Recent advances in genetics and neuroimaging of children with holoprosencephaly (HPE) are reviewed from Stanford University School of Medicine, CA. Four major types of HPE are delineated by MRI findings: alobar, semilobar, lobar, and middle interhemispheric (MIH) variant, the lobar and MIH types being most prevalent. In etiology, both genetic and environmental factors are identified. Chromosomal anomalies account for 40% and include trisomies (> half of these cases), duplications, deletions, and ring arrangements. Outcome in HPE cases with cytogenetic abnormalities is very poor, only 2% surviving beyond 1 year, compared to 30-54% for those without genetic causes. Smith-Lemli-Opitz syndrome carries an increased risk of HPE. Mutations have been identified in 15% to 20% of HPE cases with normal karyotypes. In the autosomal dominant form of HPE, SHH is the most frequently identified gene defect. Environmental causes include antiepileptic drugs, alcohol, smoking, statins, gestational diabetes, and cytomegalovirus infection. Some teratogens interfere with sonic hedgehog signaling pathways by disturbing cholesterol metabolism. Neuroimaging abnormalities include non-separation of deep gray nuclei, especially thalamus, monoventricle, dorsal cyst, hydrocephalus, Sylvian fissure abnormalities, and cortical dysplasia. Clinical manifestations include mental and developmental retardation, epilepsy, spasticity, dystonia, choreoathetosis, and endocrine disorders (diabetes insipidus, growth hormone deficiency). Craniofacial malformations are severe (cyclopia, midline cleft lip and palate and flat nose), moderate (midface hypoplasia, hypotelorism), or mild (single central incisors, iris colobomas, anosmia). Feeding and swallowing difficulties are common. Microcephaly occurs in 75% of classic HPE cases, while one sixth require CSF shunting for hydrocephalus, especially in the alobar type and those with a dorsal cyst. Motor dysfunction varies and is most prevalent in the alobar and semilobar types of HPE. Outcome. This varies with the type and severity of HPE, and early mortality is expected in those with severe craniofacial or chromosomal abnormalities. Of 104 surviving cases evaluated at the Carter Centers, mean age was 4 years, and 15% were between 10 and 19 years of age. The recurrence risk of HPE is estimated at 6%, and is highest in familial forms. A thorough family hstory is advised. Prenatal diagnosis attempted by ultrasound in 93% was positive in only 22% of cases. Fetal MRI may prove effective in characterizing the malformation in cases with positive ultrasound. [1]

COMMENT. Holoprosencephaly is a congenital malformation caused by a defect in patterning of the basal forebrain in the first 4 weeks of embryogenesis, and characterized by incomplete separation of the cerebral hemispheres and basal ganglia. The mainly topographical classification of CNS malformations is being replaced by a classification based on integration of morphological and molecular genetic criteria (Sarnat and Sarnat, 2001; see Ped Neur Briefs 2001;15:57). The middle interhemispheric variant of HPE has previously been described as a distinct clinico-neuroradiologic subtype (Lewis et al, 2002; see Ped Neur Briefs Jan 2003;17:1-2). It differs from the lobar subtype by the absence of endocrine abnormalities and choreoathetosis. A delay in white matter maturation is described in 25 of 47 patients with HPE, a defect most evident in the MRI of infants and in severe subtypes (Barkovich et al, 2002; see Ped Neur Briefs Jan 2003;17:2-3).