This leads to incomplete separation of the prosencephalon (forebrain). The result is a single-lobed brain structure and severe skull and facial defects. 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). Am J Med Genet C Semin Med Genet 2010;154C(1):133–141. Prenatal testing for HPE risk genes is possible by means of amniocentesis or chorionic villus sampling. 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. Figure 6. Middle interhemispheric fusion variant holoprosencephaly. Causes, Sign, and Symptom of Holoprosencephaly: Holoprosencephaly (HPE) is the most common developmental abnormality of the forebrain in humans. Surgical correction of the lip to decrease the oral and nasal opening is usually delayed until the child is strong enough to tolerate the surgery and its consequences. Jeffrey C. Posnick DMD, MD, in Orthognathic Surgery, 2014. HPE is graded according to the severity of the brain anomaly as alobar, semilobar, and lobar. The eye field begins as a single midline structure. Early death is typical for most cytogenetically abnormal children and those individuals with the most severe facial features (cyclopia or ethmocephaly). Johns Hopkins University, Baltimore, Md. Developmental delay is present in all individuals with the holoprosencephaly spectrum of CNS (central nervous system) anomalies. Severe facial anomalies such as cyclopia, ethmocephaly, and cebocephaly are always associated with severe, Inhibits 7-dehydrocholesterol conversion to cholesterol. Failure of this interaction results in compromised Shh expression in the ventral forebrain (Jeong et al., 2008). Midline defects of the upper lip can also be attributed to holoprosencephaly (see Figure 12(c)). Other malformations include arhinencephaly (absent olfactory bulbs and tracts), absent thalami, hydrocephalus and neural migration abnormalities. The alobar holoprosencephaly is the most severe type of the defect and the affected fetus are usually stillbirth, or die soon after birth, or during the first 6 months of life. 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. Stashinko EE, Clegg NJ, Kammann HA et al. Footnote: (a) The primary vesicles at 4 weeks (fetus). For children with cleft lip and/or palate, referral to a specialized cleft or craniofacial clinic is recommended. Finally, impaired horizontal cleavage manifests as a failure to form the olfactory bulbs and optic vesicles. Hydrocephalus can occur, and may result in macrocephaly, rather than the more commonly-observed microcephaly. I. Embryologic basis for brain malformation. Growth hormone deficiency and/or chromosome anomalies may in part be responsible for poor growth in some individuals. Am J Obstet Gynecol 2001;184(6):1256–1262. They may also have an underlying endocrine deficiency, requiring assessment and treatment. The gene tests, in conjunction with fetal MRI, have been found to be helpful in prenatal diagnosis and counseling in a series of pregnancies. Children with diabetes insipidus need careful monitoring of fluid and electrolyte intake. Gastrostomy tubes often are necessary to address the complex management issues of ensuring adequate calories related to feeding dysfunction and delivery of adequate free water necessary for management of diabetes insipidus. Extra craniofacial manifestations are common. Lobar Holoprosencephaly is the official diagnosis from Carsyn’s MRI. A series of facial anomalies are frequently associated, owing to the common origin of the embryonic forebrain and mid-face from the prechordal mesoderm, along with some other anomalies. Orioli IM, Castilla EE. Holoprosencephaly may also affect other systems in the body. Also, HPE is seen in Smith-Lemli-Opitz syndrome, which is due to a defect in 7-dehydrocholesterol reductase, the final enzyme in cholesterol synthesis. The hypothalamus and lentiform nuclei are normally separated; however, the caudate nuclei and the thalami remain incompletely separated. Other treatments can be instituted as appropriate. Solomon BD, Lacbawan F, Mercier S, Clegg NJ, Delgado MR, Rosenbaum K, Dubourg C, David V, Olney AH, Wehner LE, Hehr U, Bale S, Paulussen A, Smeets HJ, Hardisty E, Tylki-Szymanska A, Pronicka E, Clemens M, McPherson E, Hennekam RC, Hahn J, Stashinko E, Levey E, Wieczorek D, Roeder E, Schell-Apacik CC, Booth CW, Thomas RL, Kenwrick S, Keaton A, Balog JZ, Hadley D, Zhou N, Long R, Velez JI, Pineda-Alvarez DE, Odent S, Roessler E, Muenke M. Mutations in ZIC2 in Human Holoprosencephaly: description of a novel ZIC2-specific phenotype and comprehensive analysis of 157 individuals. Even earlier in development, disturbances in BMP levels, often caused by imbalances in BMP inhibitors, can influence early formation of the forebrain and lead to holoprosencephaly. A dorsal cyst may be seen. If seizures develop, the possibility of acute reactive seizures should be evaluated for and a serum sodium level checked. Am J Med Genet. One of the most common ways to diagnose HPE is with a catscan (CT) or magnetic resonance imaging (MRI). Motor dysfunction, including hypertonia and dystonia, is common and may require physical, pharmacologic, or surgical therapies. Copyright © 2021 Elsevier B.V. or its licensors or contributors. Children with HPE may experience a variety of medical and neurologic problems. As with all types of holoprosencephaly, it is a rare congenital brain malformation in which there is failure of complete separation of the two hemispheres and failure of transverse cleavage into diencephalon and telencephalon. Of these genes, the four most commonly affected (SHH, ZIC2, SIX3, and TGIF) account for only 25% of the cases of HPE with normal chromosomes and approximately 5% to 10% of all HPE patients (Roessler and Muenke, 2010). One hypothesis is that Zic2 functions within the Shh pathway. Onset of new neurologic findings or deterioration warrant evaluation for seizures and/or hydrocephalus and/or shunt malfunction. One in every ten thousand births is affective. A significant proportion develops hydrocephalus, with 60% of alobar and 8% of semilobar requiring a VP shunt. Ocular hypotelorism and midline cleft lip/palate. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. There is separation of the anterior frontal lobes, basal forebrain, and occipital lobes. More than 50% of children with semilobar or lobar holoprosencephaly were alive at 1 year of age 26). Foetuses who survive during intrauterine life are born with varying grades of brain and facial deformities. Figure 4. Trisomies of chromosomes 13 and 18 are commonly associated with holoprosencephaly. Thickening of feeds and upright positioning after feeding may be helpful to alleviate gastroesophageal reflux. Survivors may have hypotelorism, a flattened nasal bridge, median cleft lip and palate, or a single median maxillary central incisor. Specifically, signals from the forebrain are hypothesized to affect the proliferation/survival of neural crest-derived cranial mesenchyme within the FNP. Ethmocephaly: extremely closely spaced eyes but separate orbits with proboscis between the eyes, Cebocephaly: closely spaced eyes with single-nostril nose, Premaxillary agenesis with median cleft lip, closely spaced eyes, depressed nasal ridge, Relatively normal facial appearance (especially in persons with pathogenic variants in ZIC2). Severe facial anomalies such as cyclopia, ethmocephaly, and cebocephaly are always associated with severe holoprosencephaly, and they are incompatible with life. Depending upon whether the child can manage the smaller opening and associated airway problems, some cases may necessitate a tracheostomy to reestablish the airway. The cerebral hemispheres are separated (blue/thick arrows); the ventricles are misshapen as a result of absence of the septum pellucidum. MIM number: 236100. http://omim.org/entry/236100, Stashinko EE, Clegg NJ, Kammann HA et al. 2007;2:8. doi:10.1186/1750-1172-2-8. MRI also should be considered to evaluate for focal heterotopia. Occasionally, isolated neuronal heterotopias are seen, particularly in the middle interhemispheric variant. Abnormalities in the formation of the nose may also occur. Am J Med Genet. The categorization of HPE introduced by DeMyer and Zeman in 1963 and modified by DeMyer in 19778 is still generally accepted. SHH (sonic hedgehog) was the first identified HPE-associated mutated gene, and the SHH protein is a secreted intercellular signaling molecule involved in establishing cell fates at several points during development. In addition to these types, another subtype is identifiable: the middle interhemispheric variant. Causes, Sign, and Symptom of Holoprosencephaly: Holoprosencephaly (HPE) is the most common developmental abnormality of the forebrain in humans. J Med Genet. Holoprosencephaly includes a broad spectrum of defects, all based on defective formation of the forebrain (prosencephalon) and structures whose normal formation depends on influences from the forebrain. Impaired transverse cleavage manifests as a failure to separate the telencephalon from diencephalon. Early surgical repair may improve feeding. Roessler E, Muenke M. The molecular genetics of holoprosencephaly. 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). Its incidence is of around 1 out of 10.000 births (Sanders, 1996). Mercier S, Dubourg C, Belleguic M, Pasquier L, Loget P, Lucas J, Bendavid C, Odent S. Genetic counseling and “molecular” prenatal diagnosis of holoprosencephaly (HPE). In this article, we illustrate forebrain midline development as revealed by the factors implicated in HPE in experimental organisms and humans. Holoprosencephaly includes a broad spectrum of defects, all based on defective formation of the forebrain (prosencephalon) and structures whose normal formation depends on influences from the forebrain. Approximately 30% to 50% of live births with HPE have chromosomal abnormalities, but this is likely an overestimation based on underreporting of milder cases. Holoprosencephaly is a complex brain malformation caused by the failure of the prosencephalon (the embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face 1). Holoprosencephaly (HPE) is a complex brain malformation characterized by a failure of the forebrain (prosencephalon) to separate completely into two distinct cerebral hemispheres, a process normally complete by the fifth week of gestation. SHH is expressed early in development in the ventral forebrain and is critical for ventral patterning of the developing neural tube. Often gastroesophageal reflux, choking, and gagging occur with feeds. 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). Syntelencephaly (the absence or hypoplasia of the corpus callosum or absent or hypoplastic olfactory tracts and bulbs) is compatible with life and should thus be treated. 1996;64:465–72. Am J Med Genet C Semin Med Genet. Under the signaling influence of the prechordal plate, the eye field in vertebrates splits into separate left and right eyes. HPE can be seen in association with trisomy 13, trisomy 18, or triploidy. This is a pathology with precocious origin (during the organogenesis of the brain, that originates from a cleavage failure of the primitive prosencephalon. We use cookies to help provide and enhance our service and tailor content and ads. 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