Head Circumference Is Increasing While the Child Is Deteriorating

History and Physical

A 2-month-old infant with no prior history manifested with new-onset loss of muscle tone and difficulties with head control. His physical examination was normal, and he was referred to an early intervention program. After 2 months of therapy, no improvements were noted, notable hypotonia persisted, and head control did not improve in the pull-to-sit maneuver. Neurological evaluation at 4 months showed a large head circumference (macrocephaly + 3 SD) that had developed since birth, little visual contact, global hypotonia with preserved reflexes, and general apathy. Fundoscopic examination revealed mild optic nerve pallor. There were no signs of increased intracranial pressure, and head ultrasound was normal. Blood work was also normal, including creatine kinase. Brain MRI and more detailed blood and urine testing were requested.

Diagnostic Workup

Brain MRI showed megalencephaly and cerebral white matter abnormality with centripetal progression, starting from subcortical white matter and moving toward the periventricular white matter, internal capsules, and corpus callosum. The brainstem tracts, basal ganglia, and cerebellum were also involved, with sparing of the lentiform nuclei. Involved areas showed initial edema that later evolved to atrophy. MR spectroscopy (MRS) of the affected areas showed increased N-acetylaspartate and decreased choline peaks ( Fig. 29.1 ).

A two-part axial brain scan labeled A and B displays arrows that point to internal regions on both sides of the midline. — Fig. 29.1

Clinical Differential Diagnoses

Alexander disease: Macrocephaly, frontal bossing, neurological impairment, and epilepsy. Leukodystrophy is predominantly frontal, without elevation of N-acetylaspartate in urine or on MRS. Brain biopsy confirms the presence of Rosenthal fibers. Molecular testing shows mutations in the GFAP gene.

Glutaric aciduria type 1: Nonprogressive macrocephaly and dystonic tetraparesis. There is high urine excretion of glutaric and hydroxyglutaric acid. Genetic testing shows mutations in the GCDH gene, located at 19p13.2 and encoding the enzyme glutaryl CoA dehydrogenase.

Neurometabolic diseases (gangliosidosis, mucopolysaccharidosis, megalencephalic leukoencephalopathy with subcortical cysts).Neurogenetic syndromes (fragile X, PTEN mutations, macrocephaly-polydactyly-polymicrogyria-hydrocephalus)Neurocutaneous syndromes (RASopathies)Brain tumorsChild abuse

Imaging Differential Diagnosis

Alexander disease ( Fig. 29.2 ): Infantile Alexander disease typically presents with frontal white matter edema, followed by cyst formation. There is macrocephaly with rapid neurologic deterioration in both the infantile and neonatal variants.