset of people with ASD, and their increased head size begins at birth or develops rapidly during infancy and early childhood, most commonly between 6 months and 2 years of age. Not all people with ASD exhibit macrocephaly; its presence is sometimes associated with different developmental trajectories and specific characteristics of the disorder. Research has indicated an association between large head size and certain cognitive profiles within the autism spectrum.

Prevalence of Macrocephaly in ASD

Approximately 20% of individuals with ASD have macrocephaly. While some have an increased head circumference from birth, others experience a period of rapid head growth during early development, typically before 2 years old.² This rapid growth phase is a significant indicator, often preceding full manifestation of ASD symptoms.³ Understanding these distinct growth trajectories is crucial, as they open up an avenue to the underlying biological mechanisms contributing to the condition. The relationship between head size and ASD extends beyond physical indicators, but also includes the specific phenotypes experienced. For example, studies have explored whether macrocephaly is more common in people with intellectual disability or particular repetitive behaviours.⁴

Clinical phenotypes and Associated features in ASD

The severity of macrocephaly in people with ASD differs and can be associated with a wide array of clinical features, spanning from cognitive abilities, where some individuals might experience intellectual disability, and others may exhibit areas of giftedness. There are usual social communication challenges and repetitive behaviours that characterise ASD, and sometimes macrocephaly can correlate with more pronounced expression of these traits. It has also been suggested that people with both macrocephaly and ASD have a higher likelihood of experiencing specific comorbidities, including epilepsy, sleep disorders and even gastrointestinal issues, suggesting a broader systemic impact.⁵

Genetic Syndromes with Macrocephaly and ASD Overlap

There is a large area of research dedicated to investigating the overlap between macrocephaly, ASD and genetic syndromes. Several known genetic conditions can manifest in people with autism and macrocephaly.

Genetic conditions include:

• PTEN hamartoma tumour syndrome (PHTS): These groups include conditions like Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. The PTEN gene is mutated, which is strongly linked to macrocephaly and an increased risk of PTEN⁶
• Fragile X syndrome: This is caused by a mutation in the FMR1 gene, and is best known for intellectual disability, present in both macrocephaly and autistic-like behaviours⁷
• Neurofibromatosis Type 1 (NF1): This is a genetic disorder primarily affecting nerve tissue growth, where overgrowth can lead to tumours, and is associated with macrocephaly and increased risk of ASD^8,9

Aetiology and Pathophysiology of Macrocephaly in Neurodevelopmental Disorders

The causes and biological mechanisms driving macrocephaly in neurodevelopmental disorders are complex, involving a delicate interplay of many genetic factors, brain structural changes and cellular processes.

Genetic factors

Genetics play the largest role in determining brain size and are a major contributor to macrocephaly in NDDs. 

Types of genetic factors that contribute:

• Single-gene mutations: mutations in genes like PTEN, CHD8, ADNP and SCN2A are the most common drivers of macrocephaly alongside NDDs. These genes are involved in brain development, neuronal function and cell growth regulation¹⁰
• Copy number variants (CNVs): This is when segments of the DNA are duplicated or deleted, associated with macrocephaly and a range of NDD phenotypes, including ASD¹¹
• Polygenic influences: Macrocephaly is not caused by a single gene, but by the combined effect of multiple genes, each contributing a small risk factor¹⁰

Brain structure abnormalities 

Larger head circumferences in macrocephaly also correspond to structural differences within the brain itself.

• Increased brain volume: This is the most direct anatomical correlation, where the brain volume is larger than the typical population. This increase can affect the entire brain, or regional, disproportionately affecting certain areas like the frontal lobes^13,14
• White matter overgrowth: white matter consists of nerve fibres that connect different parts of the brain. In some macrocephalic NDDs, there may be an overabundance of fibres, leading to increased brain connectivity and larger head size
• Cortical abnormalities: the brain’s outer layer, known as the cortex, can also show larger surface area or altered gyrification (folding pattern of the brain), which can be linked to changes in cognitive processing

Cellular and Molecular Mechanisms

At the cellular level, many cellular and molecular dysregulations play a role

• Dysregulation of neuronal proliferation, migration and differentiation: The precise process of neurogenesis, movement to their correct locations and specialisation can be disrupted, leading to an excess amount of brain cells, or incorrect localisation
• Abnormalities in synaptic pruning and connectivity: Synapses are the connections between neurons. Excess synapses are eliminated during development. Impaired process of elimination or altered connectivity of the synapses result in changes of brain circuitry and function
• Impaired glial cell function: Glial cells are the immune cells of the brain, supporting neurons. Dysfunctions of glial cells impact brain development and health, as they are involved in repair, regeneration and protection
• Inflammation and oxidative stress: Chronic inflammation or an imbalance of ROS within the brain can potentially contribute to abnormal brain growth and neurodevelopmental challenges

Environmental and perinatal factors

Environmental and perinatal factors interact with genetic predispositions to influence brain growth and NDD outcomes. However, further research in this area is required to fully understand the potential synergistic effects. 

Clinical Assessment and Diagnosis of Macrocephaly and Neurodevelopmental Disorders

When a larger head circumference is noticed during developmental stages in early life, a thorough clinical assessment is important to determine the cause and associated neurodevelopmental disorders

Comprehensive history taking

Making a record of medical history is important and the 1st step. Healthcare professionals need information about family history, prenatal history and developmental milestones. 

Physical examination

An accurate head circumference measurement is plotted on a standardised growth chart specific to age and sex to see how it compares to the general population. The doctor will also look for any unusual facial or body features that suggest a specific genetic syndrome. Neurological examinations also take place, assessing reflexes, muscle tone, coordination and sensory function to detect any abnormalities

Neuroimaging

An MRI or CT scan of the brain is used to detect cases of macrocephaly. If there is rapid and noticeable brain growth, new neurological signs like seizures or focal deficits, imaging is recommended. Imaging can also reveal underlying structural issues, such as excess fluid in the brain, brain tumours, megalencephaly or structural malformations. 

Genetic testing 

Genetic testing is an important component, as there are syndromic features or family history that can lead to significant developmental concerns. Genetic testing is conducted when there are specific physical characteristics suggesting a syndrome. Genetic testing ranges from a karyotype (looking at the chromosomes) and chromosomal microarray (CMA, to detect smaller deletions or duplications, to more specific targeted gene panels or comprehensive whole-exome/genome sequencing. Genetic counselling is pivotal for families to understand the implications of test results, recurrence risks and support.

Neurodevelopmental Assessment

Standardised diagnostic tools like ADOS-2 and ADI-R are used to diagnose ASD to understand a child’s abilities and needs. 

Differential Diagnosis of Macrocephaly

Healthcare professionals determine the causes of macrocephaly, once identified, to reach an accurate diagnosis

Some common causes include: 

• Benign Familial Macrocephaly: a common, harmless and inherited condition where a large head is hereditary
• Hydrocephalus involves excess cerebrospinal fluid accumulation within the brain’s ventricles, which leads to increased pressure and head size
• Structural brain lesions: brain tumours, cysts, or vascular malformations can cause enlarged heads by occupying space within the skull, and neuroimaging is needed for identification
• Metabolic disorders: some affect the body’s chemical processes, such as lysosomal storage disorders (Canavan disease), leading to macrocephaly due to substances accumulating in the brain

Management and Prognosis

The management and prognosis for macrocephaly ranges based on the underlying cause and associated impairments. 

• Monitoring and surveillance 
• Symptomatic management of NDDs, including behavioural therapies, tailored educational plans or pharmacological management
• Management of underlying causes
• Prognosis: The long-term outlook is diverse and highly dependent on the underlying cause and severity of developmental impairments. However, early diagnosis and personalised interventions can significantly improve developmental outcomes and quality of life¹⁴

Summary

Macrocephaly, where the head circumference of an individual is larger than average, is a defining feature in a subset of people with neurodevelopmental disorders, particularly Autism Spectrum Disorder. Its presence often points to underlying genetic factors, brain structural differences and complex biological mechanisms influencing brain growth and health. A comprehensive diagnostic approach, ranging from detailed history to neuroimaging, is crucial for accurate identification. While prognosis varies depending on the underlying condition, early diagnosis and tailored interventions can significantly improve developmental outcomes and quality of life for affected individuals. Further research is required to fully understand the multi-faceted connections between macrocephaly and neurodevelopmental disorders to develop more targeted therapies, enhance genetic counselling and family support.