Note the fleshy proboscis above the partially fused eye. Normally, each egg and sperm cell contains 23 chromosomes. The majority of HPE cases are sporadic in nature, resulting from exposure to teratogens or de novo genetic mutations; however, familial cases of HPE are also well documented. Approximately one-half of all cases of holoprosencephaly have a chromosomal cause. Genetic Instabilities and Neurological Diseases (Second Edition), Encyclopedia of Infant and Early Childhood Development, Swaiman's Pediatric Neurology (Sixth Edition), Ching-Fang Chang, ... Samantha A. Brugmann, in, Principles of Developmental Genetics (Second Edition), Roessler et al., 1996; Belloni et al., 1996, Matsunaga and Shiota, 1977; Edison and Muenke, 2003; Leoncini et al., 2008, Solomon et al., 1993; Geng and Oliver, 2009, Muenke and Cohen, 2000; Muenke and Beachy, 2000; Krauss, 2007; Roessler et al., 2009a, Wannasilp et al., 2011; Roessler et al., 2005; 2003, Bertolino et al., 1995; Wotton et al., 1999, Roessler et al., 2008; McKean and Niswander, 2012, Inhibits 7-dehydrocholesterol conversion to cholesterol. HPE is associated with structural abnormalities of the midface. Developmental disability affects nearly all patients with HPE. Disruptions within the Shh locus or in these receptors and co-factors disrupt the formation of the prechordal plate, which subsequently causes defects in axial patterning and forebrain defects (Warr et al., 2008). The first-trimester ultrasound can detect alobar HPE but may be much less sensitive in detecting milder cases. Holoprosencephaly (HPE) is a term that was first used in 1963 to describe a spectrum of malformations that have failure of the proper formation of midline structures of the forebrain [94]. Depending upon whether the child can manage the smaller opening and associated airway problems, some cases may necessitate a tracheostomy to reestablish the airway. These loci and genes represent signaling pathways that play an essential role in forebrain and facial development. An abnormal development of the forebrain, holoprosencephaly, ... Trisomy 13 is the third most common autosomal trisomy at birth, with Trisomy 21, followed by Trisomy 18, occurring more frequently. The degree of motor complications (hypotonia evolving into spasticity and dystonia) and developmental dysfunction is similar to that seen in lobar HPE. Terms of Use. Chromosomal microarray has a higher yield in detecting chromosomal deletions, duplications, and unbalanced rearrangements and is the preferred chromosomal test in fetuses and newborns suspected of having HPE. While Both autopsy and 7.0T postmortem MRI examinations were performed. Screening for other endocrine abnormalities should be considered, including assays of cortisol, thyroid-stimulating hormone, free thyroxine, and insulin-like growth factor-1 (IGF-1). Variants in the SHH gene itself are the most commonly detected mutations in a sample of live-born HPE patients (Roessler et al., 1996; 1997); however, a significant number of HPE cases are associated with receptors and modifiers of the pathway. Various deletions or duplications of chromosomal regions have also been associated with HPE. The most convincingly related environmental factor is maternal diabetes although other factors, including cholesterol metabolism and cholesterol-lowering drugs, are under investigation as possible contributors. We use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies. For example, PTCH is a receptor for SHH, and GLI2 is a mediator of SHH target gene transcription. The union of these cells creates 23 pairs, or 46 total chromosomes, half from the mother and half from the father. As mentioned earlier in this chapter, the midface develops from the FNP. TGIF1 interacts with Transforming Growth Factor (TGF) β-activated Smad proteins (Bertolino et al., 1995; Wotton et al., 1999). A subsequent report confirms that partial loss of ZIC2 activity leads to a similar malformation in mice [12, 96]. Trisomy 13 (Patau) syndrome and trisomy 18 (Edwards) syndrome are associated with holoprosencephaly. Mutations in TGIF limit its regulation of Nodal and thus result in inappropriate levels of Shh activity in the forebrain (Taniguchi et al., 2012). The nose can be either absent or represented by a tubular proboscis (or two such structures), sometimes even located above the eye (see Figure 13). Approximately half of the children with HPE have epilepsy, and the likelihood of developing seizures does not correlate with the severity of the brain malformation. In its most severe and usually lethal form, cyclopia with the presence of a single midline eye and a proboscis (rudimentary single-nostril nose) above the eye can be present. Trisomy 18 syndrome is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in cells of the body. Although they can exist as isolated anomalies unrelated to HPE, arhinencephaly and agenesis of the septum pellucidum also belong to the HPE spectrum. Maternal diabetes is an environmental cause of HPE. Genetic HPE is associated with four genes and has been linked to seven additional chromosomal loci. The risk of reoccurrence is small in most families. Those that present to a clinician typically have hypotelorism (narrowed midface with close set eyes), a midline cleft lip and/or palate with a small to nonexistent central strut of the nose (columella). Environmental influences link the SHH signaling network with hypocholesterolemia. Neurologically, HPE is classified by aberrant cleavage of the embryonic forebrain. Evolving Medical and Surgical Management of Infants with Trisomy 18. Feeding problems and swallowing dysfunction are common in children with HPE and are correlated with the severity of the brain malformation. Meckel's syndrome is an autosomal recessive condition. The phenotypes associated with all forms of HPE are tightly restricted to the growth and development of forebrain neuroectoderm and the facial midline. The FNP is unique among the facial prominences as it is the only singular, midline prominence and its growth and development is tightly coupled to that of the developing forebrain. In mice, defects in the Shh co-receptor Smoothened (Smo), which are associated with the response component of the Shh signaling pathway, result in neuroectoderm that is not competent to respond to the Shh signal and lead to HPE (Fuccillo et al., 2004). Other examples of trisomy include trisomy 18 and trisomy 13. The majority of HPE cases are sporadic, although families with both autosomal dominant and autosomal recessive HPE have been described. Because of the influence of the brain on surrounding structures, especially the cranial base, primary defects of the forebrain often manifest externally as facial malformations, typically a reduction in tissue of the frontonasal process. Surgical intervention/treatment: Clinically, holoprosencephaly occurs in a wide spectrum. Evidence-based information on Holoprosencephaly from hundreds of trustworthy sources for health and social care. Isochromosome 18q is a rare cytogenetic abnormality. 26-2). ©1996-2021 MedicineNet, Inc. All rights reserved. It is one of the most common congenital malformations, occurring in 1:250 fetuses and approximately 1:10,000 to 1:16,000 live births (Matsunaga and Shiota, 1977; Edison and Muenke, 2003; Leoncini et al., 2008). Multiple environmental and genetic factors have been implicated in causing HPE. Schematic Representation of the Holoprosencephaly Spectrum. Other midline anomalies, such as agenesis of the corpus callosum, absence of the septum pellucidum, and hydrocephalus with communication of the lateral ventricles, are sometimes misdiagnosed prenatally as HPE (Fig. Impaired transverse cleavage manifests as a failure to separate the telencephalon from diencephalon. HPE's cause in any individual family may be unknown. The sine qua non of HPE is incomplete cleavage of midline structures involving the telencephalon and diencephalon. By Heather. Edwards' syndrome, also known as trisomy 18, is a rare but serious condition. For example, maternal hypocholesterolemia has been implicated in HPE. Not all individuals with holoprosencephaly (HPE) are affected to the same degree, even in families where more than one individual has this predisposition. In one series of 104 HPE patients, the mean age at the time of study was 4 years, and 15% were between 10 and 19 years of age. 2012), and is often associated with malformations of midline structures. We were thrilled at how easily and quickly I was able to get pregnant as I was 35 years of age. Genetic counseling and genetic testing, such as amniocentesis, is usually offered during a pregnancy if holoprosencephaly is detected. However, with the improved understanding of phenotypes and genetics of HPE, there is a growing appreciation that HPE is a multi-factorial disease spectrum that requires not only a genetic mutation within a certain locus, but also an interaction of this mutation with factors within the patients genetic background and perhaps environmental insult (Roessler and Muenke, 2010). SHH is expressed early in development in the ventral forebrain and is critical for ventral patterning of the developing neural tube. The alternative molecular mechanism for Zic2-mediated HPE hypothesizes that Zic2 functions within the embryonic organizer at mid-gastrulation (Warr et al., 2008). The oft-quoted statement “the face predicts the brain” refers to the observation that the degree of facial malformation frequently reflects the degree of brain malformation. Cyclopia in a newborn. There also appears to be a slight female preponderance in some case series. HPE is classically associated with several chromosome imbalance, including trisomy 13, which is the most common etiology. In addition to any genetic susceptibility, however, environmental factors are thought to play a role in determining how the condition manifests in a given individual. Symptoms of the following disorders may be similar to those of Trisomy 13 Syndrome. Copyright © 2021 Elsevier B.V. or its licensors or contributors. In this article, we illustrate forebrain midline development as revealed by the factors implicated in HPE in experimental organisms and humans. When death did occur, causes included brainstem dysfunction, pneumonia, dehydration from diabetes insipidus, and rarely, intractable seizures. The leading cause of holoprosencephaly is a chromosomal disorder, comprising 40% to 50% of all documented cases. Any child with holoprosencephaly deserves a full genetic evaluation so that appropriate genetic counseling and recurrence risks can be given to the families. Facial anomalies extend from hypotelorism with a single upper central incisor, median cleft lip and palate (premaxillary agenesis), hypoplastic nose with single nostril (cebocephaly) to cyclopia (with synophthalmia and proboscis). Approximately 30% to 50% of live births with HPE have chromosomal abnormalities, but this is likely an overestimation based on underreporting of milder cases. HPE infants tend to have low muscle tone, poor feeding, and failure to thrive. The spectrum of holoprosencephaly (HPE). Evidence for this malformation being a subtype of HPE is bolstered by mutation of the ZIC2 gene, which has been implicated in causing the classic forms of HPE. Midline defects of the upper lip can also be attributed to holoprosencephaly (see Figure 12(c)). The presence of large dorsal cysts, hydrocephalus, or midline craniofacial defects may provide clues that eventually lead to the recognition of the associated HPE. Holoprosencephaly (HPE) is a birth defect in which the telencephalic vesicles emerging from the forebrain during the 5th and 6th week of development remains fused on the midline. The mildly affected person in the lower right corner has HPE manifestations limited to a single central incisor. Although the majority of HPE cases are of an unknown etiology, some genetic progress has been made in the past decade. Harm-Gerd K. Blaas, in Obstetric Imaging: Fetal Diagnosis and Care (Second Edition), 2018, HPE is a heterogeneous central nervous system (CNS) anomaly that results from a primary defect in induction and patterning of the rostral neural tube (basal forebrain), leading to varying degrees of incomplete separation of the cerebral hemispheres. Motor difficulties and dystonia may be partially responsive to trihexyphenidyl. 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