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    Drugs & Diseases > Pediatrics: Genetics and Metabolic Disease

    Holoprosencephaly

    Updated: Dec 28, 2020
    • Author: Nusrat Ahsan, MD; Chief Editor: Luis O Rohena, MD, MS, 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 of holoprosencephaly

    Holoprosencephaly has four 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, 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. [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 maxillary central incisor, median cleft lip/palate, hypotelorism, and microcephaly. [8, 9, 10]

    Microform of holoprosencephaly is a term assigned to the mildest type. Patients with this condition have craniofacial anomalies, including choanal stenosis, a flat or sharp nasal bridge, hypotelorism, or a single maxillary central incisor, but no cerebral abnormalities suggestive of holoprosencephaly on neuroimaging. [11]  They may have neurodevelopmental issues. [12, 13, 14, 15, 16]

    Symptoms of holoprosencephaly

    Epilepsy is common, occurring in about 40% of patients with holoprosencephaly. [17, 18, 19, 20] Patients often have feeding difficulties and resultant malnutrition. [21] Pituitary dysfunction is also common. [22] Other problems include temperature dysregulation, disturbed sleep cycle, brainstem dysfunction, and recurrent respiratory tract infections. [19, 23] The severity of developmental delay depends on the severity of the brain malformation. Movement disorders include spasticity, hypotonia, choreoathetosis, and dystonia. [24]

    Workup

    Prenatal diagnosis options include karyotype analysis, microarray testing, cranial ultrasonography, and magnetic resonance imaging (MRI). It is possible to arrive at an etiologic diagnosis prenatally in many cases. [25, 26, 27] Karyotype is abnormal in about a third of holoprosencephaly cases, with trisomy 13 being the most common such anomaly. [28, 29]

    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. [30, 31, 32, 33, 34]  However, many genes besides SHH have also been associated with holoprosencephaly. [35]

    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. [36]

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    Etiology

    Environmental causes

    Maternal diabetes mellitus is a known risk factor. [37] Maternal use of alcohol, retinoic acid, aspirin, misoprostol, and cholesterol-lowering agents has been implicated, as has maternal smoking. [38, 39, 40, 41, 42, 43, 44, 45, 46, 47]

    Heritable causes

    Holoprosencephaly is associated with chromosomal abnormalities such as trisomy 13, trisomy 18, and triploidy. [48, 49, 50, 51, 52, 53] It has been reported with Down syndrome, but the association is thought to be coincidental. [54, 55]  Many other chromosomal abnormalities have been reported as a cause. [56, 57, 20]

    Many syndromes are associated with holoprosencephaly, including Smith-Lemli-Opitz syndrome, Meckel-Gruber syndrome, Pallister-Hall syndrome, caudal dysgenesis, and Aicardi syndrome. [58, 59, 60, 61, 62, 63, 64, 65, 66]

    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. [67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77]

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    Epidemiology

    United States statistics

    Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births. [28, 78, 79] This is likely to be an underestimation.

    International statistics

    Holoprosencephaly occurs worldwide. [80, 81, 82, 83, 84, 85] 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. [86]

    Racial differences in incidence

    Ethnic variations have been reported. [79, 82] However, these may be due to lower prenatal detection rates in certain groups and lower rates of pregnancy terminations. [87]

    Sexual differences in incidence

    Holoprosencephaly has been reported to be more common in females than in males. [83, 88]   [89]

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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. [20, 90]

    The recurrence risk is high if parental carrier state is established, although its exact quantification may not be possible. [91] 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. [92]

    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. [81]  Persons with milder malformations usually survive beyond infancy. [93]

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