PMG and Macrocephaly: mTORopathy
- Where PMG is identifed in the setting of macrocephaly, further features suggestive of an mTORopathy shoulde be sought, specifically Megalencephaly Polymicrogyria Polydactyly Hydrocepalus (MPPH) syndrome and Megalencephaly Capillary Malformation (MCAP) syndrome.6,7
- Other abnormalities associated with the PIK3-AKT-mTOR pathway include segmental body overgrowth patterns including CLOVES syndrome, fibroadipose hyperplasia and Fibroadipose Vascular Anomalies (FAVA).
Fig. 1: mTORopathy - MCAP syndrome
Fig. 2: mTORopathy - MCAP syndrome 1
PMG and Microcephaly: CMV infection
- In the presence of microcephaly, PMG is most commonly associated with antenatal CMV infection and less commonly with antenatal Toxoplasmosis, Zika virus or Warburg Micro syndrome.
- Cytomegalovirus (CMV) infection results in a variable distribution of PMG, however usually affects both the cerebral and cerebellar surfaces.5
- Further neuroimaging features of congenital CMV infection may include intracranial calcification, caudothalamic cysts, anterior temporal cysts, ventriculomegaly, white matter abnormalities and optic atrophy/chorioretinitis.6,8
- Correlation with serology/PCR and the presence of sensorineural hearing loss and hepatosplenomegaly should be investigated.
Fig. 3: Congenital CMV
Fig. 4: Congenital CMV axial
PMG and Caudothalamic cysts: Zellweger Syndrome
- The presence of caudothalamic cysts and PMG can be associated with Zellweger Syndrome, congenital CMV and Zika viral infection.
- The Zellweger spectrum of disorders are a group of autosomal recessive peroxisomal storage disorders involving a mutation in one of the 13 PEX genes, with PEX1 being the most common.9
- The distribution of PMG in limited studies has shown a propensity to affect bilateral perirolandic regions.
- Other features of Zellweger syndrome may include scimitar-like patellar calcification on plain radiography, hyperechoic kidneys with renal dysplasia/cysts and hepatomegaly.6,9
Fig. 5: Zellweger Syndrome
Fig. 6: Zellweger Syndrome - renal cysts
PMG and Molar Tooth Sign (MTS): AH1 gene mutation
- ‘Molar tooth sign’ (MTS) describes the radiological appearances of the midbrain in the axial plane in which there is elongation and thickening of the superior cerebellar peduncles and an abnormally deep interpeduncular fossa giving the appearance of a molar tooth.10 Other associated imaging findings include a "batwing" fourth ventricle, cerebellar dysplasia and vermian hypoplasia with a cleft.
- When identified in the presence of PMG, mutations in the AH1 gene should be suspected which may point to a diagnosis of Joubert Syndrome.
- Additional extracranial features include medullary cystic kidneys, hepatic fibrosis, retinal dystrophy, ocular colobomas and polydactyly.10
Fig. 7: AH1 Gene Mutation & PMG
PMG and Septo-optic Dysplasia
- Septo-optic dysplasia is characterised by optic nerve hypoplasia and absence of the septum pellucidum and commonly includes hypothalamic-pituitary dysfunction.7
- The clinical presentation is mostly dependent on the presence or absence of schizencephaly which is used to define the two forms of the condition.
- Typically, PMG is seen where septo-optic dysplasia is seen in conjunction with schizencephaly.
- Other intracranial features may include Chiari II malformation, aqueductal stenosis and hypoplastic pituitary stalk.11
Fig. 8: Septo-optic Dysplasia
Fig. 9: Septo-optic Dysplasia - Coronal
Aicardi Syndrome
- Aicardi syndrome is a rare and severe neurodevelopmental disorder which is hypothesised to result from an X-linked genetic mutation and only manifests in females, being fatal in males.6
- The classic triad of features include agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms.
- PMG is almost universally seen in Aicardi syndrome and should be suspected when identified in conjunction with any of the classic features described.
- Other intracranial features include subcortical and periventricular heterotopia, intracranial cysts and optic nerve coloboma/hypoplasia. Extracranial findings include costovertebral defects and small hands.12
Fig. 10: Aicardi Syndrome
Absent ALIC sign and PMG: Tubulinopathy
- In cases where PMG is identified along with absent anterior limbs of the internal capsules, or the ‘absent ALIC sign’; an underlying tubulinopathy should be suspected.6,13
- The tubulinopathies encompass a variable range of brain malformations caused by mutations in tubulin encoding genes.
- Other neuroimaging findings suggestive of underlying tubulinopathy can include a range of lissencephalies, dysplastic basal ganglia, corpus callosum abnormalities and dysplasia of the brain stem and cerebellum.13
Fig. 11: Tubulinopathy & PMG
PMG and Cobblestone Cortex: Alphadystroglycanopathies
- Cobblestone cortex results from over-migration of the neuroblasts and glial cells beyond external glial limitations and into the subarachnoid space.
- It is a hallmark of the alpha-dystroglycanopathies which include a spectrum of anomalies with Walker-Warburg syndrome (WWS) being the most severe; Fukuyama congenital muscular dystrophy (FCMD), the mildest form; and muscle-eye-brain (MEB) disease the intermediate form.14
- The distinction between cobblestone cortex and PMG has become blurred in recent years with the two entities frequently seen together in the alpha-dystroglycanopathies and also in genetic mutations involving GPR56 and much more recently COL3A1.15
- Other associated anomalies include hypoplastic/absent optic nerves, micropthalmia and anterior chamber malformations.
Fig. 12: Cobblestone Cortex
Porencephalic Cysts and PMG: COL4A1/2 deficiencies
- Porencephalic cysts have been reported in association with PMG in COL4A1/2 deficiencies and also due to antenatal vascular insults.
- Type 4 collagen is ubiquitous in basement membranes and mutations in COL4A1/COL4A2 have been associated with porencephaly, schizencephaly and cobblestone cortex.3,7
Fig. 13: Porencephalic Cysts & PMG
PMG in Di George Syndrome
- Di George Syndrome is one of the 22q11.2 deletion syndrome phenotypes, among the most common microdeletion syndromes in humans.
- It results in a range of findings embraced by the acronym CATCH22 syndrome; Cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia.7,16
- In addition to these, there are a variety of skeletal, gastrointestinal, genitourinary and laryngotracheosophageal abnormalities which contribute to the diagnosis.
- PMG associated with 22q11.2 deletion syndrome has typically been described in a perisylvian distribution.7
Fig. 14: Di George Syndrome & PMG