Holoprosencephaly (HPE). It is a complex brain malformation, the result of the incomplete division of the forebrain, which occurs between days 18 and 28 of gestation, affecting both the forebrain and the face , causing neurological manifestations and facial abnormalities of varying severity.


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  • 1 Synonyms
  • 2 Prevalence
  • 3 Inheritance
  • 4 Age of onset or onset
  • 5 Epidemiology
  • 6 Clinical description
  • 7 Etiology
  • 8 Diagnostic methods
    • 1 Differential diagnosis
    • 2 Prenatal diagnosis
  • 9 Genetic advice
  • 10 Management and treatment
  • 11 Forecast
  • 12 Sources






Multigenic / multifactorial or Not applicable

Age of onset or onset

Neonatal, Prenatal


It is estimated to occur in 1 / 10,000 live and dead newborns and in 1/250 conceptions. HPE has a worldwide distribution.

Clinical description

Three types of HPE have been described, of increasing severity, depending on their anatomical characteristics: lobar, semilobar and alobar. Another milder subtype, called the medium interhemispheric variant (MIH), has also been observed. The HPE phenotype also encompasses aprosencephaly / atelencephaly (the lowest end of the spectrum), schizencephaly, and septopreoptic HPE. The less severe forms are called microforms and are characterized by midline defects without the typical brain defects of HPE. However, there is a continuous spectrum of anomalous separation of the hemispheres and not a clearly differentiated division in these forms, with significant inter- and intra-family clinical variability. In most cases,mutation in the ZIC2 gene ).

In descending order of severity, the main facial features are: ciclopía, proboscis, premaxillary agenesis, cleft lip or palate medium cleft or bilateral coloboma, dysplasia retinal, choanal stenosis, stenosis of the sinus piriformis, hypotelorism, single central incisor or normal even face . Serious forms (especially in the case of a chromosomal abnormality) are usually fatal, and mortality is correlated with the severity of the brain malformation and associated defects. In children who survive, a broad record of associated manifestations has been described: developmental delay, hydrocephalus , motor disturbances, feeding difficulties, oromotor dysfunction,epilepsy and hypothalamic dysfunction. Endocrine disorders due to pituitary defects, such as central diabetes insipidus, are common .


The etiology is very heterogeneous: from chromosomal abnormalities (such as trisomy 13), known syndrome ( Smith-Lemli-Opitz syndrome, CHARGE syndrome) to environmental factors (maternal diabetes or hypocholesterolemia during pregnancy ). At least 14 genes are involved in non-syndromic non-chromosomal HPE: 4 important (SHH (7q36), ZIC2 (13q32), SIX3 (2p21), TGIF (18p11)) and 10 minor (PTCH1 (9q22), GLI2 (2q14) , FOXH1 (8q24), TDGF1 (3p21), DISP1 (1q42), NODAL (10q22), FGF8 (10q24), GAS1 (9q21), DLL1 (6q27), and CDON (11q23-q24)).

Diagnostic methods

Molecular analysis of the 4 major genes is routinely performed with a mutation detection rate of 25%. Array-CGH (comparative genomic hybridization) analysis shows 22% micro-rearrangements in HPE. However, the genetic complexity underlying HPE remains to be clarified. The majority of severe cases are detected by systematic ultrasound and magnetic resonance imaging (MRI) during pregnancy. Later the diagnosis is based on clinical features.

Differential diagnosis

Differential diagnosis includes anencephaly , severe congenital hydrocephalus , Walker-Warburg syndrome , large interhemispheric cyst, otocephaly, and other midline defects.

Prenatal diagnosis

Due to high clinical variability, prenatal diagnosis is based on ultrasound and MRI rather than molecular diagnosis, and may be useful in mothers with diabetes and those with a family history of HPE.

Genetic advice

Genetic counseling is especially complex in HPE.

Management and treatment

Treatment is symptomatic and supportive and requires a multidisciplinary approach.


The prognosis depends on the severity and associated complications.


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