Cases Of Holoprosencephaly Research Articles

Holoprosencephaly—Report of two cases

Holoprosencephaly (HPE) is a developmental defect resulting from incomplete cleavage of the embryonic forebrain structures during early embryogenesis. It includes a series of rare complex disorders. Chromosomal abnormalities, single gene disorders and teratogenic agents are responsible for holoprosencephaly. We report two rare cases of alobar HPE with a rudimental nasal structure (proboscis) located under the eyes. One of the patients survived for 9 months and the other one survived 40 days.

Holoprosencephaly and limb reduction defects: A consideration of Steinfeld syndrome and related conditions

Individuals with holoprosencephaly (HPE) and limb reduction defects have been ascribed historically to a variety of syndromes with overlapping phenotypic features. As such, these patients are challenges for clinicians and researchers alike. In an effort to better understand this association, we reviewed our autopsy records and identified five cases of HPE with reduction defects of the limbs and other anomalies. One case appears to be the third reported instance of Steinfeld syndrome, while others represent microgastria-limb reduction sequence, VATER/VACTERL association, and an additional unique condition characterized by HPE, rhombencephalosynapsis, absent left radius, first metacarpal, and thumb, and congenital heart disease. The phenotypic heterogeneity inherent in these patients continues to complicate diagnosis, which will hopefully be simplified by continuing delineation at morphologic and especially genetic levels.

Prenatal diagnosis of trisomy 4p: a new locus for holoprosencephaly?

Trisomy of the short arm of chromosome 4 is a well-known syndrome, and several observations have been made in the last 30 years. Herein, we report a new observation of trisomy 4p in a fetus with a semi-lobar holoprosencephaly (HPE), dysmorphic features and multiple malformations. The diagnosis of HPE was made, at 33 weeks' gestation, on the fetus of a healthy G1P0 woman. Amniocentesis was performed for chromosome analysis and additional material was found on a chromosome 22. The couple elected to terminate the pregnancy and fetal examination was realized. Conventional and molecular cytogenetic studies were performed on the fetus and the parents, which showed that the additional material found on one chromosome 22 corresponded to the short arm of chromosome 4 and therefore led us to establish a diagnosis of trisomy 4p inherited from the malsegregation of a paternal translocation t(4;22)(q12;q11.1). The etiology of HPE is very heterogeneous; it includes non-genetic factors such as maternal diabetes and genetic causes. HPE cases have been described in association with many chromosomal anomalies, trisomy 13 being the most frequent. However, to our knowledge, HPE has never been previously reported in association with a trisomy involving solely the short arm of chromosome 4.

Middle interhemispheric variant of holoprosencephaly: A very mild clinical case

Middle interhemispheric variant (MIH) of holoprosencephaly or syntelencephaly was described in 19931 as a fourth subtype of holoprosencephaly (HPE), in addition to the three classic types of alobar, semilobar, and lobar HPE.2 MIH consists of an abnormal midline continuity of the posterior frontal and parietal regions of the cerebral hemispheres, with separation of the basal forebrain, anterior frontal lobes, and occipital regions. Although MIH and classic HPE share a number of similarities, they are related to different embryologic mechanisms. Classic HPE is caused by a defect in the formation of the embryonic floor plate, whereas MIH is secondary to a disturbance of formation of the roof plate.3 The ZIC2 gene plays a critical role in differentiation of the roof plate of the developing embryo in the dorsal midline of the neural tube.3 In mice, decreased levels of ZIC2 result in the failure to form midline CNS structures. In humans, mutations in the ZIC2 gene have been found in ∼3 to 4% of HPE cases, including individuals with MIH, confirming that MIH is a variant of HPE.4 …

Spectrum of holoprosencephaly.

To conduct a clinical study of holoprosencephaly (HPE). Thirteen cases of HPE were studied regarding their clinical features, family history, and prenatal and imaging studies. Chromosomal analysis was done whenever fresh sample was available. Six cases were antenatally detected by ultrasound; four cases were stillborn. Three cases were identified by neuroimaging done a part of evaluation of developmental delay or cleft lip. Eleven of them had facial anomalies characteristics of HPE. Two of these had subtle facial features and microcephaly. Karyotype was abnormal in 2 of 7 cases studied. Most of the cases of HPE present antenatally or at birth. Milder forms like lobar and semilobar can present as developmental delay during infancy. Facial anomalies are usually associated with HPE. Chromosomal study of the case and clinical examination of the parents is essential for providing information regarding risk of recurrence to the family.

White matter imaging in holoprosencephaly in children.

Holoprosencephaly is a disorder of forebrain development characterized by a failure of the brain to separate into two hemispheres during early development. It is now clear that many cases of holoprosencephaly are caused by alterations in the genetic programmes that pattern the nervous system. Less is known about how a holoprosencephalic brain either forms or fails to form connections between various brain structures. Abnormalities in the corpus callosum, corticospinal tract, medial lemniscus and cerebellar peduncles can be seen in holoprosencephaly. Diffusion tensor imaging has been and will continue to be an important tool for imaging white matter in the brain, and will be reviewed here. Furthermore, recent evidence suggests that holoprosencephaly can be associated with delays or abnormalities in myelination. The functional implications of white matter abnormalities in children with holoprosencephaly is only beginning to be understood. Modern neuroimaging has led to a better appreciation of the variability seen in holoprosencephaly, an anomaly known to have multiple etiologies. Recent reviews of the biology of holoprosencephaly identify the condition as a defect in dorsoventral patterning. More detailed white and grey matter structure-function studies are likely to shed light on how a brain with drastically altered composition and connectivity does or does not organize itself to accomplish increasingly complex developmental functions.

Solitary median maxillary central incisor syndrome: Clinical case with a novel mutation of sonic hedgehog

Solitary median maxillary central incisor (SMMCI) is a rare dental anomaly. It is usually considered as a minor manifestation of holoprosencephaly (HPE). Some reported families had severe cases of HPE in some members and SMMCI in others. Mutations of Sonic Hedgehog (SHH) have been documented in these families. SMMCI has also been found as an isolated finding or together with other anomalies such as microcephaly, short stature, endocrine pathology, and choanal atresia. We describe a patient with SMMCI and a novel SHH mutation: Val332Ala.

Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases.

To investigate the prenatal appearance of the holoprosencephaly spectrum. A database of 1750 fetuses with congenital anomalies identified by ultrasound was prospectively collected from 1987 to 2000. Among them, 30 cases (1.7%) with holoprosencephaly were prenatally identified and described. The prevalence of holoprosencephaly in the Health Region of the National Center for Fetal Medicine in Norway was 1.26 : 10 000; the sex distribution (male : female) was 1.4 : 1. Holoprosencephaly was found in one dichorionic twin pregnancy and one pair of conjoined twins. Among the 30 cases of holoprosencephaly, 18 were alobar, five were semilobar, two were lobar, two were lobar variants, and three were anencephalic. The facial features varied considerably. Sixty-seven per cent (20/30) had associated structural anomalies that were not related to the cerebral and facial holoprosencephaly condition. Thirty-seven per cent (11/30) had detectable chromosome aberrations and 23% (7/30) had nonchromosomal syndromal origin. The size or shape of the head was abnormal in 83% (25/30) of holoprosencephaly cases. This study indicates that holoprosencephaly represents a heterogeneous entity with different etiologies and clinical appearances. The fact that holoprosencephaly features are found associated with particular conditions such as fronto-nasal dysplasia (2/30; 6.7%), agnathia-otocephaly (3/30; 10%), and anencephaly (3/30; 10%), suggests that these may be underreported conditions in other large holoprosencephaly series.

Holoprosencephaly: morphological aspects of twelve cases of autopsy

The term holoprosencephaly (HPC) is used to indicate the group of hemispheric deformities caused by a failure in the development of the prosencephalic vesicle. The purpose of this study is to explain the morphologic spector of twelve cases of HPC, qualify them, and compare them to the literature. It was evaluated 5837 pediatrics necropsies, and there were 12 cases of HPC. Data like gender, age and the presence of another associated malformations were evaluated and compared to another malformations and to the total number of necropsies. The majority of the cases was male (66.66%), and stillborns (75%). The most frequently type of HPC found was the lobar type (58.3%), and the most frequently type of facial alteration was the ciclopy (25%). There is a statistic tendency to HPC affect the male sex, in comparison with other neurologic malformations. Besides, the stillborns are more frequently observed in HPC than in other neurologic malformations.

Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly

Holoprosencephaly (HPE) is genetically heterogeneous with four genes, SIX3, SHH, TGIF, and ZIC2 that have been identified to date and that are altered in 12% of patients. To analyze this prevalence in a South American population-based sample (57 HPE cases in 244,511 live and still births or 1 in 4300), we performed a mutational study of these genes in 30 unrelated children (26 newborns and 4 non-newborns) with HPE being ascertained by ECLAMC (Latin American Collaborative Study of Congenital Malformations). We identified three novel mutations: two were missense mutations of the SHH gene (Cys183-->Phe; His140-->Pro); the third mutation was a 2-bp deletion in the zinc-finger region of the ZIC2 gene. These molecular results explained 8% (2/26 newborn samples) of the HPE cases in this South American population-based sample, a proportion similar to our previously published data from a collection of cases.

Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England

Objective: This study was undertaken to provide epidemiologic data on the prevalence of holoprosencephaly and to assess the sensitivity of routine ultrasonographic screening in a low-risk population. Study Design: A population-based register of congenital abnormalities was used to identify reported cases of holoprosencephaly between 1985 and 1998. Sources included fetal losses, termination for fetal anomaly, stillbirths, and live births. Prenatal diagnoses and pregnancy outcomes were determined. Results: Sixty-eight cases of holoprosencephaly were found among 531,686 births. The total prevalence (including pregnancy terminations) was 1.2 cases/10,000 registered births, and the birth prevalence (affected live births and stillbirths at >24 weeks’ gestation) was 0.49 cases/10,000 births. Prenatal diagnosis was achieved in 71% of cases, rising to 86% during the second half of the study period; the mean gestational age at diagnosis was 19.8 weeks’ gestation. Chromosomal abnormalities (75% of which were trisomy 13) were present in 38% of cases in which a karyotype was established. All those with aneuploidy (80% diagnosed prenatally) had other nonfacial anomalies; additional anomalies were also common in the euploid group (61% diagnosed prenatally), with 90% having facial abnormalities and 70% having other abnormalities. Conclusion: The prevalence of holoprosencephaly in second-trimester pregnancies was about 1 in 8000. Prenatal detection reached 86% with a routine anomaly scanning program. The etiology could usually be determined, which has important implications for recurrence risks. (Am J Obstet Gynecol 2001;184:1256-62.)

Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination

We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame deletion of 12 amino acids. The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect (one case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation.

Malformations of the central nervous system: analysis of 157 pediatric autopsies

The malformations of the central nervous system affect about 5 to 10 children per 1000 births. We studied the central nervous system malformations in 5837 pediatric autopsies performed in the Sector of Anatomic Pathology, Hospital de Clínicas-UFPR, between 1960 and 1995. There were 157 central nervous system malformations (2.69%), the commonest were neural tube defects (61%): 47 cases of anencephaly and 45 cases classified in the group of myeloencephaloceles. The anomalies of the prosencephalic evagination corresponded to 8% of all central nervous system malformations, with seven cases of holoprosencephaly. Posterior fossa malformations occurred in 3%, with three cases of Arnold-Chiari. In the present study, the mortality rate due to central nervous system malformations was higher in the neonatal period.

Holoprosencephaly: molecular study of a California population.

Holoprosencephaly (HPE) is a common developmental anomaly of the forebrain and midface in which the cerebral hemispheres fail to separate into distinct left and right halves. HPE is extremely heterogeneous. In addition to teratogenic agents, several genes are implicated in the cause of HPE. Using samples from a population-based birth defects registry in California, we performed a mutational analysis of the known HPE genes Sonic Hedgehog (SHH), ZIC2, and SIX3, in addition to two HPE candidate genes, TG-interacting factor (TGIF), and Patched (PTC), on a group of sporadic HPE patients. This is the first molecular study of HPE in a population-based sample of patients. Among these patients, a deletion in the homeodomain of SIX3 and several polymorphisms in SIX3 and TGIF were identified. No sequence changes were detected in SHH, ZIC2, and PTC. Our results suggest that mutations in the currently recognized HPE genes may explain <5% of all sporadic HPE cases.

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.

The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly.

Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.

Absent Labial Frenulum in Holoprosencephaly

Absence of the superior labial frenulum is reported in 88% of 17 consecutive cases of holoprosencephaly examined at St Christopher’s Hospital for Children, Philadelphia, PA.

Different proximal and distal rearrangements of chromosome 7q associated with holoprosencephaly.

Four new cases of holoprosencephaly are described in fetuses exhibiting abnormal karyotypes with different distal and proximal rearrangements of the long arm of chromosome 7. Three of them showed terminal...

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.

The development of the corpus callosum in semilobar and lobar holoprosencephaly.

The objective of this study was to determine whether and how a true corpus callosum develops in milder cases of holoprosencephaly. The MR scans of seven patients with holoprosencephaly and a callosum-like structure were reviewed. The anatomy of the callosum-like structure and the pericallosal anatomy were evaluated. Six of the seven cases had a posterior corpus callosum. The seventh case was indeterminate because lack of myelination prevented confirmation that the callosum-like structure consisted only of white matter. In each case the posterior corpus callosum formed posterior to white matter which spanned the interhemispheric fissure beneath a layer of cortical gray matter. A posterior corpus callosum can develop in holoprosencephaly because the first callosal axons use the white matter of the undivided hemispheres as a bridge to cross the interhemispheric fissure.