Holoprosencephaly !

Malformation

The forebrain does not divide properly into two halves; the midline of the face is affected too, from a single eye to a single central incisor.

Updated 2026-11-01

See it in 3D: Lateral ventricles · Thalamus · Corpus callosum · Frontal lobe

What it is

Holoprosencephaly is failure of the prosencephalon to divide into two cerebral hemispheres. It is a spectrum: the alobar form has a single ventricle and severe facial defects; mild forms show only subtle facial features. It is the classic example of failed midline SHH signalling and of 'the face predicting the brain'.

Key facts

Types, from most to least severe: alobar, semilobar, lobar and middle interhemispheric variant.
Frequency: about 1 in 10,000 newborns; far more common in early miscarriages.
Genes: SHH, ZIC2, SIX3 and TGIF1 account for about a quarter of nonsyndromic cases.
Syndromic causes: trisomy 13 and Smith–Lemli–Opitz syndrome (a cholesterol defect).
Associated teratogens: maternal diabetes and alcohol.
Face: cyclopia with a proboscis, hypotelorism, median cleft lip, single central incisor.

Embryological cause

Weeks 4–5: the prosencephalon must divide into telencephalon and diencephalon, and the telencephalon into two hemispheres.
The prechordal plate secretes SHH, which sets up the ventral midline of the forebrain and splits the single eye field in two.
If SHH fails (mutation, low cholesterol that blocks its action, alcohol), the midline does not form: fused hemispheres and a single ventricle.
The same midline deficit affects the frontonasal prominence: close-set or fused eyes, defective nose and median lip.

Markers

SHH
ZIC2
SIX3
TGIF1
PTCH1
GLI2

How it presents

Alobar: single ventricle, fused thalami, cyclopia or ethmocephaly; usually lethal.
Less severe forms: microcephaly, hypotelorism, median cleft lip and palate, flat nose.
Developmental delay and intellectual disability in most.
Pituitary dysfunction, especially diabetes insipidus; seizures, feeding and temperature-control problems.
Microform: single upper central incisor, sometimes with no visible brain findings.

Diagnosis

Prenatal ultrasound: single ventricle, absent midline, facial findings.
Brain MRI to classify the type.
Karyotype or microarray (trisomy 13) and genetic testing; sterols if Smith–Lemli–Opitz is suspected.

Test yourself

Think of the answer, then tap the question to see it.

Which prechordal plate signal typically fails in holoprosencephaly?

Sonic hedgehog (SHH), which sets up the forebrain midline.

Which trisomy is classically associated with holoprosencephaly?

Trisomy 13 (Patau syndrome).

Why can Smith–Lemli–Opitz syndrome cause holoprosencephaly?

Because of a lack of cholesterol, which SHH signalling needs to work.

What minimal finding may be the only clue to a mild form?

A single upper central incisor.

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See it in 3D

The structures of Durgical's 3D anatomy where it is found.

← All of embryology

Educational content on embryonic development; not a guide to prenatal diagnosis or to medicines in pregnancy and no substitute for a health professional's advice. No doses are given.

Sources: Nonsyndromic holoprosencephaly: MedlinePlus Genetics (U.S. National Library of Medicine, 2024); Langman's Medical Embryology, 13th ed., ch. 18: Central Nervous System (Wolters Kluwer, 2015).

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Representative model, for educational purposes only.