Holoprosencephaly Sequence Research Articles

Hypotelorism

Hypotelorism

Holoprosencephaly sequence with a constellation of anomalies in Yenagoa, a Niger Delta Region: report of two cases

This report is on holoprosencephaly (HPE) sequence with other clinical and radiographic anomalies of other organs. This condition which has never been reported in Yenagoa, an oil rich Niger Delta Region was observed simultaneously in two neonates within a period of two months at different hospitals in this area. The inhabitants who include pregnant mothers with their fetuses are predisposed to health challenges associated with the exposure to toxic chemicals derived from environmental degradation and pollution due to oil spillage/processing. This report is therefore aimed at providing a description of HPE associated with varying multi-systemic conditions in order to motivate researches on prevalence of congenital anomalies and induce support in ensuring appropriate health care services. The approach to clinical evaluation and experience on diagnostic evidence is discussed. The importance of karyotypingwhich could not be carried out cannot be overlooked. However, the clinical and radiological features suggested the diagnoses of HPE Sequence. Holoprosencephaly (HPE) occurs due to a primary defect in prechordal mesoderm, resulting in fusion anomaly of the forebrain with also varying degrees of midline facial development anomalies. Although, HPE could be isolated, in certain conditions, it may occur in combination with other anomalies of the central nervous system and other organs. The causes of HPE are generally unknown but genetic and environmental factors have been implicated. Recognizing the prognosis in management, considerations vary from being conservative to reconstructive surgeries. The first neonate died on the 13th day of life, while the second neonate is still alive on supportive management of anticonvulsants and nutritional support on the 11th week of life at the time of writing this report.Keywords: Congenital malformations, Craniofacial malformations, Dysmorphism, Holoprosencephaly sequence, Niger Delta region

Macroscopic Analysis of Fetus Having Arhinencephaly, Synophthalmia and Holoprosencephaly

We report here a macroscopic analysis of one fetus conserved in Bouin then in formol having an arhinencephaly, synophthalmia associated with holoprosencephaly. We aimed to relate the various etiologies of observed anomalies in conjunction with the literature review. To perform the study, a fetopathologic examination including autopsy and radiologic analysis were done. Assay of FISH and OncoScan were made. Fetopathologic examination showed severe craniofacial malformations associated with extracranial defects including persistent troncus arteriosus communis, abnormal lung lobulation, extremities deformities and single umbilical artery. FISH and OncoSan had given unsuccessful results, because nucleic acids were highly degraded. The macroscopic examination of the fetus having arhinencephaly and synophthalmia highlights asymptomatology association with holoprosencephaly sequence and visceral defects.

Associated syndromes and other genetic variations at a South African cleft lip and palate clinic

A retrospective study was done of data on all patients registered at one of the largest cleft lip and palate clinics in South Africa (n = 3174). The associated syndromes and other genetic variations [(abbreviation:) ASGV] found in the population of persons suffering from facial cleft deformities (FCD) were analysed. 832 (26.2%) cleft lip and/ or palate patients presented with ASGV. Fifty-seven different types of syndromes were recorded of which the Fairbaim-Robin appearance (FRA) (or Pierre Robin sequence) 169 (5.3%), the Demarque-van der Woude syndrome 40 (1.3%), and the holoprosencephaly sequence cases 32 (1.0%) were the three most common ones. The three most common genetic variations found in the non-syndromic patients, were heart involvement 53(1.7%), club foot 42 (1.3%) and various eye problems 39 (1.2%). The main facial cleft deformity, namely the cleft lip, alveolus and palate (CLAP), was found in 26.2% of the ASGV-group. This particular cleft deformity was recorded at 39.7% in the FCD clinic. On the other hand, the hard and soft palate cleft (hPsP) group was found in 32.9% of patients who also had ASGV; in the total group of patients registered at the clinic, it accounted for only 16.6%. This means that ASGV occur less commonly in the CLAP group of patients, than in the hPsP group of patients.

Speculations on the pathogenesis of CHARGE syndrome

To be seriously considered, a theory about the pathogenesis of a multiple congenital anomaly syndrome should meet three criteria: (1) it should explain all of the anomalies associated with the syndrome; (2) it should explain why certain anomalies are not associated with the syndrome; and (3) it should predict anomalies that could be associated with the syndrome, but have not yet been described. The theory must eventually pass the ultimate test, that is, molecular confirmation of the proposed mechanism. Several theories about the pathogenesis of CHARGE syndrome have been proposed, but none of these meet the three criteria stated above. In this study, the author proposes that CHARGE syndrome is due to a disruption of mesenchymal-epithelial interaction (epithelial includes ectoderm and endoderm). The theory is tested against the major, minor, and occasional anomalies that are used to make the clinical diagnosis of CHARGE syndrome. Review of the known embryology of the organs and tissues involved in CHARGE syndrome confirms that mesenchymal-epithelial interactions are necessary for proper formation of these organs and tissues. The presence of limb anomalies in approximately one-third of CHARGE syndrome patients fulfills criteria #3 above, in that limb anomalies were not felt to be a part of CHARGE syndrome until relatively recently. It is known that some patients with chromosomal abnormalities have a phenotype that overlaps with CHARGE syndrome. Given that critical developmental pathways must be robust and redundant in order to minimize errors, it may be that disruption of more than one gene is necessary to generate the CHARGE phenotype, as has been proposed for the holoprosencephaly sequence. Mutations and deletions of CHD7 have recently been identified as causing CHARGE syndrome in more than 50% of tested patients. Given this gene classes' putative role as a general controller of developmental gene expression as well as mesodermal patterning, it would fit the hypothesized mechanisms discussed in the study.

A case of median cleft of the nose followed for a long period of time

Median cleft of the nose was first reported in 1989 by Trendelenburg as Doggennase. This is a very rare disease, and only approximately 30 cases of this condition have been reported in Japan [2]. Tessier’s classification is often used to classify facial clefts [4]. Median cleft of the nose corresponds to a No. 0 cleft according to this classification. No. 0 cleft of Tessier’s classification has two subtypes: frontonasal dysplasia sequence and holoprosencephaly sequence. The case to be reported was of the former type. The patient was followed for 15 years after birth; only soft tissue surgery was performed. The patient is now satisfied with her external appearance. She will be followed carefully and subsequent treatment will be provided.

Congenital anomalies in the teratological collection of Museum Vrolik in Amsterdam, The Netherlands. III: primary field defects, sequences, and other complex anomalies.

The Museum Vrolik collection of the Department of Anatomy and Embryology of the Academic Medical Center, University of Amsterdam, founded by Gerardus Vrolik (1775-1859) and his son Willem Vrolik (1801-1863), consists of more than 5,000 specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, the collection of congenital anomalies, comprising 360 specimens, was recatalogued and redescribed according to contemporary morphogenetic views. The original descriptions, if preserved, were compared with the clinical, radiographical, and magnetic resonance imaging findings. In 120 specimens the following midline anomalies, primary field defects, and sequences were diagnosed: holoprosencephaly sequence; aprosencephaly/atelencephaly; cleft lip; Pierre Robin sequence; omphalocele; diaphragmatic hernia; ectopic heart; bladder exstrophy; cloacal exstrophy; caudal dysgenesis; prune belly sequence; sirenomelia; fetal akinesia sequence; and disruption sequences. Polytopic field defects and associations were diagnosed in 25 specimens. We discuss the opinions of Gerardus and Willem Vrolik, who tried to find reasonable explanations for the dysmorphogenetic entities they investigated, rather than accepting the traditional superstitions.

Central Nervous System Anomalies

The authors review the most common congenital anomalies of the central nervous system (CNS): neural tube defects (NTDs), ventriculomegaly/holoprosencephaly, hydranencephaly, holoprosencephaly sequence, iniencephaly, and microcephaly. They emphasize the importance of the diagnostic tools (biochemical markers of the maternal serum, ultrasound screening, invasive techniques), methods which are complementary to each other.

Osteopathia striata with cranial sclerosis: highly variable phenotypic expression within a family

We report a four-generation family, with five individuals affected by osteopathia striata with cranial sclerosis (OS-CS). The family illustrates the wide spectrum of gene expression in this autosomal dominant condition. Of particular note is the unusually severe expression in the proband, who exhibits virtually all of the reported associations of the syndrome. Proximal osteolysis of the fibula and congenital urological abnormalities, in the proband, and holoprosencephaly sequence, in the proband's sister, have not previously been described in the syndrome.

CLINICAL SPECTRUM OF PATIENTS WITH RSH/SMITH-LEMLI-OPITZ SYNDROME. •474

The biochemical finding of increased 7-dehydrocholesterol (7-DHC) provides a reliable marker for diagnostic confirmation of the clinical diagnosis of the RSH/Smith-Lemli-Opitz (SLO) syndrome. We report on 80 patients with biochemically confirmed SLO to delineate the clinical spectrum of this disorder and to provide information about population genetics. The 7-DHC levels varied from 1.7 mcg/ml to 470 mcg/ml (normal ± SD = 0.10± 0.05 mcg/ml). Although 7-DHC levels were not correlated with clinical severity, cholesterol levels were inversely correlated, indicating that low cholesterol rather than high 7-DHC is the primary teratogenic factor in SLO. A continuum of biochemical and clinical severity was observed, with no discrete separation between those patients with the “type I” and“type II” phenotypes, suggesting that the type I and II phenotypes do not represent separate disorders. The most common clinical finding was 2-3 toe syndactyly (99%), followed by cleft palate (52%), postaxial polydactyly(43%), and cardiac defects (38%). One patient had alobar holoprosencephaly; and 2 others had midline cleft lip, a feature commonly seen in those with the holoprosencephaly sequence. Two patients died of cholestatic liver disease. Cases were generally restricted to those of Northern European and Hispanic ancestry, and none was identified in those of African or Asian background. In 3 of 68 index families studied there were additional cases identified in extended family members. These included 2 first cousins, 2 maternal aunts, and 1 paternal uncle. No instances of known consanguinity were identified, although parents of one child were both of Native American Cherokee ancestry. This high rate of affected relatives and low rate of consanguinity indicate that the heterozygote frequency for SLO may be high, as has been suggested previously.

Syndromal hypothalamic hamartoblastoma with holoprosencecephaly sequence, microphthalmia, pulmonary malformation, radial hypoplasia and M??llerian regression

A 24-week-old fetus is described here with holoprosencephaly sequence (arhinencphaly and agensis of the corpus callosum) associated with brain and meningeal dysplasia, microphthalmia with an ectopic pigementary layer, hypothalamic hamartoblastoma, preaxial asymmetric limb reduction, lung hypoplasia, gastric hypoplasia, Müllerian regression, intestinal malrotation, asplenia and normal chromosomes. The differential diagnosis includes the Cerebroacrovisceral-Early Lethality (CAVE) phenotype, and the Pallister-Hall syndrome, but the anomalies best fit the severe form of microgastira-limb reduction syndrome. Together with a previous case reported by Meinecke, the pattern of anomalies appears to represent a combination of defects, related to but distinct from the microgastira-limb reduction syndrome.

Cytogenetic findings indicate heterogeneity in patients with blepharophimosis, epicanthus inversus, and developmental delay.

Three unrelated, mentally retarded boys with typical blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) were found to have chromosomal aberrations. One of them had a del(3)(p25), another patient had a de novo translocation t(2; 3), which after high resolution banding combined with chromosome painting was interpreted to be unbalanced with a loss of band q23. The third patient had a del(7)(q34). The phenotypes of the two patients with chromosome 3 related syndromes were similar, but the third also had genital malformations resembling the Smith-Lemli-Opitz syndrome. This patient had a palatal ridge, and a single mesial maxillary tooth suggesting the holoprosencephaly sequence, but CT scans of the brain were normal.

The face???brain relationship

An infant with midline facial cleft and a severe brain malformation, not typical of holoprosencephaly, is reported. The CNF abnormalities suggested a malformation in the same category, but distinguishable from the various forms of holoprosencephaly sequence.

Nasal pyriform aperture stenosis and the holoprosencephaly spectrum

Recent reports have described congenital nasal pyriform aperture stenosis, but do not address its etiology in detail. We describe a child with nasal pyriform aperture stenosis, submucus cleft palate, and hypoplastic maxillary sinuses. Chromosome analysis revealed a ring chromosome 18. Awareness of the association of midline facial defects with midline brain defects allowed us to predict that features of the holoprosencephaly sequence would be found. Subsequent evaluation revealed growth hormone deficit. Eventually the child manifested a single central incisor. We review the association between midline facial defects and holoprosencephaly to remind the otolaryngologist of the need to look at the whole patient as he treats specific upper airway problems.

Trisomy 4 in a fetus with cyclopia and other anomalies

We report on an 18-week fetus with cyclopia, alobar holoprosencephaly, complex congenital heart defect, anal atresia, oligosyndactyly, cystic hygroma, and skeletal abnormalities with trisomy 4. Structural anomalies were detected on routine ultrasound of the pregnancy of a 17-year-old G3 P1 TAB1 woman with sickle cell trait. Trisomy 4 conceptuses usually miscarry in the first trimester. We are aware of no other reports of a fetus with trisomy 4 and cyclopia. Causal association of chromosome abnormalities and holoprosencephaly sequence may be more apparent in embryos and early fetuses than term fetuses because of poor viability of affected conceptuses.

Five Cases of DeMyer Sequence: An Interophthalmic Dysplasia

Five cases with vomero-septal-prolabium agenesis, four with premaxillary agenesis, and one with hemipremaxillary agenesis are presented. All five patients had complete clefts of the secondary palate. No known family history for craniofacial dysmorphia was reported. Height and weight ranged from 2nd to 10th centile. Psychological testing showed intelligent quotients of 121, 93, 72 for three patients; two were microcephalic with undetermined IQ, but severe generalized developmental delay. CT scans for the patient with the IQ of 72 and for one of the two microcephalic subjects showed normal brain structures. The other microcephalic patients had midline prosencephalic dysgenesis. Cephalometric analysis of the cranial base and interorbital dimension using normal standards and self indexing showed hypotelorism and small anterior cranial bases to be apparently related to reduced size of the sphenoid. An intact ethmoid, nasal bone, and crista galli appear to represent key anatomic differences in these patients as compared to classical holoprosencephaly sequence subjects. It was suggested that this pattern of midline facial agenesis may range from a solitary central incisor to the most severe variant presented. Using the embryologic classification, these subjects fall best under the heading of craniofacial dysplasia rather than cerebral craniofacial dysplasia, as a different type of interophthalmic dysplasia or DeMyer sequence.

Five Cases of DeMyer Sequence: An Interophthalmic Dysplasia

Five cases with vomero-septal-prolabium agenesis, four with premaxillary agenesis, and one with hemipremaxillary agenesis are presented. All five patients had complete clefts of the secondary palate. No known family history for craniofacial dysmorphia was reported. Height and weight ranged from 2nd to 10th centile. Psychological testing showed intelligent quotients of 121, 93, 72 for three patients; two were microcephalic with undetermined IQ, but severe generalized developmental delay. CT scans for the patient with the IQ of 72 and for one of the two microcephalic subjects showed normal brain structures. The other microcephalic patients had midline prosencephalic dysgenesis. Cephalometric analysis of the cranial base and interorbital dimension using normal standards and self indexing showed hypotelorism and small anterior cranial bases to be apparently related to reduced size of the sphenoid. An intact ethmoid, nasal bone, and crista galli appear to represent key anatomic differences in these patients as compared to classical holoprosencephaly sequence subjects. It was suggested that this pattern of midline facial agenesis may range from a solitary central incisor to the most severe variant presented. Using the embryologic classification, these subjects fall best under the heading of craniofacial dysplasia rather than cerebral craniofacial dysplasia, as a different type of interophthalmic dysplasia or DeMyer sequence.