Macrocephaly: Symptoms, Types, Causes and Treatment

Macrocephaly, defined as an abnormally large head, is more than just a physical characteristic—it can be a visible clue to underlying genetic, neurological, or developmental conditions. For families and clinicians alike, understanding macrocephaly’s presentations, variations, and implications is crucial for early intervention and appropriate care. This article explores the symptoms, types, causes, and treatment options for macrocephaly, synthesizing current research to provide a comprehensive overview.

Symptoms of Macrocephaly

Macrocephaly is most commonly identified during routine pediatric check-ups, when a child's head circumference measures significantly above age- and sex-matched norms. But there's much more to this condition than just a measurement.

Symptom	Description	Associated Features	Source(s)
Increased Head Size	Head circumference >2 SD above mean	Can be isolated or syndromic	2 4 6 7 9
Developmental Delay	Delayed milestones, motor or cognitive	Often with neurological signs	2 3 5 9
Autism Spectrum Disorder	Social, communicative, or behavioral challenges	May co-occur with macrocephaly	2 3 4 8 9 10
Other Physical Signs	Cutaneous, skeletal, or vascular anomalies	Includes hemangioma, polydactyly, syndactyly	1 5 8

Table 1: Key Symptoms

Common Presentations

Macrocephaly often manifests as a head size well above the average for a child's age and sex, typically defined as greater than two standard deviations (SD) above the mean. In clinical practice, some cases are even more pronounced, exceeding three SDs or more 2 4 7.

Associated Developmental Features

Many children with macrocephaly will experience developmental delays. These can affect motor skills (such as sitting or walking), language acquisition, and cognitive abilities. In some cases, intellectual disability or learning difficulties are also present 2 3 5 9.

Behavioral and Neurological Associations

A strong link exists between macrocephaly and neurodevelopmental disorders, especially autism spectrum disorder (ASD). Research shows that a significant proportion of children with both macrocephaly and ASD may have underlying genetic mutations, such as those in the PTEN gene 2 4 8 9 10. Neurological symptoms like seizures or hypotonia may also be present, depending on the underlying cause 3 5.

Additional Physical Findings

Macrocephaly can be accompanied by other distinctive features, such as:

• Dermatological anomalies (e.g., hemangiomas, cutis marmorata) 1 5
• Skeletal abnormalities (e.g., polydactyly, syndactyly) 5 8
• Body asymmetry or vascular malformations 5

These associated symptoms often provide valuable clues to the underlying syndrome or disorder.

Types of Macrocephaly

Not all macrocephaly is the same. Understanding the different types helps clinicians narrow down the potential causes and guide further evaluation.

Type	Defining Feature	Examples/Syndromes	Source(s)
Benign (Familial)	Large head with normal development	Familial macrocephaly	3 6 7
Syndromic	Occurs as part of a genetic syndrome	PTEN hamartoma tumor syndrome, MLC	2 3 4 5 6
Disproportionate	Head size > body size	Overgrowth syndromes	4 5
Relative	Mildly increased head size, normal body	ASD with macrocephaly	4
Hydrocephalic	Enlarged head due to excess CSF	Hydrocephalus-related macrocephaly	5 11

Table 2: Macrocephaly Types

Benign (Familial) Macrocephaly

Some individuals inherit a naturally larger head size from one or both parents. These cases, termed "benign familial macrocephaly," are not associated with developmental delays or neurological deficits. The head circumference is elevated, but the child’s growth and development are otherwise normal 3 6 7.

Syndromic Macrocephaly

Macrocephaly can be a hallmark of various genetic or metabolic syndromes. In these cases, the large head is just one part of a broader clinical picture, which may include developmental delays, intellectual disability, or physical anomalies. Examples include PTEN hamartoma tumor syndrome, megalencephalic leukoencephalopathy with subcortical cysts (MLC), and macrocephaly-capillary malformation syndrome 2 3 4 5 6.

Disproportionate and Relative Macrocephaly

Patients may be classified based on how the head size compares to the rest of the body:

• Disproportionate Macrocephaly: The head is much larger relative to the body, often seen in overgrowth syndromes 4 5.
• Relative Macrocephaly: The head is slightly larger, but this is less pronounced and may occur in some children with ASD 4.

Hydrocephalic Macrocephaly

This type results from an abnormal accumulation of cerebrospinal fluid (CSF), leading to an expanded head size. Hydrocephalic macrocephaly may present with additional neurological symptoms and often requires surgical intervention 5 11.

Causes of Macrocephaly

The underlying causes of macrocephaly are diverse, ranging from benign familial traits to complex genetic and metabolic disorders.

Cause Category	Key Mechanism/Disorder	Notable Genes/Pathways	Source(s)
Genetic	Inherited or de novo mutations	PTEN, HEPACAM, PI3K-AKT-mTOR	2 3 4 6 8 9 10
Overgrowth Syndromes	Excessive growth of tissues/organs	PTEN hamartoma tumor syndromes	2 4 5 8 9
Metabolic	Storage disorders, leukodystrophies	Various	6
Hydrocephalus	Excess CSF enlarges cranial vault	Structural brain anomalies	5 11
Familial/Benign	Hereditary, non-pathological	Familial trait	3 6 7

Table 3: Causes of Macrocephaly

Genetic Factors

PTEN Mutations and the PI3K-AKT-mTOR Pathway

Mutations in the PTEN gene are a leading cause of syndromic macrocephaly and are often seen in children with ASD, intellectual disability, and/or developmental delay. PTEN mutations can result in PTEN hamartoma tumor syndrome, which encompasses a spectrum of disorders (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and others) 2 4 8 9.

Beyond PTEN, recent research highlights the role of genes in the PI3K-AKT-mTOR pathway (including PIK3CA, MTOR, PPP2R5D) in macrocephaly and associated neurodevelopmental conditions. Mutations in these genes can lead to abnormal brain overgrowth and developmental issues 9 10.

HEPACAM (GlialCAM) and MLC1 Mutations

Another genetic cause is mutations in HEPACAM (also called GlialCAM) and MLC1, which are associated with megalencephalic leukoencephalopathy with subcortical cysts (MLC). These can result in classic, deteriorating, or even benign familial forms of macrocephaly 3.

Overgrowth and Syndromic Associations

Macrocephaly can be a feature of overgrowth syndromes, where excessive growth affects not only the head but also other body tissues. Examples include macrocephaly-capillary malformation syndrome and other PTEN-related conditions. These syndromes often include skin, vascular, and skeletal anomalies 2 4 5 8 9.

Metabolic and Structural Causes

Some metabolic disorders, such as storage diseases and leukodystrophies, can result in macrocephaly due to accumulation of abnormal substances in the brain or disrupted myelination processes 6. Hydrocephalus, characterized by excess CSF within the brain, is a structural cause that can lead to rapid and significant head enlargement 5 11.

Familial/Benign Macrocephaly

In many cases, a large head simply runs in the family and is not associated with any medical problems. These children have normal development and no associated symptoms 3 6 7.

Treatment of Macrocephaly

Treatment strategies for macrocephaly depend on its underlying cause, associated symptoms, and potential complications. Early identification and multidisciplinary care are key to optimal outcomes.

Treatment Approach	Indication/Goal	Notes/Considerations	Source(s)
Surveillance/Monitoring	Benign/familial cases, mild symptoms	Regular growth and development checks	2 6 7
Genetic Counseling	Syndromic/genetic macrocephaly	Family planning, risk assessment	2 3 4 6 9
Developmental Support	Developmental delay, ASD, ID	Early intervention services	2 4 9 10
Neurosurgical Intervention	Hydrocephalus, cranial abnormalities	Shunting, cranial vault remodeling	5 11
Medical Management	Associated conditions (e.g., seizures)	Symptom-specific treatments	2 3 5

Table 4: Treatment Approaches

Surveillance and Monitoring

Children with benign or familial macrocephaly and no neurological symptoms typically require only regular monitoring. This includes tracking head circumference, growth parameters, and developmental milestones to ensure no subtle deficits emerge over time 2 6 7.

Genetic Counseling

For children with syndromic or genetic macrocephaly, referral to a geneticist is important. Genetic counseling helps families understand inheritance patterns, recurrence risks, and potential implications for other family members 2 3 4 6 9.

Developmental and Supportive Therapies

Early intervention is crucial for children with developmental delays, intellectual disability, or ASD. This may include:

• Physical, occupational, and speech therapy
• Behavioral interventions for ASD
• Educational support and individualized education plans (IEPs) 2 4 9 10

Neurosurgical and Medical Management

When macrocephaly results from hydrocephalus or structural brain anomalies, neurosurgical intervention may be necessary. Procedures might include:

• Placement of a ventriculoperitoneal (VP) shunt to drain excess CSF
• Cranial vault remodeling and postoperative helmet therapy for hydrocephalic macrocephaly with significant cranial deformity 5 11

Other medical management may address seizures, vascular anomalies, or other associated symptoms on a case-by-case basis 2 3 5.

Conclusion

Macrocephaly is a complex and heterogeneous condition with diverse causes, presentations, and outcomes. Understanding its symptoms, types, underlying causes, and available treatments is vital for clinicians and families navigating the diagnostic journey.

Main Points Covered:

• Macrocephaly is typically defined as a head circumference greater than two standard deviations above the mean for age and sex, but can have many different clinical implications 2 4 6 7 9.
• Symptoms range from isolated increased head size to developmental delays, intellectual disability, ASD, and physical anomalies 2 3 4 5 8 9 10.
• Types of macrocephaly include benign familial, syndromic, disproportionate, relative, and hydrocephalic forms 3 4 5 6 7 11.
• Causes are diverse and include genetic mutations (especially PTEN and other PI3K-AKT-mTOR pathway genes), overgrowth syndromes, metabolic/storage disorders, hydrocephalus, and benign familial traits 2 3 4 5 6 8 9 10 11.
• Treatment depends on the underlying cause but can include regular monitoring, genetic counseling, developmental therapies, and in some cases, surgical intervention 2 3 4 5 6 7 9 10 11.

Recognizing macrocephaly as a potential signpost for underlying conditions allows for timely assessment, tailored interventions, and better outcomes for affected individuals and their families.