Holoprosencephaly

Updated: Sep 07, 2017
  • Author: Jay Desai, MD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Overview

Practice Essentials

Holoprosencephaly is a structural malformation of the brain that results from complete or incomplete nonseparation of the prosencephalon (forebrain). [1]

Classification

Holoprosencephaly is categorized into 4 subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly). [2, 3]

Alobar holoprosencephaly is the most severe form with no separation of the cerebral hemispheres. There is usually a single ventricle. The corpus callosum and interhemispheric fissure are absent, and the thalami are unseparated.

In semilobar holoprosencephaly, the cerebral hemispheres separate posteriorly but not anteriorly.

Lobar holoprosencephaly is characterized by almost complete separation of the cerebral hemispheres except at the frontal lobes.

A middle interhemispheric fusion variant (also known as syntelencephaly) 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. [4] The term septopreoptic holoprosencephaly has been used to describe a mild subtype of lobar holoprosencephaly with nonseparation restricted to the septal or preoptic region. [5] However, it must be emphasized that holoprosencephaly represents a continuous spectrum of malformations based on the severity of lack of cleavage.

Most cases of holoprosencephaly are characterized by various craniofacial malformations . The most severe craniofacial deformity is cyclopia with a single or partially divided eye in a single orbit with a proboscis (tubular appendage) above the eye and absent nose (arhinia). Ethmocephaly is characterized by hypotelorism with a proboscis between the eyes. Cebocephaly represents hypoteloric eyes with a single nostril nose. Other malformations include a single central maxillary incisor, midline cleft lip and palate, bilateral cleft lip and palate with intermaxillary rudiment, flat nose, absent nasal bridge, microphthalmia, absence of lateral philtral ridges, and absence of the superior lingual frenulum. [6, 7, 8, 9, 10]

Microform of holoprosencephaly is a term reserved for the relatives of probands who have craniofacial anomalies such as hypotelorism, sharply angular nose, thin nasal bridge, congenital nasal pyriform aperture stenosis, bifid uvula, and single central maxillary incisor but no cerebral abnormalities suggestive of holoprosencephaly on neuroimaging. They may have microcephaly, developmental delay, and attention deficit hyperactivity disorder. [11, 12, 13, 14, 15]

Workup

Prenatal diagnosis options include karyotype, testing for known gene mutations, ultrasonography, and magnetic resonance imaging (MRI). Microarray testing on fetal blood has also been used. It is possible to arrive at an etiologic diagnosis prenatally in most cases. [16, 17, 18] Karyotype has been reported to be abnormal in 24-41% of cases of holoprosencephaly, with trisomy 13 being most common. [19, 20]

Management

Medical care is necessary for problems commonly associated with holoprosencephaly, such as seizures, spasticity, choreoathetosis, dystonia, pituitary dysfunction, and gastroesophageal reflux.

Hydrocephalus, if present, requires neurosurgical intervention with a ventriculoperitoneal shunt. Gastrostomy tube and Nissen fundoplication may be required for feeding difficulties, poor weight gain, and gastroesophageal reflux.

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Anatomy

During early human brain development, the prosencephalon (forebrain) divides into telencephalon and diencephalon. Telencephalon differentiates into cerebral hemispheres and subcortical structures such as basal ganglia, amygdala, and hippocampal formation. Diencephalon gives rise to the thalamus, hypothalamus, and related structures.

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Pathophysiology

An interplay of various 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]  More than 10 other genes besides SHH have also been associated with holoprosencephaly. For example, in a study by Kakar et al, a homozygous truncating mutation in the SCL/TAL1 interrupting locus (STIL) gene was found to be associated with lobar holoprosencephaly. [26]

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Etiology

Environmental causes

Maternal diabetes mellitus is a known risk factor. [27] Maternal use of alcohol, retinoic acid, diphenylhydantoin, aspirin, misoprostol, methotrexate, and cholesterol-lowering agents has been implicated but not proven to be causative. [28, 29, 30, 31, 32, 33, 34, 35, 36]

Heritable causes

Holoprosencephaly is associated with chromosomal abnormalities leading to aneuploidy, such as trisomy 13, trisomy 18, and triploidy. [37, 38, 39, 40, 41, 42] It has been reported with Down syndrome, but the association is thought to be coincidental. [43, 44]

Many other chromosomal abnormalities have been reported as a cause, particularly of 13q. [45, 46, 47]

Many syndromes due to genetic mutations are associated with holoprosencephaly, including Smith-Lemli-Opitz syndrome, Genoa syndrome, Meckel-Gruber syndrome, Lambotte syndrome, Pallister-Hall syndrome, Steinfeld syndrome, caudal dysgenesis, Aicardi syndrome, and pseudotrisomy 13 syndrome, and may be inherited in an autosomal-dominant, autosomal-recessive, X-linked–dominant, or unknown fashion. [48, 49, 50, 51, 52, 53, 54, 55, 56]

Mutations in various genes have been reported in nonsyndromic holoprosencephaly, including SHH, ZIC2, SIX3, and TGIF, and are inherited in an autosomal-dominant fashion. [57, 58, 59, 60, 61, 62, 63, 64, 65]

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Epidemiology

United States statistics

Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births. [19, 66, 67] This is likely to be an underestimation owing to recognition of milder cases later in life.

International statistics

Holoprosencephaly occurs worldwide. [68, 69, 70, 71, 72, 73] Reported frequency rates of holoprosencephaly have wide variations depending on the study design. The rates are higher if terminations of pregnancy are included. 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. [74]

Racial differences in incidence

Ethnic variations have been reported, with a higher birth prevalence among Far East Asians and Filipinos than in whites in Hawaii and among Pakistanis in Midlands. [67, 70] However, these may be due to lower prenatal detection rates in these groups and hence lower rates of pregnancy terminations. [75]

Sexual differences in incidence

Holoprosencephaly has been reported to be more common in females than in males. [71, 76]  According to a study by Michalski et al, drawing data from the National Birth Defects Prevention Study (1997-2009), the male-to-female ratio for holoprosencephaly is 1:1.56. [77]

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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. [78] The recurrence risk is usually low if the genetic abnormalities occur de novo in the proband, although the possibility of germline mosaicism should be kept in mind. [79]

Complications

Possible complications of holoprosencephaly include those due to ventriculoperitoneal shunt malfunction and aspiration pneumonia.

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. [69] Most persons with milder malformations survive beyond infancy. Life expectancy is poorest among those with syndromal and alobar holoprosencephaly. [20]

A retrospective study by Kaliaperumal et al found that among patients with alobar holoprosencephaly, the early death rate was 95%, while in those with lobar and semilobar holoprosencephaly, the overall survival rate beyond infancy was 56%. [80]

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