Alobar Holoprosencephaly Research Articles

Prenatal diagnosis of alobar holoprosencephaly, by use of ultrasound and magnetic resonance imaging in the second trimester

Prenatal diagnosis of alobar holoprosencephaly, by use of ultrasound and magnetic resonance imaging in the second trimester

Early Prenatal Diagnosis of Semilobar Holoprosencephaly Combined with A Dorsal Cyst and No Facial Defect

Holoprosencephaly (HPE) is a complex human brain abnormality caused by incomplete cleavage of the prosencephalon into the right and left hemispheres, occurring between the 18 th and 28 th day of gestation. Different levels of increasing severity are defined: (1) lobar HPE, where the right and left ventricles are separated, but with some continuity across the frontal cortex; (2) semilobar HPE with a partial separation; and (3) alobar HPE, the most severe form, with a single brain ventricle and no interhemispheric fissure. Mettler [1] described the dorsal cyst of HPE as a structure that “occupies the area of the calvarium above the dorsocaudal aspect of the diencephalons” and indicated that the “walls of this cyst are always directly continuous with the most caudal parts of the walls of the telencephalon medium and its cavity communicates directly with the common ventricle of the telencephalon”. Furthermore, he added that a variable amount of the anterior wall of the dorsal cyst is “fused with the dorsal surface of the thalamus, sealing over the third ventricle”. Other authors have suggested that aqueduct stenosis or atresia results in dorsal cyst formation [2,3]. There have been many reports on the nature of dorsal cyst in HPE, but it was always noted after birth. HPE is the most common but lethal defect in the congenital cerebral abnormalities. It is a heterogeneous etiologic disease that can be caused by both a teratogenic and/or a genetic basis. Alobar or semilobar HPE is usually combined with a facial defect due to the missed embryogenesis, but early prenatal diagnosis of semilobar HPE with a dorsal cyst and no facial defect is rare. Herein, we report a case of early detection of HPE with a dorsal cyst and no facial defect in a low-risk mother, to present the distinctive features of semilobar HPE and the hypotheses involving a dorsal cyst. A 27-year-old, gravida 1, para 0, woman first visited our prenatal clinic at 9 weeks of gestation. Previous obstetric history and family history were unremarkable. An ultrasound (US) scan confirmed an intrauterine pregnancy with a fetus of crown–rump length of 2.5 cm without abnormal findings. During the second visit at 12 weeks’ gestation, a second US scan illustrated a nuchal translucency measuring 1.8 mm and a clear nasal bone structure. However, a dorsal cyst over the magnum cisterna in the transverse view (Figure A) was noted. The follow-up scans showed abnormalities of the forebrain, including partial absence of the midline echo, partial fusion of the thalami and abnormal ventricular configuration (Figures B and C), but facial structure was normal. Semilobar type of HPE with a dorsal cyst was diagnosed at that time. The other organs and systems, including cardiovascular, gastrointestinal and urinary systems, were unremarkable under the sonographic examination. Examinations for the presence of toxoplasmosis, rubella, cytomegalovirus, herpes (TORCH) were performed but without positive findings. Consequently, amniocentesis was scheduled for the next visit.

Exploring 3-Dimensional Imaging Techniques in the Prenatal Interrogation of Cebocephaly

Cebocephaly is a very rare craniofacial abnormality defined by a tubular nose with a single median nostril and ocular hypotelorism noted almost exclusively in association with alobar holoprosencephaly. Because of the additional presence of a median cleft lip, this case report may represent a transitional form of facial dysmorphism in the well-established spectrum of facial defects associated with holoprosencephaly. Three-dimensional (3D) sonographic evaluation of this condition allows for the opportunity to reconstruct the imaging planes not obtainable by traditional 2-dimensional (2D) scanning. Volume slicing is particularly useful in the interrogation and diagnosis of the intracranial and facial anomalies characteristic of cebocephaly. This technique allows for the manipulation of the slice depth and thickness to optimize depiction of the targeted intracranial and facial structures.

Hydranencephaly Associated with Interruption of Bilateral Internal Carotid Arteries

Hydranencephaly is a rare and fatal central nervous system disorder where all or nearly all of the bilateral cerebral hemispheres are absent. The extensive hollow cerebrum is replaced with cerebrospinal fluid. Clinically, the differential diagnoses of hydranencephaly include severe hydrocephalus and alobar holoprosencephaly. Nearly all cases are sporadic, involving approximately 1 in 5000 continuing pregnancies. The exact main cause is still unknown, but hydranencephaly is usually found to develop secondarily to the occlusion of cerebral arteries above the supraclinoid level. We present the case of a 1-month-old male infant with hydranencephaly initially thought to be severely hydrocephalus via routine antenatal intrauterine sonography performed at 35 weeks of gestation. Hydranencephaly was confirmed by brain sonography, brain magnetic resonance imaging and magnetic resonance angiography postnatally. We discuss several imaging features that are helpful in distinguishing hydranencephaly from extreme hydrocephaly. Different theories that have been recently proposed regarding the origin of hydranencephaly are reviewed.

Prenatal Visualization of Cebocephaly with a Prominent Nose in a Second-trimester Fetus with Alobar Holoprosencephaly and Trisomy 13

Prenatal Visualization of Cebocephaly with a Prominent Nose in a Second-trimester Fetus with Alobar Holoprosencephaly and Trisomy 13

First trimester three‐dimensional transvaginal imaging of alobar holoprosencephaly associated with proboscis and hypotelorism (ethmocephaly) in a 46,XX fetus

A 19-year-old woman was scanned at 10(+6) weeks gestation by 2D-3D ultrasound. The fetus had a crown-rump length of 40.9 mm, with the cephalic pole occupied by a single cystic cavity measuring 10.6 x 7.7 x 6.8 mm and severe hypotelorism associated with mid-facial hypoplasia. 3D ultrasound confirmed the malformations seen on the 2D scan and enabled the visualization of a proboscis and a low-set right ear. Fetal karyotyping was performed by chorionic villus sampling. Due to major fetal malformations of the fetus, the patient opted for termination of pregnancy. First trimester sonographic diagnosis of holoprosencephaly relies on bilateral visualization of choroid plexuses in what has been called the 'butterfly' sign. Differential diagnosis between holoprosencephaly and hydranencephaly may be difficult in the first trimester of pregnancy. However, midline structures such as falx cerebri, interhemispheric fissure and third ventricle are present in hydranencephaly and are absent in alobar holoprosencephaly, and thalami are never fused in hydranencephaly. 3D ultrasound has demonstrated an increased definition of anatomical abnormalities of malformations, compared with 2D ultrasound, and has proven to be crucial in the decision-making process of parents and in later prenatal counseling, especially in this case where necroscopy examination was refused by the parents. Images obtained by 3D ultrasound gave detailed insight into this ventral midline anomaly, depicting much of the disordered prosencephalic development.

Three-Dimensional Sonographic Evaluations of Embryonic Brain Development

The purpose of this presentation is to show 3-dimensional development of the ventricles of the brain in early pregnancy, from 6 to 13 weeks, and to provide a reference for early diagnosis of central nervous system anomalies such as hydrocephalus and holoprosencephaly. From March 2007 to August 2007, 46 patients were included. All patients had routine first-trimester 2- and 3-dimensional sonographic examinations at the same time. All cases were examined with a Voluson 730 Expert or Voluson E8 ultrasound scanner (GE Healthcare, Milwaukee, WI) using a 4- to 8- or 6- to 12-MHz transvaginal probe. Volumes were reviewed and analyzed with GE 4DView release 6 software. After the inversion-rendering mode was selected, volumes were dissected by the MagicCut function to show the ventricles. A total of 34 volumes from 7 to 12 complete gestational weeks were successfully dissected. Those before 7 and after 12 weeks could not be dissected properly. The crown-rump length ranged from 12.7 to 68 mm. Twelve representative images of the rendered volumes in chronologic order are shown. The brain volume dissections of 2 fetuses with ventriculomegaly and alobar holoprosencephaly are shown for comparison. Early human brain ventricular structures could be evaluated in vivo with 3-dimensional sonography. This presentation shows the timeline of brain development and provides reference images to compare possible anomalies of development.

Clinical epidemiologic study of holoprosencephaly in South America

ECLAMC: Latin American Study of Congenital Malformations examined 4,157,224 births (1967-2000), detecting 370 newborns with suspected holoprosencephaly (HPE): 182 (49.2%) had only craniofacial defects; 99 (26.8%) had defects in other systems; (15.1%) had chromosomal anomalies; 5 (1.4%) had recognized syndromes; and 28 (7.6%) had isolated median cleft lip. The latter group was excluded from subsequent analyses because of epidemiological differences from the other groups. The birth prevalence rate (BPR) of isolated HPE was homogeneous among the 11 sampled countries, increasing from 0.5/10,000 births to 1/10,000 births between 1967 and 2000, suggesting improved ascertainment, mainly after 1996. Microtia, cleft lip/palate, and microstomia were preferentially associated with HPE, but cleft palate only was not. Maternal diabetes was more prevalent in HPE than in controls when adding the isolated and associated groups (OR: 3.5; 95% CI: 0.9-16.2). Maternal flu was more prevalent in isolated HPE (OR: 3.6; 0.9-16.6) and in isolated plus associated HPE (OR: 2.8; 1.0-7.9) than in controls. A second series of better documented HPE cases, 179 in number (2.2/10,000), ascertained from 827,968 births occurring from 2000 to 2003, was used for phenotypic definition of cerebral and facial anomalies. In 83 of 174 HPE cases with specified cerebral defects, 40% were alobar, 43% were semilobar, and 17% were lobar. All cases of cyclopia, ethmocephaly, and cebocephaly were of the alobar or semilobar types. Female excess occurred in the total sample, but not within the subgroups themselves because of their small sample sizes. Neither alobar HPE nor cyclopia was associated with female predilection. Among the 174 HPE cases, 39% had neither oral clefting nor a severe dysmorphic face. Of facial phenotypes, 26% had cyclopia, ethmocephaly, or cebocephaly; 25% had premaxillary agenesis; and 10% had cleft lip and palate or cleft palate only. Cyclopia was not associated with oral clefts; 6 of 8 cases of ethmocephaly had cleft palate; 6 of 20 cases of cebocephaly had oral clefts; 4 of 20 cases had premaxillary agenesis; and 2 of 20 cases had cleft palate.

A case of cebocephaly associated with abnormal genitalia

Holoprosencephaly is frequently accompanied by midline facial abnormalities such as hypotelorism, cyclopia, etmocephaly, and cebocephaly. Cebocephaly is a very rare congenital anomaly combining alobar holoprosencephaly, ocular hypotelorism, and a proboscis-like nose with single nostril. There is only one cebocephaly case with abnormal genitalia. We report to our knowledge the second case of cebocephaly associated with abnormal genitalia in the relevant literature.

Holoprosencephaly at 9 Weeks 6 Days in a Triploid Fetus

Received October 29, 2006, from the Fetal Medicine Center (W.S., I.L.), Department of Obstetrics and Gynecology, and Cytogenetics Laboratory (C.B.), Clinica Las Condes, Santiago, Chile. Manuscript accepted for publication November 2, 2006. We thank Filiberto Guerra, MD, for performing the postmortem examination and Medison Co, Ltd (Seoul, Korea) for an equipment loan. This work was supported by Sociedad Profesional de Medicina Fetal “Fetalmed” Limitada, Chile. Address correspondence to Waldo Sepulveda, MD, Fetal Medicine Center, Clinica Las Condes, Casilla 208, Santiago 20, Chile. E-mail: fetalmed@yahoo.com Abbreviations 3D, 3-dimensional oloprosencephaly is a rare intracranial abnormality arising from failure of the prosencephalon to cleave during early embryonic life, which results in different degrees of lateral ventricular fusion and facial defects.1 This condition is classified according to brain structures into lobar, semilobar, and alobar, the latter being the most severe form.1 In this report, we describe one of the earliest prenatally diagnosed cases of holoprosencephaly, in which 3-dimensional (3D) imaging was used to assist in the diagnosis. A 27-year-old woman, gravida 4, para 2, spontaneous aborta 1, was referred at the menstrual age of 9 weeks 6 days for sonographic evaluation because of a suspected fetal brain anomaly detected at the dating scan. Her medical and obstetric histories were unremarkable, and the current pregnancy was otherwise uncomplicated. Transvaginal sonographic evaluation at referral revealed a live singleton fetus with a crown-rump length of 34 mm and a large anechoic area behind the forehead (Figure 1). With the assistance of 3D eXtended Imaging technology (Accuvix XQ; Medison Co, Ltd, Seoul, Korea), including Multislice View and Volume CT, multiple sections of the fetal brain were obtained, which helped in selecting the best plane to show the single ventricular cavity and fused thalami (Figure 2). A follow-up scan 1 week later revealed a 45-mm live fetus with alobar holoprosencephaly, midfacial hypoplasia, small orbits, a suspected small omphalocele, and an increased nuchal translucency thickness of 5.6 mm (Figure 3). The placenta appearance was normal. Trophoblast culture obtained from chorionic villus sampling revealed a 69,XXY karyotype. The patient miscarried at 13 weeks. Pathologic examination of the fetus and placenta confirmed the prenatal diagnosis (Figure 4).

Holoprosencephaly

Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life.

Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’

Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’

Fetal central nervous system anomalies: fast MRI vs ultrasonography

目的 探讨快速MRI对胎儿中枢神经系统先天畸形的诊断价值并与超声(US)对照.方法 对48例孕妇产前行US和MRI检查,胎儿尸检及出生后随访检查证实中枢神经系统畸形22例,共26处.于US检查后3 d内行胎儿颅脑脊柱及胸腹部MR扫描,并与US诊断结果和尸检及随访结果进行比较.结果 引产后尸检发现17处畸形,出生后随访检查证实9处畸形,共26处(无脑畸形6处、脊柱裂2处、脑膜脑膨出3处、先天性脑积水7处、前脑无裂畸形1处、脑穿通畸形3处、蛛网膜囊肿2处、脉络丛囊肿2处),US诊断24处,准确率92.3%(24/26),误、漏诊各1处,假阳性率3.8%(1/26),漏诊率为3.8%(1/26),MRI诊断23处,准确率88.5%,误诊1处,假阳性率3.8%(1/26),漏诊2处,漏诊率为7.7%(2/26).比较2种方法差异无统计学意义(χ2 ＝0.22,P＞0.05).但快速MRI视野大,运动伪影少,组织分辨率高,能清楚显示脑灰白质、脑室系统、脑沟裂、蛛网膜下腔、脊柱等中枢神经系统解剖结构.结论 MRI对胎儿中枢神经系统先天畸形具有较高的诊断价值,可作为胎儿中枢神经系统先天畸形的一种重要的影像学诊断手段。

Alobar holoprosencephaly, mobile proboscis and trisomy 13 in a fetus with maternal gestational diabetes mellitus: a 2D ultrasound diagnosis and review of the literature

Alobar holoprosencephaly is a rare and severe brain malformation due to early arrest in brain cleavage and rotation. We report a congenital anomalous fetus with alobar holoprosencephaly, prenatally diagnosed by two-dimensional (2D) sonography at the 40 weeks of gestation. The mother was affected by gestational diabetes mellitus and was obese (BMI > 30 kg/m(2)). 2D Ultrasound depicted the cerebral malformation, cyclopy, proboscis, cardiac defects (atrial septal defect, hypoplastic left heart, anomalous communication between right ventricle and aorta) and extremities defects. The newborn died just after delivery. External examination confirmed a mobile proboscis-like nose on the normal nose position. The fetus had both claw hands. The right and left feet showed to be equine. Autopsy confirmed the ultrasound diagnosis and chromosome analysis revealed trisomy 13 (47,XY,+13). Fetopathologic examination showed cyclopy, proboscis and alobar holoprosencephaly of the fetus, which was consistent with Patau syndrome. The teratogenic effect of diabetes on fetus has been described, but no previous clinical case of a congenital anomalous fetus with trisomy 13 and maternal gestational diabetes has been reported. This case report is the first to describe 2D ultrasound diagnosis of alobar holoprosencephaly and trisomy 13 with maternal gestational diabetes mellitus.

Interstitial deletion of the short arm of chromosome 2 in a mother and child, with facial dysmorphism and mild learning difficulties

We report a mother and son with an interstitial deletion of chromosome 2: del(2)(p21p22.2). Both have mildly dysmorphic facial features and learning difficulties. This phenotype contrasts with two previously described cases with a similar deletion that presented with cyclopia and alobar holoprosencephaly.

PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly‐like features and normal MRI

We report five Brazilian probands with PATCHED (PTCH) mutations and highly variable phenotypes with holoprosencephaly in four cases and holoprosencephaly-like facial features with a normal MRI in a fifth case. Three of our mutations were novel: Ala443Gly, Val751Gly, and Val908Gly. Two patients had the same mutation (Val908Gly), but were phenotypically different: alobar holoprosencephaly, absent nasal septum, and midline cleft lip-palate in one case, and lobar holoprosencephaly, macrocephaly, hypertelorism, clefting of the nose, severe microphthalmia, and a single maxillary central incisor in the other. One of our patients had a Thr1052Met mutation, holoprosencephaly-like facial features, and a normal MRI. Ming et al. [(2002); Hum Genet 110:297-301] reported an identical mutation, but with alobar holoprosencephaly.

Single maxillary central incisor, holoprosencephaly, and holoprosencephaly‐like phenotype

Three patients--one with alobar holoprosencephaly and two with a holoprosencephaly-like phenotype--are reported with no identifiable mutations. In each case, one parent had a single maxillary central incisor (SMCI). We briefly review the holoprosencephaly-like phenotype and present a table of 25 conditions with SMCI.

Holoprosencephaly: Clinical, anatomic, and molecular dimensions

Holoprosencephaly is addressed under the following headings: alobar, semilobar, and lobar holoprosencephaly; arrhinencephaly; agenesis of the corpus callosum; pituitary abnormalities; hindbrain abnormalities; syntelencephaly; aprosencephaly/atelencephaly; neural tube defects; facial anomalies; median cleft lip; minor facial anomalies; single maxillary central incisor; holoprosencephaly-like phenotype; epidemiology; genetic causes of holoprosencephaly; teratogenic causes of holoprosencephaly; SHH mutations; ZIC2 mutations; SIX3 mutations; TGIF mutations; PTCH mutations; GLI2 mutations; FAST1 mutations; TDGF1 mutations; and DHCR7 mutations.

Prenatal Diagnosis of Alobar Holoprosencephaly with Cystic Hygroma

Holoprosencephaly is a kind of brain anomaly characterized by inadequate cleavage of the prosencephalon during early embryogenesis. In addition, holoprosencephaly associated with cystic hygroma and hydrops fetalis has never been reported. In this article, we report a rare case of holoprosencephaly associated with cystic hygroma and hydrops fetalis diagnosed prenatally. A 28-year-old woman, gravida 2, para 0, artificial abortion 1, was referred to our antenatal clinic at 16 weeks of gestation due to fetal cystic hygroma detected by prenatal routine ultrasonography at a local hospital. In our clinic, single ventricle with fused thalami and cystic mass at the fetal neck as well as hydrops fetalis were noted by level II ultrasound. Under the impression of holoprosencephaly with cystic hygroma and hydrops fetalis, termination of pregnancy with misoprostol was undertaken. The histopathology of fetal autopsy confirmed our diagnosis and disclosed additional intracranial abnormalities. Fetus with holoprosencephaly might have other associated structural abnormalities. Cystic hygroma and hydrops fetalis are rare associations. Meticulous sonographic examination to depict the associated defects are necessary in any fetus with holoprosencephaly.

Three-Dimensional First-Trimester Transvaginal Diagnosis of Alobar Holoprosencephaly Associated with Omphalocele in a 46,XX Fetus

A three-dimensional (3D) transvaginal diagnosis of alobar holoprosencephaly (HPE) with associated omphalocele is reported at 12 weeks, 3 days gestation. Diagnosis of HPE was based on visualization of a single holoprosencephalic cavity with absent falx and basal ganglia and omphalocele by the presence of abdominal wall defect with mid-gut herniation. Chorionic villus sampling showed a normal 46,XX karyotype. 3D volumetric reconstruction allowed a more detailed definition of the anatomic landmarks of the lesion, including visualization of a thin rim of cortical mantel within the prosencephalic cavity, the dysmorphic face with flattened nose, and the abdominal eventration that looked like an abdominal air bag on 3D volumetric reconstruction.