Non-syndromic Holoprosencephaly Research Articles

Anaesthetic considerations in a neonate with unrepaired D-transposition of great arteries with non-syndromic holoprosencephaly for emergency exploratory laprotomy: A case report

D-Transposition of great arteries (D-TGA) is a cyanotic congenital heart disease (CHD) characterized by parallel circulation. Non syndromic holoprosencephaly is an abnormality of brain development resulting from failure or incomplete division of embryonic forebrain into distinct cerebral hemisphere. Major challenges in patients of D-TGA are hemodynamic instability, cyanotic spell, coagulopathy, acid base and electrolyte imbalance. We report successful management of one day old neonate posted for emergency resection anastomosis for ileal atresia with unrepaired d-TGA and non-syndromic holoprosencephaly.

Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly

Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS-HPE. These manifestations have been described in case reports and in large cohorts of patients with "single-gene" mutations, suggesting that the NCNS-HPE phenotype can be more complex than traditionally thought. Likely, a complex network of interacting genetic variants and environmental factors is responsible for these systemic abnormalities that deviate from the usual brain and craniofacial findings in NCNS-HPE. In addition to the systemic consequences of pituitary dysfunction (as a direct result of brain midline defects), here we describe a number of extracephalic findings of NCNS-HPE affecting various organ systems. It is our goal to provide a guide of extracephalic features for clinicians given the important clinical implications of these manifestations for the management and care of patients with HPE and their mutation-positive relatives. The health risks associated with some manifestations (e.g., fatty liver disease) may have historically been neglected in affected families.

EP09.12: The pattern of facial clefts in Hong Kong Chinese

To analyse the pattern of facial clefts in Hong Kong Chinese. From 2001–2014, 165 facial clefts were delivered in our hospital. Clinical data of these cases including type of cleft, sex and other anomalies were retrieved from hospital records. Statistical analysis was performed using chi square test. During the 14-year period, 87,989 live births were delivered. The incidence of facial cleft was 1:533. 9 cases were excluded due to incomplete information. For the remaining 156 cases, 142 (91%) were typical cleft and 14 (9%) were atypical cleft. Male [85 (54%)] was more frequently affected than female [71 (46%)]. M:F ratio was 1.2:1. For the 142 typical clefts, majority were cleft lip and palate [83 (58%)], followed by cleft lip only [31 (22%)] and cleft palate only [28 (20%)]. Unilateral cleft [84/114 (74%)] was more common than bilateral [30/114 (26%)] and left side [52/84 (62%)] was more common than right side [32/84 (38%)]. All 14 atypical clefts and 46 (32%) typical clefts had associated anomalies: 23 (39%) aneuploidy, 12 (20%) genetic syndrome, 14 (23%) non-genetic syndrome and 11 (18%) other structural anomalies. The aneuploidies were 16 (70%) trisomy 13 and 7 (30%) Trisomy 18. The non-genetic syndromes were 11 (79%) amniotic band syndrome and 3 (21%) twin reversed arterial perfusion sequence. The genetic syndromes were achondrogenesis, Apert, arthrogryposis multiplex congenita, Cornelia de Lange, distal arthrogryposis, ectodermal dysplasia, frontonasal dysplasia, non-syndromic holoprosencephaly, Treacher Collins and 3 cases of Goldenhar. Significantly more atypical clefts [3/14 (21%)] and cleft palate only [5/28 (18%)] were involved in genetic syndromes than cleft lip with or without cleft palate [4/114 (4%)] (p = 0.005). The incidence of facial cleft is higher in Chinese than other ethnic groups. Given the high incidence of associated anomalies, clinicians should be wary of these associations, particularly when atypical cleft or cleft palate only is encountered.

Antenatal detection of maternal unipartental disomy of chromosome 2 in a fetus with non‐chromosomal, non‐syndromic alobar holoprosencephaly

Holoprosencephaly (HPE) refers to a group of disorders caused by incomplete division of the forebrain with awide range of associated phenotypes [Solomon et al., 2010]. It is themost common forebrain anomaly with a prevalence of 1:250 in embryos and 1:10,000 in liveborn infants [Bous et al., 2012]. Fetal development of HPE may be caused by genetic and teratogenic phenomena [Cohen and Shiota, 2002; Solomon et al., 2010], by aneuploidy (e.g., trisomy 13), or by other genetic syndromes with autosomal recessive, autosomal dominant, or X-linked mutations [Solomon et al., 2000; Cohen and Shiota, 2002]. Diabetes mellitus is a teratogenic risk factor for HPE [Solomon et al., 2000; Cohen and Shiota, 2002]. Mutations in 12 genes are known to cause apparently non-syndromic HPE [Solomon et al., 2010; Bous et al., 2012]. Mutations of four genes, SHH, ZIC2, SIX3, and TGIF, account for most non-chromosomal, non-syndromic HPE [Solomon et al., 2010]. This 24-year-old primigravidwomanpresented for prenatal care in her first trimester. Anatomic screening, performed at 18 6/7 weeks, showed the fetus to have hydrocephalus, alobar holoprosencephaly (HPE), mid-face hypoplasia with bilateral cleft lip and palate, a proboscis, a cervical meningocele, and post-axial polydactyly in the fetal feet (Fig. 1). The family history was unremarkable, and no known environmental or teratogenic exposures were identified. Her hemoglobin A1C was 4.8, suggesting a low likelihood of diabetes mellitus. An amniocentesis was performed and amniotic fluid was tested for karyotype, alpha fetoprotein, and single nucleotide polymorphism (SNP) chromosomal microarray (CMA). The karyotype was 46,XY. CMA showed evidence of isodisomy of chromosome 2 (UPD2) as (arr 2p25.3q37.3 (12, 771–243, 783, 384) 2 hmz). No deletions, mosaicism, or supernumerary chromosomes were noted. Ultrasonography was performed again at 21 4/7 weeks at the patient’s request and the above findings were confirmed. The patient was counseled about her options for continuation and termination of the pregnancy and she opted for termination by dilation and evacuation (D&E), which was performed at 22 weeks gestation. Counseling included that a D&E would preclude the

Risk factors for nonsyndromic holoprosencephaly: A Manitoba case–control study

Holoprosencephaly (HPE) is one of the most common developmental field defects, occurring in 1 in 250 conceptuses and in 1 in 10,000-20,000 live births. Nearly half of patients with HPE have a recognized syndrome or a single gene defect. However, little is known about the risk factors for the remainder with "nonsyndromic" HPE. In our case-control study, we examine factors associated with nonsyndromic HPE. We identified 47 patients with HPE from the genetics clinic database with an equal number of controls matched for gender and birthdate. Of the 47 patients, 23 were identified as nonsyndromic. No statistically significant differences were noted between the mean maternal and paternal ages of patients and controls. Factors associated with nonsyndromic HPE were: having an Aboriginal mother (unadjusted odds ratio [OR] 3.5, 95% confidence interval [CI] 1.1-11.1), an Aboriginal father (OR 12.8, 95% CI 3.0-55.1), at least one Aboriginal parent (OR 5.0, 95% CI 1.6-16.0), or two Aboriginal parents (OR 8.8, 95% CI 2.0-37.8), the presence of a family history of a midline facial defect (OR 8.2, 95% CI 1.5-45.2), and being of low socioeconomic status (OR 3.0, 95% CI 1.0-9.1). Having an Aboriginal background remained statistically significant after adjusting for low socioeconomic status. Other associations evaluated--history of prior spontaneous abortion, stillbirth, neonatal death, prepregnancy diabetes, infections during pregnancy, alcohol exposure, smoking, and substance abuse--were not significantly associated with nonsyndromic HPE. The use of periconceptional folic acid or vitamins was not associated with a lower risk of nonsyndromic HPE.

TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype

Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-β signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1–2% of patients with non-syndromic, non-chromosomal HPE.We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ²₍₂₎ = 6.97, p_permutated = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

Analysis of genotype–phenotype correlations in human holoprosencephaly

Since the discovery of the first gene causing holoprosencephaly (HPE), over 500 patients with mutations in genes associated with non-chromosomal, non-syndromic HPE have been described, with detailed descriptions available in over 300. Comprehensive clinical analysis of these individuals allows examination for the presence of genotype-phenotype correlations. These correlations allow a degree of differentiation between patients with mutations in different HPE-associated genes and for the application of functional studies to determine intragenic correlations. These early correlations are an important advance in the understanding of the clinical aspects of this disease, and in general argue for continued analysis of the genetic and clinical findings of large cohorts of patients with rare diseases in order to better inform both basic biological insight and care and counseling for affected patients and families.

Genetic counseling and “molecular” prenatal diagnosis of holoprosencephaly (HPE)

Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. The poor prognosis in the most severe forms justifies the importance of genetic counseling in affected families. The genetic counseling requires a thorough clinical approach given the extreme variability of phenotype and etiology. The karyotype is an essential diagnostic tool. Since mutations in the four major genes (SHH, ZIC2, SIX3, and TGIF) have been identified in HPE patients, molecular study is performed routinely in nonsyndromic HPE. New molecular tools, such as array-CGH analysis, are now part of the diagnostic process. Prenatal diagnosis is based primarily on fetal imaging, but "molecular" prenatal diagnosis can be performed if a mutation has been previously identified in a proband. Interpretations of molecular diagnosis must be given with caution, given the lack of strict genotype-phenotype correlation, and should be offered in addition to fetal imaging, using ultrasound followed by fetal MRI. We report on our experience of 15 molecular prenatal diagnoses from chorionic villi or amniotic fluid sampling. In eight instances, we were able to reassure the parents after taking into account the absence of the mutation in the fetus, previously identified before in a parent and/or a proband. Fetal RMI was normal later in pregnancy, and no child had medical problems after birth. The mutation was found in the seven other cases: four children were born, either without brain malformation and asymptomatic, or had a less severe form than the index case.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function

Background:Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator...

Risk factors for cytogenetically normal holoprosencephaly in California: A population-based case-control study

Holoprosencephaly is a developmental field defect manifested by a spectrum of abnormalities of the forebrain and midface. Approximately 50% of holoprosencephaly cases are associated with a cytogenetic abnormality or a monogenic syndrome. Suggested risk factors for the remaining 50% of cases have been described in case reports, but have not been confirmed in systematically conducted studies. We report the results of a population-based case-control study of holoprosencephaly. Live births, fetal deaths, and terminations with a diagnosis of cytogenetically normal holoprosencephaly were identified by the California Birth Defects Monitoring Program. Telephone interviews were conducted with the mothers of 58 cases and 107 live born, nonmalformed controls. Women were questioned about their health and reproductive histories, family demographics, and exposures occurring during their pregnancies. Among nonsyndromic cases, increased risks were observed for females (OR=1.8, 95% C.I. 0.9-3.9), foreign-born vs. U.S. or Mexico-born women (OR=3.1, 95% C.I. 1.1-8.6), and women with early menarche (OR=2.3, 95% C.I. 0.9-5.7). Maternal periconceptional exposures associated with increased risks for nonsyndromic holoprosencephaly included alcohol consumption (OR=2.0, 95% C.I. 0.9-4.5), cigarette smoking (OR=4.1, 95% C.I. 1.4-12.0), and combined alcohol and smoking (OR=5.4, 95% C.I. 1.4-20.0), insulin-dependent diabetes (OR=10.2, 95% C.I. 1.9-39.4), medications for respiratory illnesses (OR=2.3, 95% C.I. 0.9-6.0), and salicylate-containing medications (OR=2.5, 95% C.I. 0.8-7.9). These findings are consistent with risk factors identified in some previous reports, and identify several new potential risk factors that require confirmation in future studies.

Segregation analysis in nonsyndromic holoprosencephaly

Holoprosencephaly (HPE) is a developmental defect due to a failure of cleavage of the forebrain. The brain malformations are usually associated with facial anomalies. From a series of 258 HPE records involving at least one affected child, 97 cases in 79 families with nonsyndromic and nonchromosomal HPE were selected.The male:female ratio was 0.87. A high degree of familial aggregation was observed in 23/79 families (29%). A segregation analysis performed in the 79 nuclear families led to the conclusion that the transmission of nonsyndromic HPE is compatible with an autosomal dominant mode of inheritance. Under this hypothesis, the penetrance was estimated as 82% for major types (alobar, semilobar, lobar) and 88% when major and minor types (atypical) were included. The proportion of sporadic cases was estimated to be 68%. This genetic model allows a prediction of the recurrence risk after an isolated case of 13% for major types and 14% when minor types are included. Am. J. Med. Genet. 77:139–143, 1998. © 1998 Wiley-Liss, Inc.

Segregation analysis in nonsyndromic holoprosencephaly

Holoprosencephaly (HPE) is a developmental defect due to a failure of cleavage of the forebrain. The brain malformations are usually associated with facial anomalies. From a series of 258 HPE records involving at least one affected child, 97 cases in 79 families with nonsyndromic and nonchromosomal HPE were selected. The male:female ratio was 0.87. A high degree of familial aggregation was observed in 23/79 families (29%). A segregation analysis performed in the 79 nuclear families led to the conclusion that the transmission of nonsyndromic HPE is compatible with an autosomal dominant mode of inheritance. Under this hypothesis, the penetrance was estimated as 82% for major types (alobar, semilobar, lobar) and 88% when major and minor types (atypical) were included. The proportion of sporadic cases was estimated to be 68%. This genetic model allows a prediction of the recurrence risk after an isolated case of 13% for major types and 14% when minor types are included.

Descriptive epidemiology of holoprosencephaly and arhinencephaly in metropolitan Atlanta, 1968-1992.

We report the descriptive epidemiology of holoprosencephaly and arhinencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system with multiple sources of ascertainment. From 1968-1992, we ascertained 63 cases of holoprosencephaly and arhinencephaly from approximately 734,000 births, for a birth prevalence of 0.86 per 10,000. Thirteen case infants with holoprosencephaly and four case infants with arhinencephaly were categorized as having syndromes. Of the case infants with non-syndromic holoprosencephaly, 55% had malformations not attributable to the underlying brain defect. The rate of holoprosencephaly and arhinencephaly increased from 0.58 per 10,000 during 1968-1972 to 1.2 per 10,000 during 1988-1992 (P for trend = 0.016). Rates were higher for females than for males (risk ratio = 1.45, 95% C.I. 0.88-2.41) and higher for nonwhites than for whites (risk ratio = 1.74, 95% C.I. 1.06-2.86). There was a U-shaped distribution of risk associated with maternal age with a slightly increased risk for younger women (risk ratio for maternal age < 20 years, compared with age 25-29 years = 1.68, 95% C.I. 0.77-3.62) and older women (risk ratio for maternal age > 34 years, compared with age 25-29 years = 2.30, 95% C.I. 0.93-5.7), but this was not statistically significant. The increased risk in the older age group could be largely explained by the presence of cases with autosomal trisomies. Neonatal mortality was higher for infants with malformations that were not attributable to the underlying brain defect and for infants with syndromes than for infants with isolated holoprosencephaly. This analysis is the first population-based study with long-term data on this rare defect. Further epidemiologic studies will be necessary to assess the risk factors for holo-prosencephaly and arhinencephaly.

Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology.

This paper provides an updated, comprehensive, critical review of the epidemiology, genetics, and syndromic aspects of holoprosencephaly and is divided into four parts. In the first part, epidemiologic aspects are discussed under the following headings: prevalence, temporal trends, socioeconomic status, exposure to environmental teratogens, maternal and paternal ages, pregnancy histories, and birth weights. The second part analyzes the facial phenotypes because the genetic and syndromic aspects of holoprosencephaly cannot be understood without knowledge of facial variability and its meaning. Topics discussed include cyclopia, ethmocephaly, cebocephaly, median cleft lip, and less severe facial dysmorphism. The third section, on genetics, analyzes associated anomalies, chromosomal and non-chromosomal holoprosencephaly, family studies, twin studies, genetics of nonsyndromic holoprosencephaly, and recurrence risks. The final section on syndromology summarizes 48 conditions in which some degree of holoprosencephaly may be a feature.