Diagnosis Of Holoprosencephaly Research Articles

Holoprosencephaly spectrum: an up-to-date overview of classification, genetics and neuroimaging.

Holoprosencephaly (HPE) is a complex forebrain congenital malformation with widely variable outcomes. It represents a disorder of ventral induction, which begins in the fifth gestational week. Its main feature is forebrain cleavage failure, which prevents the brain complete division into right and left hemispheres, the normal development of midline structures, and the deep brain structure. Based on the severity of prosencephalic cleavage failure, three classic forms (lobar, semilobar, and alobar) were described, and subsequently, interhemispheric variant (syntelencephaly) and septopreoptic variants were proposed. This review proposes a practical imaging approach to diagnosing HPE spectrum disorders, allowing an easier recognition and earlier diagnosis, which is essential for prenatal care and adequate parental counseling. In addition, we intend to simplify the understanding of HPE through a didactic discussion, schematic illustrations, and descriptions of each entity's current classification and critical neuroimaging features, as well as the main differential diagnosis of HPE.

Semilobar holoprosencephaly with cebocephaly associated with maternal early onset preeclampsia: a case report

BackgroundThe term holoprosencephaly was proposed by DeMyer and Zeman. It is a developmental defect of the embryonic forebrain with heterogeneous etiology including genetic and environmental factors. It is commonly associated with midfacial defects and has a spectrum of presentations. There are four types: alobar, semilobar, lobar, and variant. Holoprosencephaly is relatively rare. The overall prevalence in a multicenter study was 1 in 13,000 to 18,000 live births. However, the presentation of holoprosencephaly with cebocephaly, micropenis, agenesis of middle phalanges of the fifth finger, and postaxial polydactyly in association with early onset preeclampsia is extremely rare. We report a case with a constellation of the above congenital anomalies.Case presentationA 34-year-old gravida II para l woman presented to Felege Hiwot Referral Hospital with the diagnosis of semilobar holoprosencephaly and early onset preeclampsia with severity features. The gestational age at admission was 26 + 3 weeks. She is Amhara by ethnicity. The pregnancy was from a non-consanguineous marriage. She presented with the complaints of severe and persistent headache associated with blurring of vision and generalized body swelling. After she was stabilized, she and her husband were counselled and termination was decided. She gave birth after three doses of 100 microgram misoprostol given vaginally every 3 hours. The outcome was 1.1 kg male neonate; there were associated dysmorphic features of holoprosencephaly such as cebocephaly, micropenis, and postaxial polydactyl with agenesis of middle phalanges of the fifth finger. Only basic care was given and the neonate died after 20 minutes’ stay in our neonatal intensive care unit. The mother was counselled to have preconception and antenatal screening in her next pregnancy. She left the hospital relatively well.ConclusionIn women with a history of holoprosencephaly or holoprosencephaly in the current pregnancy, antenatal workups should include workup for fetal chromosomal disorders and metabolic workup for maternal preeclampsia. Sonographic diagnoses of holoprosencephaly always need a careful search for other congenital anomalies. In the severe forms, early termination should be counseled for its poor prognosis. Associated severe congenital anomalies and severe morbidities of the survivor can be discussed while counselling.

Challenging issues arising in counseling families experiencing holoprosencephaly.

The provision of information and support to families experiencing holoprosencephaly (HPE) in a loved one is unequivocally challenging, even for the most experienced clinicians. It deserves the balance of pertinent information coupled with medical guidance that forms the basis for shared decision-making; all of which is ideally contained within a supportive environment. It requires a willingness to carefully listen to the specific concerns of the parents and family allowing them to revisit challenging issues as much as needed to encourage existing road blocks to be resolved. It necessitates that professionals see each and every family as unique, without preconceived notions about what is or is not important and being prepared to accept thoughts and decisions that may not fit with the professional's own beliefs. To some, this may sound impractical, inefficient, or even impossible within the time constrained models of modern day clinical services. However, in practice, this patient-focused approach is arguably the most essential step in providing "personalized medicine" to the populations we encounter. This manuscript is intended to provide a brief review of relevant literature and case discussions to highlight issues for families learning of the diagnosis of HPE during a pregnancy, at birth, during childhood or more rarely, in adolescence.

Molecular testing in holoprosencephaly.

Holoprosencephaly (HPE) is a structural brain anomaly characterized by failure of the forebrain to separate during early embryogenesis. Both genetic and environmental etiologies of HPE have been discovered over the last three decades. Traditionally, the genetic workup for HPE has been a karyotype, chromosomal microarray, and/or Sanger sequencing of select genes. The recent increased availability of next-generation sequencing has changed the molecular diagnostic landscape for HPE, associating new genes with this disorder such as FGFR1. We conducted a systematic review of the medical literature for the molecular testing of HPE for studies published in the last 20 years. We also queried known commercial diagnostic laboratories and used information on their websites to construct a list of available commercial testing. Our group released its first recommendations in 2010 and this update incorporates the technology shifts and gene discoveries over the last decade. These recommendations provide a guide for genetic diagnosis of HPE, which is paramount for patients and their families for prognosis, treatment, and genetic counseling.

First trimester screening for holoprosencephaly with choroid plexus morphology (‘butterfly’ sign) and biparietal diameter

The aim of this study was to determine whether choroid plexus morphology ('butterfly' sign) and biparietal diameter (BPD) are effective sonographic screening tools for holoprosencephaly (HPE) in the first trimester. An axial view of the fetal head was obtained routinely to determine the presence of the 'butterfly' sign in pregnancies presenting for sonographic screening at 11-13 weeks of gestation. The same view was also used to obtain BPD measurements. The definitive diagnosis of HPE was established by the sonographic demonstration of an anterior cerebral monoventricular cavity and thalamic fusion. During a 9-year study period, 11 068 live fetuses were screened. There were 11 cases of HPE (prevalence 1/1006); all of them were detected by demonstration of an absent 'butterfly' sign with no false-positive cases. The BPD was less than the 5th percentile in 40% of the cases. The 'butterfly' sign appears to be a highly sensitive marker for HPE in the first trimester. On the other hand, BPD measurements had a lower sensitivity, implying that microcephaly is not a prominent first-trimester feature in these cases. Incorporation of the 'butterfly' sign into the first trimester anatomy scan is simple and can facilitate the identification of the vast majority of fetuses with HPE in the first trimester.

Alobar holoprosencephaly, cebocephaly, and micropenis in a Klinefelter fetus of a diabetic mother

ObjectiveCoexistence of Klinefelter syndrome and holoprosencephaly (HPE) is rare. We report alobar HPE, cebocephaly, and micropenis in a Klinefelter fetus of a mother with type 2 diabetes mellitus with obesity and poor metabolic control. Case ReportA 38-year-old woman was referred for therapy of type 2 diabetes mellitus with poor glycemic control at 24 weeks of gestation. On examination, she had a body height of 162 cm and a body weight of 105 kg. She had been treated with oral medication for diabetes mellitus for 4 years with poor maternal metabolic control. She had prominent glucosuria and glycemia. Her hemoglobin A1c was 7.5% (normal range: 3.4–6.1%), and the fasting glucose level was 141 mg/mL (normal range: 70–99 mg/mL) during this visit. Her husband was 46 years old. Prenatal ultrasound revealed a singleton fetus with fetal biometry equivalent to 24 weeks, alobar HPE, cebocephaly, and micropenis. As a result of poor maternal heath and fetal anomaly, the parents elected to terminate the pregnancy, and a 986-g male fetus was delivered with hypotelorism, HPE, cebocephaly, micropenis, and cryptorchidism. Cytogenetic analysis of the cord blood revealed a karyotype of 47,XXY. The parental karyotypes were normal. Polymorphic DNA analysis revealed a paternal origin of the extra X chromosome. Molecular analysis of the HPE genes of SHH, ZIC2, SIX3, and TGIF revealed no mutations. ConclusionPrenatal diagnosis of HPE should include a biochemical examination to identify metabolic factors such as maternal diabetes, and preventive management should be considered in subsequent pregnancies to achieve good control of maternal diabetes.

Familiäre Holoprosencephalie – Späte Diagnose trotz Wiederholungsfall

Holoprosencephaly (HPE) is a serious malformation of the central nervous system which occurs between the 18th and 28th day of gestation. HPE can appear in different manifestations within one family. The diagnosis of HPE can be performed in an early sonographic scan between the 12th and the 14th week of gestation, according to the guidelines for the examination of the foetal nervous system. The history of a pregnant woman with a previous birth of a foetus with cerebral malformation and having a partner with minor signs for HPE justifies an intensified sonographic examination and molecular analysis. An amniocentesis was done just for the basic analysis, not for further genetic testing. However, it is very important to have information about a recurrency risk for every subsequent pregnancy.

P15.11: Holoprosencephaly at prenatal ultrasound: different etiologies for the same ultrasound finding

Objectives: To assess the possibility of finding an etiology in a prenatal diagnosis of holoprosencephaly. Methods: From 1996–2009, 11116 prenatal diagnoses through CVS or amniocentesis were performed in a single center. Every diagnosis of holoprosencephaly at ultrasound was considered. Gestational age, ultrasound findings and karyotype were recorded. When relevant, molecular diagnosis or parental karyotype was studied. Results: 22 fetuses were diagnosed with holoprosencephaly (0.19%). Mean gestational age was 19 weeks. All cases had additional ultrasound findings (100%). A definitive etiology was found in 18 cases (81.8%): Karyotype was abnormal in 14 cases (63.6%) and normal in 8 (36.4%). There were 10 free trisomies (9 trisomies 13 and 1 trisomy 18), 4 structural chromosomal anomalies (3 inherited from parental balanced translocations and one de novo). In the group with normal karyotype: one autosomal dominant mutation of gene SIX was diagnosed. Both parents tested negative. One case had a postnatal diagnosis of dysgnathia complex. Two fetuses had Smith Lemli Opitz: low cholesterol levels at cordocentesis and 2 mutations at the gene DHCR were found. Both parents were carriers. In four cases with normal karyotype no etiology was found: in one case, no results were achieved due to a cytogenetic culture failure and in three other cases no etiology could be found. Conclusions: Our results showed that a definitive etiology can be achieved in 8 out of 10 cases when holoprosencephaly is found at a prenatal ultrasound. The fact that holoprosencephaly is strongly associated with chromosomal anomalies was supported with our data. However, in euploid fetuses, the searching for a molecular diagnosis is warranted since different genes with different patterns of inheritance may be responsible for this malformation. The finding of parents carrying mutations or structural chromosome balanced rearrangements is crucial for planning PGD in future pregnancies.

Prenatal Ultrasound Diagnosis in 51 Cases of Holoprosencephaly: Craniofacial Anatomy, Associated Malformations, and Genetics

To analyze the prenatal ultrasound findings of the craniofacial and extracephalic anatomy, the postnatal pathological findings, and the genetic anomalies in 51 cases of holoprosencephaly (HPE). Between 1990 and 2005, a collective of 51 fetuses with tentative ultrasound diagnosis of HPE was recruited at two tertiary referral centers for prenatal ultrasound diagnostics via the Pia Fetal Database (GEMedical Systems, Webling, Germany). Cephalic as well as extracephalic anomalies were investigated, and all cases were subdivided into the subgroups lobar, a lobar, and semilobar HPE. In addition to the ultrasound investigation, 45 fetuses were analyzed for genetic anomalies and 21 fetuses underwent an autopsy. The average age at diagnosis was 21.9 weeks of gestation. There was a greater number of female fetuses, with an overall ratio of 2.67:1. In 61% of all cases, there was a reduction of growth in comparison with healthy fetuses of the same age. Within the second trimenon, the cephalic anomalies became evident when investigating the diameter of the fetal head (second trimenon: 71%below the fifth percentile; third trimenon: 92% below the fifth percentile). In 82%of the cases, extracephalic anomalies were diagnosed additionally. In 63%, the diagnosis of holoprosencephaly led to a termination of pregnancy. Ten percent of the fetuses were born alive. In 81% of the cases, the diagnosis of HPE was confirmed postnatally. The remaining 19% showed other severe cephalic and extracephalic anomalies. Chromosomal anomalies were detected in 79% of the fetuses, most frequently trisomy 13 (59%). Because of recent advances in the development and improvement of high-resolution ultrasound, early diagnosis of congenital anomalies such as HPE is now possible. In this study, which represents the largest collection of prenatally diagnosed HPE reported in the literature to date, the average age at diagnosis was earlier than in other studies. The ultrasound devices of today provide excellent images of the fetus that allow an exact diagnosis of craniomaxillofacial anomalies as well as extracephalic anomalies. Apart from a very few cases, the diagnosis of HPE is incompatible with life.

3-D reconstruction of a human fetus with combined holoprosencephaly and cyclopia

BackgroundThe purpose of this study was to examine a human fetus with combined holoprosencephaly and cyclopia by means of histology and 3-D reconstruction to determine the internal structure and extent of the malformation.MethodsThe head from a human fetus at 20 weeks gestation and a diagnosis of holoprosencephaly and cyclopia was investigated histologically and three-dimensionally reconstructed with CAD techniques. The cranial bones, blood vessels, nerves, eye and brain anlagen were reconstructed.ResultsThe 3-D reconstruction revealed both severe malformation and absence of the facial midline bones above the maxilla, and a malformation of the maxilla and sphenoid bone. The mandible, posterior cranial bones, cranial nerves and blood vessels were normal. A synophthalmic eye with two lenses was found. The prosencephalon was a single small protrusion above the diencephalon. No nasal cavity was present. Above the single eye a proboscis was found.ConclusionThe absence of the facial midline bones above the maxilla and the presence of a proboscis as a nose-like structure above the cyclopic eye both mean that there was a developmental defect in the fronto-nasal facial process of this fetus.

Holoprosenzephalie: Kriterien und Konsequenzen der pränatalen Diagnostik

Two cases of prenatal diagnosis of holoprosencephaly are described. The characteristic sonographic findings in the second trimester were: microcephaly, absence of the midline echo, hypotelorism and typically flattened profile without sufficient configuration of the nose. Both foetuses had midline facial clefts, one of which was diagnosed prenatally. One case demonstrated a dorsal intracranial cyst. Analysis of the karyotype after foetal blood sampling and amniocentesis revealed translocation trisomy 13 in one case. The mother of this foetus had a balanced translocation 13/14. This foetus also had many extracranial abnormalities in contrast to the other foetus, which had a normal karyotype. Additionally we report of the prenatal diagnosis of a third case with cyclopia and trisomy 13. The findings of the autopsy of the foetuses are described and the criteria for prenatal diagnosis are compared to those found in the literature.

The Risk of Recurrence of Holoprosencephaly in Euploid Fetuses

To determine the cause of and devise a management strategy for holoprosencephaly cases seen at a regional tertiary referral fetal medicine unit. Holoprosencephaly cases referred to University College London Hospital's Fetal Medicine Unit in the past 15 years were ascertained from a fetal database. We examined maternal, neonatal, genetic, and pathology records for prenatal and postnatal management, outcome, and genetic follow-up. Forty-three women presented with a diagnosis of holoprosencephaly in one or more pregnancy. In one woman with a single affected pregnancy, there were incomplete data, and the postnatal diagnosis was not holoprosencephaly. For the remaining 41 women with complete outcome data, parental consent for fetal karyotyping was given in 36 women (88%) and was abnormal in 21 women (58%). Fifteen women had a euploid fetus or fetuses, of whom three women (20%, 95% confidence interval 4-48%) had a recurrence of holoprosencephaly. One woman had six affected pregnancies, the first diagnosed at 20 weeks of gestation and then at 12-14 weeks. The parental karyotypes were normal, but molecular analysis showed a mutation in the sonic hedgehog gene. In two women, holoprosencephaly was diagnosed at 27 weeks and birth, with a recurrence diagnosed at 22 and 24 weeks of gestation, respectively. In this series there was a 20% recurrence risk for parents whose fetus had holoprosencephaly and a normal karyotype. Genetic review for parental examination, magnetic resonance imaging scanning, and mutation analysis is important in these cases. First-trimester ultrasound scanning is advised to detect recurrence early in gestation. III.

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.

Prenatal Diagnosis of Holoprosencephaly With Cyclopia

The authors report a case of holoprosencephaly with cyclopia, diagnosed prenatally at a gestational age of 19 weeks. The patient’s clinical history was normal, except for aspirin usage for her headache. The sonographic diagnosis was based on the intracranial finding of fused thalami with no visible midline structures and facial abnormalities, including cyclopia, proboscis, and absence of the nose. These findings are characteristic of alobar holoprosencephaly. With the informed consent of the patient, the pregnancy was terminated by induction after proper counseling. Postmortem examination of the abortus material confirmed the presence of cyclopia and a proboscis.

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.

The decision to continue: the experiences and needs of parents who receive a prenatal diagnosis of holoprosencephaly.

Holoprosencephaly (HPE) is a condition characterized by a defect in the development of the midline embryonic forebrain. When detected prenatally, the diagnosis of HPE offers parents a poor but often uncertain prognosis. Since the majority of parents receiving a prenatal diagnosis of an abnormality terminate their pregnancies, few studies have examined parents' experiences and needs surrounding the decision to continue a pregnancy. We present a descriptive study of in-depth interviews with 24 parents who chose to continue their pregnancy after receiving a prenatal diagnosis of HPE. Parents were asked about their decision-making process to continue the pregnancy. Qualitative analysis was used to identify common themes that emerged from these parents' experiences. The results suggest that most parents did not make an active decision about continuing the pregnancy. Rather, they described a more subtle decision-making process that evolved over time and consisted of several factors. These factors included the parents' religious and personal beliefs, past experiences, and the uncertainty involved in the diagnosis of HPE. Throughout the decision-making process, they described informational, emotional, and supportive needs from family, friends, and health professionals. All of these factors contributed to the evolution of the parents' decision to continue the pregnancy and the acceptance of their decision. Results of this exploratory study suggest health care professionals need to work with parents as they make their decision to continue an affected pregnancy. The results also provide the groundwork for prospective investigation into parents' decision-making process as they receive and adjust to prenatal diagnoses of an abnormality.

Midline Skeletodental Morphology in Holoprosencephaly

Abstract Objective: The purpose of the present study was to analyze histologically the midline structures in a human fetus with holoprosencephaly and a single median maxillary central incisor. Methods: A human male fetus, CRL 137 mm, postconceptional age 18 weeks, with a diagnosis of holoprosencephaly, the cebocephalic type (one nostril), and alobar brain development, was investigated. After radiography, the cranial midline structures were examined histologically. Results: The histological examination revealed partial absence of the intermaxillary suture (in the region anterior to the central incisor), absence of the internasal suture, and partial absence of the metopic suture (caudal part). A single midline nasal bone was observed instead of two bilateral nasal bones, and a midline maxillary central incisor was found instead of two bilateral incisors. A short nasal septum, absence of crista galli, and partial absence of cartilaginous tissue anterior to the sella turcica in the region of the presphenoid b...

Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly

Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the...

Surgical treatment of patients with lobar holoprosencephaly: A personal note

The diagnosis of holoprosencephaly usually implies a poor prognosis and is often regarded as a contraindication for surgical correction of associated clefts of the lip or palate. Between 1985 and 1991, 4 patients with lobar holoprosencephaly were evaluated and studied with computed tomography or magnetic resonance imaging. All had cleft palate and 3 had paramedian cleft lip; all 4 exhibited some degree of nasal dysplasia. All patients are presently alive, at a mean age of 26.6 +/- 2.4 months (mean +/- SD). Three of the children showed normal or near normal development, whereas the fourth was severely retarded. Our experience suggests that some children with lobar holoprosencephaly have a highly variable degree of intellectual development and that long-term survival may be expected.

Surgical treatment of patients with lobar holoprosencephaly: a personal note.

The diagnosis of holoprosencephaly usually implies a poor prognosis and is often regarded as a contraindication for surgical correction of associated clefts of the lip or palate. Between 1985 and 1991, 4 patients with lobar holoprosencephaly were evaluated and studied with computed tomography or magnetic resonance imaging. All had cleft palate and 3 had paramedian cleft lip; all 4 exhibited some degree of nasal dysplasia. All patients are presently alive, at a mean age of 26.6 +/- 2.4 months (mean +/- SD). Three of the children showed normal or near normal development, whereas the fourth was severely retarded. Our experience suggests that some children with lobar holoprosencephaly have a highly variable degree of intellectual development and that long-term survival may be expected.