Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-18 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Synonyms: The following are part of the holoprosencephaly complex: arhinencephaly, cebocephaly, ethmocephaly, and cyclopia.

Definition: Holoprosencephaly is a heterogeneous entity of central nervous system anomalies caused by the impaired midline cleavage of the embryonic forebrain. In the most cases it is associated with midfacial anomalies. Holoprosencephaly is graded according to the severity of the brains anomaly as alobar, semilobar and lobar. In the alobar form, the ventricle is continuous, whereas in the lobar form an attempt to form occipital horns and abnormal frontal horns is present. Because of a mechanism of reciprocal induction between the brain and the skull, the facial structures are also abnormal. The severity of the facial malformation reflects the severity of the intracranial anomalies.

Incidence: The incidence is about to 6-12:10,000 among live born but 40:10,000 in embryos. Half of these are associated with trisomy 13. The sex distribution shows a female predominance.

Etiology: Autosomal-dominant, recessive, and monogenic inheritance as well as infectious (cytomegalovirus, toxoplasmosis), toxic (hydantoin), and maternal conditions such as gestational diabetes have all been reported.

Pathogenesis: Failure of sagittal cleavage of the telencephalon that results in the presence of a midline single ventricle with variable degrees of separation. This is probably due to mutations in the gene for the sonic hedgehog morphogen and genes that encode its downstream intracellular signaling pathway. There is also some evidence for a defect in the cholesterol biosynthesis.

Diagnosis: The diagnosis is suggested by numerous findings such as cyclopia, cebocephaly, ethmocephaly, hypotelorism, proboscis; median cleft lip, single ventricular cavity, thalami fusion, absence of median structures, and microcephaly.
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Figure 1: The appearance of cyclopia at 16 weeks. Note the proboscis above the fused eye and the midfacial hypoplasia.

Figure 2: The appearance of cyclopia at 16 weeks. Note the proboscis above the fused eye and the midfacial hypoplasia.

Figure 3: Axial view of alobar holoprosencephaly at 10 weeks. The lack of cleavage of the telencephalon has resulted in an undivided midline cavity that extends rostrally in a balloon shape. (trisomy 18).

Figure 4: Coronal view of alobar holoprosencephaly at 10 weeks

Figure 5: Sagittal view of alobar holoprosencephaly at 10 weeks.

Figure 6: Normal and abnormal brain development leading to holoprosencephaly.

Recurrence risk: The risk of recurrence depends of the basis for the actual condition, such as chromosome defect or syndrome. Both autosomal dominant and recessive conditions have been described but incomplete penetrance or an incomplete form or microform can make the interpretations of familial occurrence difficult. The proportion of sporadic cases is estimated to be 68%, with a 6% recurrence rate for sporadic, non-chromosomal forms. In the autosomal dominant form, the penetrance is estimated as 82% for major types (alobar, semi lobar, lobar) and 88% when major and minor types (atypical) were included. Thus, the recurrence risk after an isolated case is 13% for major types and 14% when minor types are included.

Genetic anomaly: Possibly located on the short arm of chromosome 3, the long arm of chromosome 7 or the long arm of chromosome 14 .

Associated anomalies: Median cleft lip, proboscis, arhinencephaly, cebocephaly, ethmocephaly and cyclopia.

Differential diagnosis: The associated aneuploidies (trisomy 13 and 18 should be excluded by karyotype.

Prognosis: Depends on the form. The severe forms are usually associated with neonatal death. Some of the mildest form (single front incisor) may have mild to moderate mental retardation and are at risk for pituitary dysfunction.

Management: Termination of pregnancy can be offered for the severe cases (semi-lobar, alobar).

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