ABSTRACT
BACKGROUND: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. AIM: To estimate holoprosencephaly prevalence at birth. PATIENTS AND METHODS: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. RESULTS: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. CONCLUSIONS: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).
Subject(s)
Holoprosencephaly/epidemiology , Adolescent , Adult , Chile/epidemiology , Cleft Lip/epidemiology , Cleft Lip/etiology , Cleft Palate/epidemiology , Cleft Palate/etiology , Female , Holoprosencephaly/classification , Holoprosencephaly/complications , Humans , Live Birth , Male , Maternal Age , Prevalence , Sex Factors , Stillbirth , Young AdultABSTRACT
Background: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. Aim: To estimate holoprosencephaly prevalence at birth. Patients and Methods: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. Results: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. Conclusions: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).
Subject(s)
Adolescent , Adult , Female , Humans , Male , Young Adult , Holoprosencephaly/epidemiology , Chile/epidemiology , Cleft Lip/epidemiology , Cleft Lip/etiology , Cleft Palate/epidemiology , Cleft Palate/etiology , Holoprosencephaly/classification , Holoprosencephaly/complications , Live Birth , Maternal Age , Prevalence , Sex Factors , StillbirthABSTRACT
BACKGROUND: Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes. METHODS: We report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups. RESULTS: We detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues). CONCLUSIONS: From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012.
Subject(s)
Genetic Association Studies , Holoprosencephaly/genetics , Mutation , Nuclear Proteins/genetics , Transcription Factors/genetics , Adult , Alleles , Brazil/epidemiology , Case-Control Studies , Child , Child, Preschool , Female , Gene Frequency , Genotype , Heterozygote , Histidine/genetics , Holoprosencephaly/classification , Holoprosencephaly/ethnology , Humans , Male , Molecular Typing , Phenotype , Racial Groups , Sequence Analysis, DNAABSTRACT
Here we report on the clinical and genetic data for a large sample of Brazilian patients studied at the Hospital de Reabilitação de Anomalas Craniofaciais-Universidade de São Paulo (HRAC-USP) who presented with either the classic holoprosencephaly or the holoprosencephaly-like (HPE-L) phenotype. The sample included patients without detected mutations in some HPE determinant genes such as SHH, GLI2, SIX3, TGIF, and PTCH, as well as the photographic documentation of the previously reported patients in our Center. The HPE-L phenotype has been also called of HPE "minor forms" or "microforms." The variable phenotype, the challenge of genetic counseling, and the similarities to patients with isolated cleft lip/palate are discussed.
Subject(s)
Face , Holoprosencephaly/classification , Holoprosencephaly/diagnosis , Brazil , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/etiology , DNA Mutational Analysis , Face/abnormalities , Holoprosencephaly/complications , Holoprosencephaly/genetics , Hospitals , Humans , PhenotypeABSTRACT
Amplio espectro de anormalidades del desarrollo intracraneano y de la región media de la cara, producido por una división incompleta o inexistente del prosencéfalo (lóbulo frontal del embrión) en los hemisferios cerebrales laterales. Se describen su embriología, incidencia, etiología, formas de presentación, malformaciones asociadas, diagnóstico prenatal, y diagnóstico diferencial.
Subject(s)
Humans , Pregnancy , Infant, Newborn , Female , Congenital Abnormalities , Fetal Diseases/diagnosis , Holoprosencephaly/classification , Holoprosencephaly/diagnosis , Holoprosencephaly/etiology , Ultrasonography, PrenatalABSTRACT
Amplio espectro de anormalidades del desarrollo intracraneano y de la región media de la cara, producido por una división incompleta o inexistente del prosencéfalo (lóbulo frontal del embrión) en los hemisferios cerebrales laterales. Se describen su embriología, incidencia, etiología, formas de presentación, malformaciones asociadas, diagnóstico prenatal, y diagnóstico diferencial.
Subject(s)
Humans , Pregnancy , Infant, Newborn , Female , Holoprosencephaly/diagnosis , Holoprosencephaly/etiology , Holoprosencephaly/classification , Fetal Diseases/diagnosis , Congenital Abnormalities , Ultrasonography, PrenatalABSTRACT
La holoprosencefalia es un defecto medio del cerebro con amplio espectro malformativo cuya forma extrema es la ciclopia y es el resultado de una falla en la división del prosencefalo, que involucra el desarrollo del cráneo y rostro fetal puede verse en recién nacidos vivos y más frecuente en mortinatos y abortos. Se reporta 2 casos en el Hospital Patrocinio Peñuela Ruiz del Seguro Social. Un lactante menor de 9 meses de edad quién presentó como única manifestación hemiparesia isquierda y al realizar tomografía de cráneo se evidencia holoprosencefalia lobar y preescolar de 4 años y 4 meses quién al momento de nacer presenta perímetro cefalico de 31 cms, pérdida de la relación cráneo facial, fontanela anterior puntiforme, hendidura palpebral oblicua, diámetros craneales a los rayos X inferior al percentil 50, cariotipo. Tomografía revela holoprosencefalia lobar. Actualmente ambos en condiciones estables. A nivel mundial no existe reporte de sobrevida más allá de los 2 años