Holoprosencephaly

Updated: Nov 10, 2017
  • Author: Nusrat Ahsan, MD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Overview

Practice Essentials

Holoprosencephaly is a congenital Induction disorder of the brain occurring at 3-6 weeks' gestation, with failed segmentation of the neural tube. This leads to incomplete separation of the prosencephalon (forebrain). [1, 2, 3, 4]

Classification

Holoprosencephaly has 4 subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly). [2, 5]

Alobar holoprosencephaly is the most severe form, with no separation of the cerebral hemispheres; it is characterized by a single ventricle, absence of the corpus callosum and interhemispheric fissure, and fused thalami.

In semilobar holoprosencephaly, the cerebral hemispheres are fused anteriorly, while lobar holoprosencephaly is characterized by fusion of the cerebral hemispheres at the frontal lobes.

A middle interhemispheric fusion variant results from nonseparation of posterior frontal and parietal lobes.

Some researchers have attempted to incorporate degree of nonseparation of subcortical structures into the classification system. [6] The term septopreoptic holoprosencephaly has been used to describe a mild subtype of lobar holoprosencephaly with nonseparation restricted to the septal or preoptic region. [7]

Most cases of holoprosencephaly are characterized by various midline craniofacial malformations. The most severe craniofacial deformity is cyclopia, with a single or partially divided eye existing in a single orbit, along with a proboscis (tubular appendage) above the eye and an absent nose (arhinia). Several less severe midline malformations have been described, such as a single central maxillary incisor. [8, 9, 10]

Microform of holoprosencephaly is a term assigned to the relatives of probands who have minor craniofacial anomalies but no cerebral abnormalities suggestive of holoprosencephaly on neuroimaging. They may have neurodevelopmental issues. [11, 12, 13, 14, 15]

Workup

Prenatal diagnosis options include karyotype analysis, microarray testing, ultrasonography, and magnetic resonance imaging (MRI). It is possible to arrive at an etiologic diagnosis prenatally in many cases. [16, 17, 18] Karyotype is abnormal in about a third of holoprosencephaly cases, with trisomy 13 being the most common such anomaly. [19, 20]

Management

Medical care is necessary for problems commonly associated with holoprosencephaly, such as seizures, movement disorders, pituitary dysfunction, failure to thrive, feeding issues, and gastroesophageal reflux. Neurosurgical intervention is needed if hydrocephalus is present.

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Anatomy

During early human brain development, the forebrain divides into telencephalon and diencephalon. Telencephalon develops into cerebral hemispheres and subcortical structures such as basal ganglia, amygdala, and hippocampus. Diencephalon gives rise to the thalamus and hypothalamus.

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Pathophysiology

A combination of genetic and environmental factors is thought to be responsible for the pathogenesis of holoprosencephaly. Defective sterol metabolism leading to abnormalities in the sonic hedgehog (SHH) signaling pathway may have a role in its causation. [21, 22, 23, 24, 25]  However, many genes besides SHH have also been associated with holoprosencephaly. [26]

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Etiology

Environmental causes

Maternal diabetes mellitus is a known risk factor. [27] Maternal use of alcohol, retinoic acid, aspirin, misoprostol, and cholesterol-lowering agents has been implicated, as has maternal smoking. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37]

Heritable causes

Holoprosencephaly is associated with chromosomal abnormalities such as trisomy 13, trisomy 18, and triploidy. [38, 39, 40, 41, 42, 43] It has been reported with Down syndrome, but the association is thought to be coincidental. [44, 45]  Many other chromosomal abnormalities have been reported as a cause. [46, 47, 48]

Many syndromes are associated with holoprosencephaly, including Smith-Lemli-Opitz syndrome, Meckel-Gruber syndrome, Pallister-Hall syndrome, caudal dysgenesis, and Aicardi syndrome. [49, 50, 51, 52, 53, 54, 55, 56, 57]

Mutations in various genes have been reported in nonsyndromic holoprosencephaly, including SHH, ZIC2, SIX3, and TGIF, and are inherited in an autosomal-dominant fashion. Autosomal-recessive and X-linked patterns have also been described. [58, 59, 60, 61, 62, 63, 64, 65, 66, 67]

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Epidemiology

United States statistics

Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births. [19, 68, 69] This is likely to be an underestimation.

International statistics

Holoprosencephaly occurs worldwide. [70, 71, 72, 73, 74, 75] The frequency among all pregnancies has been reported to be 1 in 250 based on a study on embryos obtained through induced abortion, making this the most common human forebrain malformation. [76]

Racial differences in incidence

Ethnic variations have been reported. [69, 72] However, these may be due to lower prenatal detection rates in certain groups and lower rates of pregnancy terminations. [77]

Sexual differences in incidence

Holoprosencephaly has been reported to be more common in females than in males. [73, 78]   [79]

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Prognosis

The prognosis of holoprosencephaly depends on the severity of the malformation.

The recurrence risk is high if parental carrier state is established, although its exact quantification may not be possible. [80] The recurrence risk is usually low if the genetic abnormalities occur de novo in the proband, although there is always the possibility of germline mosaicism. [81]

Complications

Possible complications of holoprosencephaly include those due to secondary manifestations such as seizures and ventriculoperitoneal shunt malfunction.

Mortality/morbidity

Mortality and morbidity associated with holoprosencephaly depend on the severity of the malformations. Most affected pregnancies result in miscarriage. Among live births, those with the severe type often die within days of birth. [71]  Persons with milder malformations usually survive beyond infancy. [82]

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