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    Drugs & Diseases>Pediatrics: Genetics and Metabolic Disease

    Holoprosencephaly

    Updated: Mar 14, 2024
    • Author: Nusrat Ahsan, MD; Chief Editor: Luis O Rohena, MD, PhD, 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, 5, 6]

    Classification of holoprosencephaly

    Holoprosencephaly has four subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly). [2, 7]

    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, with posterior separation, while lobar holoprosencephaly is characterized by fusion of only the most ventral frontal neocortex.

    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. [8] The term septopreoptic holoprosencephaly has been used to describe a mild subtype of lobar holoprosencephaly with nonseparation restricted to the septal or preoptic region. [9]

    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).

    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. [32, 33, 34, 35, 36]  However, many genes besides SHH have also been associated with holoprosencephaly. [37]

    Using a collection of over 44,000 human conceptuses from Kyoto University, in Japan, Abe et al reported that spontaneous abortions occurred in about 30% of women with a conceptus suffering from holoprosencephaly, approximately twice the rate found in pregnancies in general. The study also indicated that an association exists between bleeding in pregnancy and holoprosencephaly, with such bleeding experienced by 70% of women with a holoprosencephalic conceptus. [38]

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    Etiology

    Environmental causes

    Maternal diabetes mellitus is a known risk factor. [39] Maternal use of alcohol, retinoic acid, aspirin, misoprostol, and cholesterol-lowering agents has been implicated, as has maternal smoking. [40, 41, 42, 43, 44, 45, 46, 47, 48, 49]

    A study by Addissie et al indicated that during pregnancy, risk factors for holoprosencephaly include maternal pregestational diabetes, greater consumption of alcohol (adjusted odds ratio [aOR] = 1.73), and “exposure to consumer products such as aerosols or sprays,” including hair sprays (aOR = 2.46). Significant gene-environment interactions were found to be associated with the consumption of cheese and espresso. [50]

    A report by Taruscio and Mantovani suggests that certain pollutants in food may, because of a link to pregestational diabetes, raise the likelihood of holoprosencephaly in susceptible embryos. The report mentions, for example, that polychlorinated biphenyls (PCBs) remain significant nutritional contaminants despite bans on the compounds instituted in various countries decades ago. The authors point to human studies in which PCB serum levels have been linked to abnormal glucose metabolism and greater diabetes risk. Taruscio and Mantovani also mention inorganic arsenic, a food pollutant that has been associated with type 2 diabetes mellitus, and per- and polyfluoroalkyl substances (PFASs), which research suggests can act at the hepatic level to promote glucose intolerance. [51]

    Heritable causes

    Holoprosencephaly is associated with chromosomal abnormalities such as trisomy 13, trisomy 18, and triploidy. [52, 53, 54, 55, 56, 57] It has been reported with Down syndrome, but the association is thought to be coincidental. [58, 59]  Many other chromosomal abnormalities have been reported as a cause. [60, 61, 22]

    Many syndromes are associated with holoprosencephaly, including Smith-Lemli-Opitz syndrome, Meckel-Gruber syndrome, Pallister-Hall syndrome, caudal dysgenesis, and Aicardi syndrome. [62, 63, 64, 65, 66, 67, 68, 69, 70]

    Mutations in various genes have been reported in nonsyndromic holoprosencephaly, including in SHH, ZIC2, SIX3,TGIF, and FGFR1, and are inherited in an autosomal-dominant fashion. Autosomal-recessive and X-linked patterns have also been described. [71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81]

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    Epidemiology

    United States statistics

    Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births. [30, 82, 83] This is likely to be an underestimation.

    International statistics

    Holoprosencephaly occurs worldwide. [84, 85, 86, 87, 88, 89] 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. [90]

    Racial differences in incidence

    Ethnic variations have been reported. [83, 86] However, these may be due to lower prenatal detection rates in certain groups and lower rates of pregnancy terminations. [91]

    Sexual differences in incidence

    Holoprosencephaly has been reported to be more common in females than in males. [87, 92]   [93]

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    Prognosis

    The prognosis of holoprosencephaly depends on the severity of the malformation. Patients with milder forms of holoprosencephaly have variable life expectancies, with survival into adulthood possible; however, they may experience behavioral disorders and intellectual disability. [22, 94]

    The recurrence risk is high if parental carrier state is established, although its exact quantification may not be possible. [95] 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. [96]

    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. [85]  Persons with milder malformations usually survive beyond infancy. [97]

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