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Holoprosencephaly Overview.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2000 Dec 27 [updated 2013 Aug 29].

Author information

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
Pediatric Neurologist and Clinical Geneticist Consultant, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
Departments of Pediatrics and Neurology, George Washington University of the Health Sciences, Attending, Children's National Medical Center, Washington, DC
Chief, Medical Genetics Branch, Director, Medical Genetics Residency and Fellowship, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland



Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.


Imaging of the brain by CT scan or (preferably) MRI confirms the diagnosis of HPE, may define the anatomic subtype, and identifies associated CNS anomalies. Approximately 25%-50% of individuals with HPE have a numeric or structural chromosome abnormality detectable by chromosome analysis. Approximately 18%-25% of individuals with monogenic HPE have a recognizable syndrome and the remainder have nonsyndromic HPE. Molecular genetic testing is possible for many of the genes associated with nonsyndromic HPE. Approximately 10% of individuals with HPE have defects in cholesterol biosynthesis.


HPE can result from environmental causes; an inherited or de novo chromosome abnormality; an inherited monogenic syndromic disorder; an inherited or de novo pathogenic variant for a gene associated with nonsyndromic autosomal dominant HPE; copy number variations (CNVs); or unknown causes. Genetic counseling and risk assessment depend on determination of the specific cause of HPE in an individual.


Treatment of manifestations: Treatment by a multidisciplinary team when possible; hormone replacement therapy for pituitary dysfunction; antiepileptic drugs for seizures; gastrostomy tube/Nissen fundoplication for feeding difficulties/gastroesophageal reflux; special feeding devices and surgical repair of cleft lip and/or palate; ventriculo-peritoneal shunt placement for hydrocephalus; parental support and counseling. Prevention of secondary complications: Prompt evaluation of children with hormonal disturbances during times of stress (e.g., illness, surgery); attention to fluid and electrolyte management during surgery. Surveillance: During health maintenance evaluations, measurement of height, weight, and head circumference and evaluation for endocrine deficiencies.

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