Megalencephaly

Macrocephaly is diagnosed when the occipitofrontal head circumference (OFC or HC) is above the 95th percentile, or greater than +2 SD above the mean for gestational age. As many fetuses whose HC is between +2 and +2.5 SD will be normal, some authors use 98th centile or greater than +3 SD above the mean as clinically relevant. Macrocephaly can result from hydrocephalus, cerebral edema, focal and pericerebral fluid collections, thickened calvarium, neoplasia and megalencephaly. Megalencephaly denotes an increase in the weight and size of the brain due to true hyperplasia or overproduction of central nervous system parenchyma¹.  The terms macrocephaly and megalencephaly have, unfortunately, been used interchangeably, but do not denote the same process.  Megalencephaly is a subset of macrocephaly. Differentiation between macrocephaly and megalencephaly is important, as diagnosis, prognosis and treatment differ². Here we will focus on megalencephalic causes of macrocephaly. Most cases of megalencephaly are diagnosed postnatally. Of those diagnosed prenatally, diagnosis in the third trimester is most common³.

Prevalence of macrocephaly, by definition, includes approximately 2% of pregnancies. In these cases, most of the macrocephalic fetuses will be normal if between +2SD and +2.5SD. The degree of macrocephaly is important, with mild macrocephaly ≤ 2.5SD carrying a good prognosis. It should be noted that the sonographic diagnosis of an enlarged fetal HC has low specificity, with only 67% of the children diagnosed with fetal macrocephaly born with an enlarged HC.  Cognitive outcome was better in the familial cohort than in the non-familial cohort. Furthermore, at the time of the neuropsychological evaluation at a mean age of 4.3 years, only 35% remain macrocephalic. Distribution across sexes was similar and the presence or absence of associated megalencephaly was not addressed^{4, 5.} 

The prevalence of megalencephaly, a subset of macrocephaly, at birth is unknown, as the imaging to exclude other causes of macrocephaly may not be made prior to birth and many of the differentiating clinical features may not be identified until birth or following genetic evaluation. Assessment of fetal brain volume is not commonly performed, but correlation can be made on both US and MRI by specific cortical mantle measurements and correlated with normative data provided by autopsy specimens ^{6, 7}. Fetal brain volume measurement can be performed by fetal MRI using semiautomated post processing methods⁸.

The main differential diagnosis of macrocephaly is often noted to be a transient CSF disturbance, benign external hydrocephalus.  There are numerous alternative terms for this disorder, including extraventricular obstructive hydrocephalus, benign enlargement of the subarachnoid spaces and benign subdural hygromas or collections. Pericerebral fluid prominence has only rarely been described in the fetus⁹. HC is usually near normal at birth, reaching 97.5 percentile between 3 and 8 months of age. In addition to the rapidly increasing HC, there may be a tense anterior fontanel, dilated scalp veins, motor delay and irritability. Most infants are male (86.4%).  The prominent fluid spaces largely resolve between 12 and 18 months of age¹⁰.  The HC, however, remains enlarged, stabilizing around the 98th percentile. 

Benign familial megalencephaly usually has its onset with benign external hydrocephalus, has a normal outcome and is identified when there are other family members with large heads.  As the subarachnoid space normalizes, brain volume remains large, and the head circumference stabilizes usually around the 98th percentile. Most children are functionally normal. Measurement of the parental and sibling HC is an important clue to this diagnosis. 
 
Conditions leading to fetal and neonatal macrocephaly that are unrelated to megalencephaly include ventriculomegaly, CSF obstruction due to tumor, venous congestion or intraventricular hemorrhage and scalp edema.  Abnormal calvarial thickness due to skeletal osteodysplasias, such as craniometaphyseal dysplasia (ANKH), or skeletal storage disease usually doesn’t become apparent until later in infancy or childhood. 

Megalencephaly can occur as an isolated condition, or it may be associated with other genetic, syndromic, and non-syndromic conditions¹ (Table 1). Clinically significant megalencephaly, HC>+2.5-3SD, is divided into a metabolic type and an anatomic type (developmental). Metabolic megalencephaly refers to various storage and degenerative encephalopathies.  Like the osteodystrophies, these often become apparent later in infancy.  Examples include mucopolysaccharidoses and other lysosomal storage disorders, as well as Glutaric aciduria Type 1 (GCDH deficiency), Alexander (GFAP mutation), Canavan disease (ASPA deficiency) and megalencephalic leukoencephalopathy with subcortical cysts (MLC1)^{3, 11}.
 
The most common form of anatomic megalencephaly is benign familial megalencephaly, as described above.  In this disorder, initial imaging may demonstrate benign external hydrocephalus, but the brain remains large as the peri-cerebral spaces resolve and there is usually a normal cognitive outcome.  
 
When megalencephaly is accompanied by a broad pattern of extra CNS anomalies and dysmorphic features it is referred to as syndromic megalencephaly. It may be relative, as in skeletal dysplasias such as thanatophoric dysplasia and achondroplasia, where the brain/body weight ratio is increased. Both are caused by FGFR3 mutations and have varying degrees of accompanying temporal lobe dysplasia. 
 
Many megalencephalic malformations result from mutations of genes that encode components of the mammalian target of rapamycin (mTOR) pathway, an intracellular signaling pathway that plays an important role in regulating cellular growth and homeostasis¹². Hyperactivation of the mTOR pathway through activation of PTEN, PIK3CA or AKT3, results in ribosome biogenesis and elevated messenger RNA translation and, eventually, increased proliferation with production of dysmorphic neurons seen in dysplastic megalencephalies.  Loss of TSC1 and TSC2 genes in Tuberous Sclerosis leads to activation of the mTOR and downstream elements. Klippel-Trenaunay, CLAPO and CLOVES syndromes are PIK3CA related disorders. Other disorders in this pathway include Proteus (AKT1), Bannayan-Ruvalcaba-Riley/Cowden (PTEN), megalencephaly capillary malformation MCAP (PIK3CA) and megalencephaly, polydactyly and polymicrogyria hydrocephaly syndrome MPPH1 and 2 (PIK3R2 and AKT3 respectively), both of which have a large HC at birth^13-17. 
 
 
Megalencephaly can also accompany the RASopathies, syndromes caused by variants in genes encoding components of the RAS/MAPK signal transduction pathway. The RAS-MAPK pathway has roles in proliferation, differentiation, and migration with variable effect on brain volume and callosal size. The most common RASopathy is neurofibromatosis type 1. Other classic RASopathies include Noonan, cardiofaciocutaneous, Costello and Legius syndromes, epidermal nevus syndrome and capillary malformation-arteriovenous malformation syndrome (CM-AVM). 
 

Megalencephaly is diagnosed when the HC is greater than 2SD and after exclusion of other causes of macrocephaly, such as CSF expansion. The use of appropriate charts should be stressed since the variability between them can be very significant. This fetal diagnosis should be approached carefully due to limitations in accuracy of HC measurement (particularly in late gestation); lack of nomograms for specific populations based on fetal sex, ethnicity, and parental HC; and inconsistencies between prenatal and postnatal HC growth curves and progression over time³.
 
In syndromic megalencephaly the HC is typically >2.5 SD and the diagnosis is generally made earlier in pregnancy than in non-syndromic megalencephaly (early third trimester, rarely before 28 weeks, versus mid third trimester, respectively). The brain may appear normal, large, or dysmorphic depending on the underlying condition. A variety of gyral and structural CNS anomalies are also common in syndromic megalencephaly. These may include mild ventriculomegaly, callosal anomalies, mostly thick corpus callosum, malformations of cortical development (polymicrogyria, pachygyria, overdeveloped sulcation, heterotopias), large CSP and large extra-axial spaces3 Assessment of the cortical mantle layering and gyral development has been documented on both fetal US and fetal MRI^18,19.

In addition to the disorders involving the PTEN and PI3K/AKT/mTOR pathways, megalencephaly is seen with somatic overgrowth syndromes such as Beckwith–Wiedemann (CDKN1C and other mutations), Sotos (NSD1), Simpson-Golabi-Behmel (GPC3),  and Weaver syndromes (EZH2), fragile X (FMR1), and also with myotonic dystrophy²⁰ and chromosomal disorders (Klinefelter syndrome (47, XXY)¹. Many of the features that point towards a diagnosis in syndromic megalencephaly may be extracranial, as enlarging brain volume and head circumference may become apparent only after the initial anatomy scan or even after birth. These features include placental dysplasia (Beckwith-Weaver),  cardiac rhabdomyomas (TSC), cardiac anomalies (RASopathies), limb anomalies or overgrowth and linear skin abnormalities or vascular birthmarks. While genetic mutations may affect all body cells, mosaic status is common in the asymmetric somatic disorders and skin biopsy may be needed to confirm a diagnosis prior to treatment²¹.

Hemimegalencephaly (HME) is a rare congenital hamartomatous malformation of the brain, remarkable for its extreme asymmetry. It is characterized by enlargement and overdevelopment of one cerebral hemisphere. Many cases of HME belong to the spectrum of disorders related to hyperactivation of the mTOR pathway²², which is responsible for unilateral brain and spinal cord overgrowth. HME may result from somatic mutations in the mTOR, PIK3CA or AKT3 genes or may be a part of neurocutaneous or somatic hemihypertrophy syndromes. The former includes epidermal nevus syndrome, Proteus syndrome, Klippel–Trenaunay–Weber syndrome, neurofibromatosis type 1 and Tuberous Sclerosis, among others. Many of the syndromic features are not readily discernible at birth or in early infancy. It is, therefore, imperative to continually evaluate infants with HME for signs and symptoms of these and other syndromes²³.  
 
HME shows hemispheric asymmetry with the larger hemisphere having abnormal texture, gyration, and often ventriculomegaly. On MR disruption of the radial glial fibers (“transient structures”) of the developing hemisphere is characteristic.  Asymmetric prominent diffusion weighted imaging is present in the involved hemisphere on fetal MRI24.
Somatic, brain stem and posterior fossa asymmetry may occur, albeit less frequently²⁵. The other hemisphere is compressed and distorted¹⁸. Associated CNS pathologies, such as agenesis of the corpus callosum, Dandy-Walker malformation or abnormal cerebellum may be present. The cerebral findings can be similar in both isolated and syndromic forms, although tubers in TSC may be present on fetal MRI and extracranial features involving viscera, limbs, and skin aid in differentiation²⁶.

The fetal HC should always be measured during a sonographic examination performed in the second or third trimester. If the value is larger than +2 SD from the mean and/or there is a disproportion with the size of the trunk or limbs, the possibility of megalencephaly should be considered. If other conditions associated with a relatively large head, such as intrauterine growth restriction, hydrocephalus, fetal tumors and triploidy have been ruled out, a targeted examination is recommended. 
 

The available experience suggests that even expert ultrasound in pregnancies at risk will fail to diagnose fetal megalencephaly in many cases. Attention should be focused not only on the cranial measurements but on the cerebral anatomy as well. Multiplanar brain imaging and MRI are useful adjuncts to the biometric evaluation. 

Isolated megalencephaly, particularly when the HC is < 2.5 SD above the norm, may be clinically benign³ and even in the presence of subtle signs, such as enlarged subarachnoid spaces, frontal bossing, or polyhydramnios, carries a good prognosis.  Concerning markers include crossing of percentiles, asymmetry, cortical malformations, and extracranial abnormalities. Prognosis depends on the underlying etiology, the head size, and the presence of associated abnormalities. HME has a poor outcome in most cases, especially if it is syndromic. Epilepsy, often intractable, severe psychomotor retardation, and contralateral hemiparesis are the typical clinical presentations regardless of the severity of the condition²⁶. 
Diagnosis of megalencephaly and hemimegalencephaly syndromes is crucial due to the need for surveillance for childhood and later cancers.  PI3K-AKT-MTOR pathway inhibitors are available for some disorders^{21, 25}.

When the HC of a fetus is greater than +2 SD above the mean for gestational age, the HC of both parents and siblings should be measured and a detailed history obtained. In cases of familial large heads, a physical examination for stigmata of autosomal dominant conditions should be completed. With a negative examination and a HC<2.5 SD above the mean, follow up ultrasound measurements every 3-4 weeks are recommended, and the prognosis is usually good with normal neurodevelopmental outcomes. When the history and/or physical exam are positive or when parental HC are normal, a targeted neurosonogram, a fetal MRI and an amniocentesis for chromosomal microarray are recommended to better delineate the underlying etiology and offer appropriate counseling. Whole exome sequencing should be considered in cases of normal chromosomal microarray.
 

Table 1: Syndromes associated with megalencephaly and hemimegalencephaly 
• Isolated (familial), check parental head circumferences 
• PTEN and PI3K-AKT-MTOR, including vascular syndromes  
• RASopathies, RAS/MAPK signal transduction pathway (NF1, Costello etc) 
• FGFR3 mutations, increased brain:body ratio with relative or absolute megalencephaly (achondroplasia, thanatophoric)  
• Metabolic and degenerative disorders (mucopolysaccharidoses, other lysosomal disorders, Alexander (GFAP) and Canavan (ASPA), megalencephaly with cysts (MLC1), megalencephaly with cysts (MLC1) 

• Megalencephaly, head circumference greater than 2 SD above the mean and large volume brain, may not manifest until third trimester or later after birth 
• Isolated benign megalencephaly, the most common etiology, has favorable outcome and can be familial; head circumference of parents should be measured 
• HC greater than 2.5 SD suggests syndromic megalencephaly 
• Many associated syndromes and abnormalities, look for extracranial features (viscera, limbs, skin) to aid in diagnosis 
• Detailed US, MRI, multidisciplinary investigations, and counseling are useful 
• Mosaic forms may require biopsy of affected tissue to confirm diagnosis

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