corpus callosum agenesis

Hypotonia may be noted at birth but ankle clonus and spasticity can develop later.  Progressive kyphoscoliosis has been diagnosed as early as the age of 4 years and may result in restrictive lung disease requiring spine surgery by the second decade of life.  Developmental milestones such as walking and talking are delayed and intellectual development is subnormal.  Mirror movements may be present.  Gait may be unsteady but can be normal.

Brain MRI reveals a variety of malformations.  Agenesis of the corpus callosum is present and the white matter tracts appear disorganized.  The superior cerebellar peduncles fail to decussate and transverse pontine fibers may be absent.  The pons and midbrain are hypoplastic while there is a midline cleft throughout the brainstem resulting in a butterfly-shaped medulla.

Septal defects involving both the atrium and the ventricle are consistently present.  Pulmonary valve abnormalities are present in some patients.

Posteriorly rotated pinnae and a small mouth with a thin upper lip have been observed.  Camptodactyly and clinodactyly are common.  Some patients have mild microcephaly.

Global developmental delay is a consistent feature manifest as delays in walking and speech and eventual intellectual disability.  Feeding difficulties are common.  Hypotonia and hypermobile joints are often noted.  Imaging of the brain may reveal agenesis of the corpus callosum, incomplete formation of the inferior vermis, and leukomalacia of periventricular tissue.

Infants at birth have striking hypotonia with a weak cry and feeding difficulties.  Dysmorphic features such as micrognathia, microcephaly, low-set ears, some degree of generalized hypopigmentation (hair and skin), and a broad nose with a long philtrum may be present. The face may appear triangular.  Cleft lip and palate may be present.  Evidence of cardiac dysfunction may also be present early with both dilated and hypertrophic cardiomyopathy reported.  Hearing loss has been reported in some individuals.  Recurrent infections are common and immunologic studies have revealed, in some patients, granulocytopenia, low T cell counts (primarily T4+ cells), thymic dysplasia, and low levels of IgG.  Seizures may occur.  Liver dysfunction has been variably reported.

Neurological and brain evaluations have reported agenesis of the corpus callosum, defects in the septum pellucidum, and hypoplasia of the cerebellar vermis along with pontocerebellar hypoplasia.  Psychomotor retardation is severe in most individuals along with general growth retardation.

Histologic studies of skeletal muscle fibers have shown considerable variation in fiber size, centralized nuclei, fucsinophilic inclusions, and enlarged abnormal mitochondria.  Other central nervous system abnormalities include in some individuals a paucity of white matter, schizencephaly, neuronal heterotopias, and enlargement of the ventricles.

The cumulative effects of these multiorgan abnormalities lead to death within the first year or two of life, generally of heart failure or sepsis.