Background Gross Pathology Histopathology & Immunohistochemistry

BACKGROUND AND CLINICAL INFORMATION: Head

Summary: (holo-, Greek, whole; pro-, Greek, in front): "A median holosphere with a single ventricular cavity instead of two hemispheres with symmetrical lateral ventricles" (Yakovlev 1959). This is a developmental failure of cleavage of the proencephalon with, and sometimes without, a deficit in midline facial development. The cardinal features include a single telencephalic ventricle and continuity of the cerebral hemisphere across the midline and associated with different degree of craniofacial malformations. The malformation is of graded severity (alobar, semilobar, and lobar holoprosencephaly) with respect to both the brain and the face. The degree of craniofacial malformation usually correlates with the degree of malformation of the brain. It is frequently associated with cyclopia in the severe form; sometimes due to trisomy 13.

Classification: Holoprosencephaly is not purely a failure of hemispheric cleavage. Severe hypoplasia of the neopallium is a prominent feature in the more severe cases such as alobar type. In these cases, the cortical architecture is often abnormal and association malformations of the circle of willis are often present.

Incidence: 48-88/1,000,000 in live born but about 4000/1,000,000 in abortus.

Etiologic factors:

Environmental: maternal diabetes, maternal alcohol consumption, maternal toxoplasmosis, maternal syphilis, maternal rubella. Association with alkaloids has been observed in lambs and experimental animals; inked with the signal pathway of the Sonic hedgehog pathway.

Chromosomal disorder: out of the 30 cases studied in the British Columbia's Children Hospital, about 1/3 of the cases have normal karyotype. For those with abnormal chromosomes, trisomy 13 (translocation, deletion) is the most common, followed by trisomy 18, then followed by other abnormalities.

GROSS PATHOLOGY: Head

Alobar holoprosencephaly (the most severe form): A very small brain with a single cerebrum with no lobe and no interhemisphere fissure. The surface, even at term, is usually smooth and has few or no gyrus formation. There is a single ventricle. The most dorsal part of the cerebrum is covered by a thin membrane that is thought to be the evaginated tela choroidea (should not be mistaken as a cyst but a real cyst can be present). The thalami are usually fusesd. The basal ganglia are fused and may be absent. The corpus callosum, anterior commissure, and the fornix may all be absent. The optic nerve and chiasm are usually hypoplastic and poorly myelinated.

Semilobar holoprosencephaly: the interhemispheric fissure is present posteriorly but the frontoparietal lobes are continuous. They usually lack olfactory bulbs or have hypoplastic olfactory bulbs. The gyral pattern is abnormal.

Lobar holoprsencephaly (the least severe form): The entire interhemispheric fissure is present and the left and right cerebral hemispheres are completely separated. There is a continuation of gray matter between the left and right hemisphere and only one single hemisphere is found. The thalami and caudate may still be fused. If the coprus callosum is starting to develop, it is usually seen posteriorly and the development is proportional to how normal the rest of the brain is formed.

Other neurologic abnormalities: a wide range of other cerebral malformations can occur in association with holoprosencephaly, including aqueduct stenosis, spina bifida and hydromyelia, the Chiari II malformation, arachnoid cysts, and vascular malformation.

Systemic abnormalities: about 75% of cases of holoprosencephaly, particularly if the condition occurs as part of a chromosomal disorder, such as trisomy 13, trisomy 18, and triploidy. Patients may have abnormalities of cardiac, genitourinary, and gastrointestinal development.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Cortex: histologic picture varies from cases to cases but the degree of disturbance is usually directly proportional to the severity of the gross malformation.

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