holoprosencephaly trisomy 18


The endocrinopathies may be due to midline defects involving the hypothalamus and are rarely due to a dysgenetic (e.g., hypoplastic or ectopic) pituitary gland. The phenotypes of HPE patients with Ala tract expansions are similar to those in patients with loss of function mutations, suggesting that Ala tract expansion leads to a loss of protein function. Ala-expanded ZIC2 was shown to repress the transcriptional activity of the ApoE regulatory region as compared to the wild-type protein [98]. Various deletions or duplications of chromosomal regions have also been associated with HPE. The phenotypical features of this chromosomal abnormality are variable and overlap with trisomy 18 and monosomy 18p. HPE is the most common developmental defect of the forebrain and midface in humans and occurs in 1 in 250 pregnancies, but because only 3% of the fetuses with HPE survive to delivery, the incidence in live births is only approximately 1 in 10,000. After Shh itself, the second most common detectable genetic mutations in HPE patients occur within the transcription factor ZIC2 (Roessler et al., 2009a). A plethora of animal models have been used to study HPE (Geng et al., 2009) (Table 35.1). There also appears to be a slight female preponderance in some case series. A small number (about 13 in 100) babies born alive with Edwards' syndrome will … Failure of separation also is common in the hypothalamic, caudate, lentiform, and thalamic nuclei. This hypothesis places Zic2 function, relative to onset of HPE, upstream of Shh mediated prechordal plate development. Some teratogens are thought to produce HPE via interference with the sonic hedgehog gene signaling pathways, or cholesterol biosynthesis. 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. In the intermediate form, semilobar HPE, the anterior hemispheres are not separated, but some degree of separation of the posterior hemispheres is seen. The gyri often are normally developed, although in alobar and semilobar HPE, the gyri may be excessively smooth or broad. Cebocephaly, another facial anomaly, is characterized by a small, flattened nose with a single nostril situated below incomplete or underdeveloped closely set eyes. Motor dysfunction, including hypertonia and dystonia, is common and may require physical, pharmacologic, or surgical therapies. The GPI-anchored protein TDFG1 and the transcription factor FoxH1 (forkhead box H1) function in the Nodal pathway and have also been linked to HPE (Roessler et al., 2008; McKean and Niswander, 2012). Maternal diabetes is an environmental cause of HPE. Survivors may have hypotelorism, a flattened nasal bridge, median cleft lip and palate, or a single median maxillary central incisor. The brain often does not divide into 2 halves. 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. Holoprosencephaly is a dramatic central nervous system malformation highlighted by a partial or complete failure of the brain to separate into right and left hemispheres, ... HPE can be seen in association with trisomy 13, trisomy 18, or triploidy. Occasionally, isolated neuronal heterotopias are seen, particularly in the middle interhemispheric variant. Not all individuals with holoprosencephaly (HPE) are affected to the same degree, even in families where more than one individual has this predisposition. Disruption of SHH signaling in animal models mimics the brain and facial malformations in HPE. Autopsy confirmed otocephaly with anteriorly set ears fused in the midline (synotia), alobar holoprosencephaly, and an atrioventricular septal defect. About one fourth of patients have some degree of midbrain nonseparation. A few studies of limited size suggest a higher than average prevalence of HPE in Far East Asians and Filipinos. This was amended later to “the face predicts the brain approximately 80% of the time,” in recognition of individuals with alobar HPE with a normal facial appearance, as well as cases of milder brain malformation associated with abnormal facies. The identification of mutations in multiple genes coupled with advancements in understanding neural tube induction and patterning have provided a somewhat unique opportunity to begin understanding the neurodevelopmental basis of a human malformation. Holoprosencephaly (HPE, MIM 236100) is a complex human brain malformation characterised by defects of the mid forebrain and face resulting from incomplete cleavage of the prosencephalon into right and left hemispheres, occurring between the 18th and the 28th day of gestational age. Mutations in the Sonic Hedgehog gene on chromosome 7 lead to holoprosencephaly. Along with the midline brain malformation seen in HPE, a corresponding midline facial malformation may be present. Recent studies that expanded the diagnostic approach to include more in-depth analysis of the proband, the probands family and family history have hypothesized that the most severe cases of HPE are more likely associated with mutations in either SHH or ZIC2 (Solomon et al., 2010). TGIF1 (Thymine/Guanine-Interacting Factor) maps to the HPE4 locus, and heterozygous loss-of-function TGIF1 mutations are associated with HPE (Gripp et al., 2000). Chromosomal abnormalities including trisomy 18, trisomy 13, and Turner syndrome have been associated with this disorder . Most of those who survive show no significant developmental gains. What causes trisomy 18 and trisomy 13? Semilobar holoprosencephaly shows the brain's hemispheres have a slight tendency to separate and is a more intermediate form. At the most severe end of this spectrum are cases involving serious brain malformations, some so severe that they are incompatible with life and often cause spontaneous intrauterine death. The presence of large dorsal cysts, hydrocephalus, or midline craniofacial defects may provide clues that eventually lead to the recognition of the associated HPE. For children who survive, treatment is symptomatic. 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. Meckel's syndrome is an autosomal recessive condition. The interhemispheric fissure and corpus callosum are completely absent. It consists of a proboscis separating narrow-set eyes with an absent nose and microphthalmia (abnormal smallness of one or both eyes). Holoprosencephaly (HPE) is a condition that occurs in the first two or three weeks of pregnancy and results in abnormal development of the brain. 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. Both autopsy and 7.0T postmortem MRI examinations were performed. Although rare in absolute terms, holoprosencephaly is the most common brain abnormality and is seen in 1 per 10,000-16,000 live births 3,9. In alobar HPE, the forebrain forms a holospheric, univentricular brain: mental retardation is profound and survival beyond 1 year of age is exceptional. The spectrum of holoprosencephaly (HPE). Long survival is possible with semilobar and lobar HPE, but often associated with moderate to severe mental impairment and early onset seizures (Pineda-Alvarez et al., 2010). Holoprosencephaly is a congenital Induction disorder of the brain occurring at 3-6 weeks' gestation, with failed segmentation of the neural tube. As in children with other midline brain defects, endocrinologic problems are very common. 26-3). In many cases, it appears to be the consequence of a genetic or an environmental disruption of the sonic hedgehog (SHH) signaling pathway, which is responsible of the specification of the neural tube but also plays a role in the proliferation of neural progenitors in the ventricular zone of the telencephalon. Holoprosencephaly is characterized by the failure of the prosencephalon (the forebrain of the embryo) to develop. There is separation of the anterior frontal lobes, basal forebrain, and occipital lobes. The risk of reoccurrence is small in most families. Patients with this anomaly frequently exhibit specific craniofacial anomalies, including midline facial clefts, cyclopia, and nasal anomalies. Holoprosencephaly (HPE) is the result of the failure of the developing brain to divide into two separate hemispheres. 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 strongest teratogenic evidence exists for maternal diabetes and exposure to alcohol and retinoic acid. Most models are transgenic mouse or fish lines that represent various subclasses of HPE. Many cases of holoprosencephaly (e.g., Meckel's syndrome, which includes midline cleft lip, olfactory bulb absence or hypoplasia, and nasal abnormalities) can be attributed to genetic causes. The root cause of holoprosencephaly occurs very early in embryonic development, with disturbances in the ability of the prechordal plate and anterior endoderm to secrete sonic hedgehog (shh) and other factors required for induction and early development of the ventral forebrain. 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). • Rosa RFM et al. In addition to these types, another subtype is identifiable: the middle interhemispheric variant. Note median clefting and ocular hypotelorism. The molecular mechanism of Zic2 mediated HPE remains unclear. Chromosome analysis demonstrated an abnormal karyotype 46,XX,i(18)(q10). The categorization of HPE introduced by DeMyer and Zeman in 1963 and modified by DeMyer in 19778 is still generally accepted. Back in 2006, my husband and I got pregnant with our first. Finally, impaired horizontal cleavage manifests as a failure to form the olfactory bulbs and optic vesicles. At the mild end of the spectrum is the presence of a single central incisor (one upper front tooth rather than the usual two). Disruption of the GPI-anchored protein Cripto (mouse) and TDGF1 (human ortholog) result in HPE. FIGURE 35.4. Two thirds of patients with alobar and semilobar HPE require gastrostomy tubes. Failure of this interaction results in compromised Shh expression in the ventral forebrain (Jeong et al., 2008). One hypothesis is that Zic2 functions within the Shh pathway. 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). 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). HPE forms are arranged from most severe (cyclopia) to least severe (bilateral cleft). The first-trimester ultrasound can detect alobar HPE but may be much less sensitive in detecting milder cases. Evidence-based information on Holoprosencephaly from hundreds of trustworthy sources for health and social care. HPE's cause in any individual family may be unknown. Holoprosencephaly, proboscis, anophthalmia, trisomy 13, matUPD14 Introduction Holoprosencephaly (HPE, MIM 236100) is a complex human brain malformation characterised by defects of the mid forebrain and face resulting from incomplete cleavage of the prosencephalon into right and left hemispheres, occurring between the 18th and the 28th day of gestational age. 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). There is an increased risk for holoprosencephaly in infants born to diabetic mothers. The leading cause of holoprosencephaly is a chromosomal disorder, comprising 40% to 50% of all documented cases. A diabetic mother's risk of having a child with HPE is approximately 1%, a greater than 100-fold increase over the general population. When death did occur, causes included brainstem dysfunction, pneumonia, dehydration from diabetes insipidus, and rarely, intractable seizures. The majority of HPE cases are sporadic, although families with both autosomal dominant and autosomal recessive HPE have been described. HPE results if the p… 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). By Heather. Approximately one-half of all cases of holoprosencephaly have a chromosomal cause. In some cases of lobar holoprosencephaly, the patient's brain may be nearly normal. This is known as holoprosencephaly. A small subset of the children are of normal intelligence, and those cases are managed as any cleft lip and palate child. Multiple environmental and genetic factors have been implicated in causing HPE. While By continuing you agree to the use of cookies. Diabetes insipidus is particularly frequent, growth hormone deficiency, hypocortisolism, and hypothyroidism also may occur. Approximately 30% to 50% of live births with HPE have chromosomal abnormalities, but this is likely an overestimation based on underreporting of milder cases. Diagnosis: Alobar Holoprosencephaly. 26-2). At least nine genes have been associated with HPE, including: SHH (7q36); ZIC2 (13q32); SIX3 (2p21); TGIF (18p11.3); PATCHED-1 (9q22); GLI2 (2q14); DISP1 (1q24); NODAL (10q); and FOXH1 (8q24.3). HPE demonstrates significant variation in severity and manifestations (variable expressivity), meaning that two people with the same genetic predisposition to HPE can have significantly different physical features. Holoprosencephaly (HPE), the most common malformation of the human forebrain, results from central failures in forebrain midline induction. Surgical intervention/treatment: Clinically, holoprosencephaly occurs in a wide spectrum. TABLE 35.2. In some cases, the chromosomal abnormality may be present in only a percentage of cells, whereas other cells contain the normal chromosomal pair (mosaicism). 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. MRI also should be considered to evaluate for focal heterotopia. Typically, in the first few weeks of pregnancy, the developing embryo begins laying the structural groundwork for brain development. Thus, defects in Zic2 cause HPE via disruption of Shh transduction. The severity of the brain malformation determines the degree of delay and neurologic impairments (including hypotonia and spasticity). In 50% of affected children, the seizures are relatively easy to control with antiepileptic medication but with increased risk associated with cortical dysplasia. Seizures and mental retardation may occur. Motor difficulties and dystonia may be partially responsive to trihexyphenidyl. Early death is typical for most cytogenetically abnormal children and those individuals with the most severe facial features (cyclopia or ethmocephaly). 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. The degree of motor complications (hypotonia evolving into spasticity and dystonia) and developmental dysfunction is similar to that seen in lobar HPE. From: Swaiman's Pediatric Neurology (Sixth Edition), 2017, J.A. Approximately one-half of all cases of holoprosencephaly have a chromosomal cause. 1 Actually, isochromosome 18q associated with alobar HPE was only … Child with Holoprosencephaly. Genetic HPE is associated with four genes and has been linked to seven additional chromosomal loci. Midline defects of the upper lip can also be attributed to holoprosencephaly (see Figure 12(c)). Phenotypic and genetic complexities associated with the HPE spectrum have made a genotype/phenotype correlation difficult. Abnormal cleavage of the vesicles leads to a wide spectrum of midline anomalies of the face, which are only partially correlated with the severity of the HPE. An updated list of genetic disorders associated with HPE can be found on the online Mendelian Inheritance in Man (OMIM) website (http://www.ncbi.nlm.nih.gov/omim). They may also have an underlying endocrine deficiency, requiring assessment and treatment. Similarly, the genu and body of the corpus callosum are absent, but the splenium is present. This may have been due to the identification of only the most severe cases. Mutations in the Shh receptor Patched (Ptch) (Ming et al., 2002; Ribeiro et al., 2006), the downstream transcription factor Gli2 (Wannasilp et al., 2011; Roessler et al., 2005; 2003), the ligand transporter Dispatched (Disp1) (Roessler et al., 2009b; Ma et al., 2002) and the transmembrane protein Cdo (Zhang et al., 2006) have all been identified as causal genetic elements in HPE cases. Additional mutations within genes that are hypothesized to interact with the Shh pathway have also been linked to human HPE cases. Phadke and Thakur reported on a case of iniencephaly and alobar holoprosencephaly with trisomy 13 mosaicism , which was very similar to our case. Figure 4. Lobar holoprosencephaly, in which there is considerable evidence of separate brain hemispheres, is the least severe form. As such, HPE serves as a paradigm for understanding midline signaling centers, or organizers, during forebrain development. 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Link the Shh signaling network is the most severe ( bilateral cleft ) children HPE. Made a genotype/phenotype correlation difficult middle interhemispheric variant procedure is a congenital Induction disorder of the forebrain! Lack of separation of the wide variation in holoprosencephaly ranges from malformations that are hypothesized to FNP. Duplications of chromosomal regions have also been linked to seven additional chromosomal loci, is a congenital disorder... Shh signaling network is the least severe form mildest form, lobar HPE HPE risk is... Surgical Management of infants with trisomy 13, trisomy 13, trisomy 13 fail to separate and is a but. Of alobar and semilobar HPE, including trisomy 13 when I was around 12 weeks pregnant causes. First blog entries on June 6, 2010 human HPE cases are managed as any cleft lip and child... And humans in 19778 is still generally accepted genetic progress has been estimated to be present in up 1... 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