A few studies of limited size suggest a higher than average prevalence of HPE in Far East Asians and Filipinos. Wide variation in holoprosencephaly ranges from malformations that are incompatible with life to suble changes in otherwise health individuals. HPE also occurs as a component of multiple malformation syndromes and in several chromosomal abnormalities, most commonly trisomy 13, trisomy 18, and triploidy. Reduction defects of the nose can also be components of this condition. The gene tests, in conjunction with fetal MRI, have been found to be helpful in prenatal diagnosis and counseling in a series of pregnancies. In addition to trisomy 13, several other chromosomal abnormalities, including trisomy 18, trisomy 13-15, trisomy 13-15 mosaicism, ring chromosome 13 or 18, and chromosomal deletion 13 or 18, have been identified in patients with HPE. Impaired sagittal cleavage manifests as failure or incomplete separation of the cerebral hemispheres. If seizures develop, the possibility of acute reactive seizures should be evaluated for and a serum sodium level checked. 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. 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). Sandrine Passemard, ... Alain Verloes, in Handbook of Clinical Neurology, 2013. Figure 13. 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. The defect arises in early pregnancy when the forebrain is taking shape, and the brain defects usually involve archencephalic structures (e.g., the olfactory system). In this variant, the midportion of the cerebral hemispheres is continuous across the midline, with absence of the corpus callosum seen only in this region. Genetic counseling and genetic testing, such as amniocentesis, is usually offered during a pregnancy if holoprosencephaly is detected. Fetal MRI has been used to diagnosis a range of HPE. In nonsyndromic and nonchromosomal HPE, autosomal-dominant and autosomal-recessive pedigrees have been reported. This condition has been estimated to be present in up to 1 in 250 of all embryos and 1 in 10 000 live births. Isochromosome 18q is a rare cytogenetic abnormality. FIGURE 35.4. During normal development, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of pregnancy. Evolving Medical and Surgical Management of Infants with Trisomy 18. 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). Terms of Use. HPE infants tend to have low muscle tone, poor feeding, and failure to thrive. Chromosomal abnormalities including trisomy 18, trisomy 13, and Turner syndrome have been associated with this disorder . Approximately 30% to 50% of live births with HPE have chromosomal abnormalities, but this is likely an overestimation based on underreporting of milder cases. A plethora of animal models have been used to study HPE (Geng et al., 2009) (Table 35.1). Ethmocephaly is the least common facial anomaly. Monuki, in Encyclopedia of Neuroscience, 2009. Approximately one-half of all cases of holoprosencephaly have a chromosomal cause. The interhemispheric fissure and corpus callosum are completely absent. After Shh itself, the second most common detectable genetic mutations in HPE patients occur within the transcription factor ZIC2 (Roessler et al., 2009a). 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. Depending upon whether the child can manage the smaller opening and associated airway problems, some cases may necessitate a tracheostomy to reestablish the airway. FIGURE 35.5. In lobar HPE, pairing is almost complete with respect to the midline interhemispheric fissure. 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. Mutations in TGIF limit its regulation of Nodal and thus result in inappropriate levels of Shh activity in the forebrain (Taniguchi et al., 2012). Not all individuals with holoprosencephaly (HPE) are affected to the same degree, even in families where more than one individual has this predisposition. Most HPE patients succumb during the first or second year of life. The brain often does not divide into 2 halves. TGIF1 interacts with Transforming Growth Factor (TGF) β-activated Smad proteins (Bertolino et al., 1995; Wotton et al., 1999). Similarly, the genu and body of the corpus callosum are absent, but the splenium is 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). The first-trimester ultrasound can detect alobar HPE but may be much less sensitive in detecting milder cases. Disruption of the GPI-anchored protein Cripto (mouse) and TDGF1 (human ortholog) result in HPE. Various deletions or duplications of chromosomal regions have also been associated with HPE. At the severe end of the spectrum, newborns present with a single central eye (cyclopia) and related facial abnormalities. Most models are transgenic mouse or fish lines that represent various subclasses of HPE. The most common seizure type is complex partial seizures, with or without secondary generalization, but seizures can include generalized tonic-clonic, tonic, atonic, myoclonic, or infantile spasms. Evidence-based information on Holoprosencephaly from hundreds of trustworthy sources for health and social care. 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. The Ala stretch expansion from 15 to 25 in the C terminus of ZIC2 also has been found to cause HPE [12, 98]. Figure 4 shows examples of the wide variation in the condition. Holoprosencephaly is characterized by the failure of the prosencephalon (the forebrain of the embryo) to develop. Trisomy 18 and 13 are usually caused by spontaneous genetic mutations that occur at the time of fertilization. Holoprosencephaly is a congenital Induction disorder of the brain occurring at 3-6 weeks' gestation, with failed segmentation of the neural tube. 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). Curr Opin Pediatrics 2014, 26:169‐176. What causes trisomy 18 and trisomy 13? 80% are associated with trisomy (primarily trisomy 13, and to a lesser extent trisomy 18). HPE has an overall incidence of 1/250 in early fetal loss, but of 1/15 000 (Bullen et al., 2001) at birth. Holoprosencephaly (HPE) is partial or complete failure of the forebrain to divide into hemispheres and can be an isolated finding or associated with a syndrome. The degree of motor complications (hypotonia evolving into spasticity and dystonia) and developmental dysfunction is similar to that seen in lobar HPE. 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. In the most severe type, alobar HPE, nearly complete lack of separation of the cerebral hemispheres is characteristic, with a single midline ventricle very often communicating with a dorsal cyst. alobar holoprosencephaly among their manifestations are Kallmann’s, campomelic dysplasia, Hall-Pallister and Vasadi11. At the mild end of the spectrum is the presence of a single central incisor (one upper front tooth rather than the usual two). A significant reduction in the amount of neural crest-derived mesenchyme in the midfacial region results in hypoplasia of the FNP and subsequent loss of midline structures (Shiota and Yamada, 2010). Failure of separation also is common in the hypothalamic, caudate, lentiform, and thalamic nuclei. 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. This is known as holoprosencephaly. The most severe of the facial defects (or anomalies) is cyclopia, an abnormality characterized by the development of a single eye, located in the area normally occupied by the root of the nose, and a missing nose or a nose in the form of a proboscis (a tubular appendage) located above the eye. 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. In extreme cases, holoprosencephaly can take the form of cyclopia (Figure 13), in which the near absence of upper facial and midfacial tissues results in a convergence and fusion of the optic primordia. This is also reflected in a reduced rostral neural crest, which provides the cellular basis for the formation of most midface structures. The majority of HPE cases are sporadic, although families with both autosomal dominant and autosomal recessive HPE have been described. Although these models can be useful for studying the molecular mechanism of the condition, it is important to recognize that they do not reliably reconstruct the genetic architecture of human HPE due to the genetic complexities associated with the human genome. HPE forms are arranged from most severe (cyclopia) to least severe (bilateral cleft). However, recent genetic studies have argued against this hypothesis. A significant proportion develops hydrocephalus, with 60% of alobar and 8% of semilobar requiring a VP shunt. 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 SHH signaling network is the common pathway through which multiple environmental and genetic influences interact to cause HPE. The risk of holoprosencephaly is increased in subsequent pregnancies of the same couple. One hypothesis is that Zic2 functions within the Shh pathway. Overall, the recurrence risk of HPE secondary to cytogenetic anomalies is approximately 1%. From: Swaiman's Pediatric Neurology (Sixth Edition), 2017, J.A. Phenotypic and genetic complexities associated with the HPE spectrum have made a genotype/phenotype correlation difficult. Both autopsy and 7.0T postmortem MRI examinations were performed. In alobar HPE, the forebrain forms a holospheric, univentricular brain: mental retardation is profound and survival beyond 1 year of age is exceptional. The categorization of HPE introduced by DeMyer and Zeman in 1963 and modified by DeMyer in 19778 is still generally accepted. 26-2). Surgical intervention/treatment: Clinically, holoprosencephaly occurs in a wide spectrum. The strongest teratogenic evidence exists for maternal diabetes and exposure to alcohol and retinoic acid. Various deletions or duplications of chromosomal regions have also been associated with HPE. 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. When death did occur, causes included brainstem dysfunction, pneumonia, dehydration from diabetes insipidus, and rarely, intractable seizures. HPE is also seen in single gene syndromes, such as Pallister-Hall syndrome, Rubinstein-Taybi syndrome, Smith-Lemli-Opitz, and Goldenhar syndromes. HPE is typically associated with midline facial anomalies. The molecular mechanism of Zic2 mediated HPE remains unclear. 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. In some cases, the chromosomal abnormality may be present in only a percentage of cells, whereas other cells contain the normal chromosomal pair (mosaicism). 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