Molecular analysis of holoprosencephaly in South America

Abstract

Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.

Premaxilla: up to which age it remains separated from the maxilla by a suture, how often it occurs in children and adults, and possible clinical and therapeutic implications: Study of 1,138 human skulls

“…The agenesis of the premaxillary bone in some diseases 48 , 49 makes its existence and autonomy obvious, because the bone posterior to the premaxillary-maxillary suture, the maxillary bone, is present and functional.…”

New <b><i>SHH</i></b> and Known <b><i>SIX3</i></b> Variants in a Series of Latin American Patients with Holoprosencephaly

“…Double strands of the coding regions and exon-intron borders of SHH, ZIC2, SIX3, and TGIF1 genes were submitted to Sanger sequencing. Amplification protocols of these regions and primers were described in Savastano et al [2014]. Amplicons were visualized in 1% agarose gel and further purified by GFX PCR DNA and Gel Band Purification kit (Ge Healthcare, UK), according to the manufacturer's instructions.…”

The role of teratogens in neural crest development

“…Additional evidence coming from studies on the chick embryo have shown that alcohol produces the suppression of Wnt and Shh signals, which thereby alter the migration, expansion and survival of the NCCs (Flentke & Smith, ). In addition, scientific evidence has shown that exposure to high levels of maternal ethanol and to high blood sugar levels during pregnancy (gestational diabetes) can also lead to a holoprosencephalic phenotype in humans (Barr et al, ; Savastano et al, ). Recently, a correlation between the increased risk of neuroblastoma and parental alcohol use has been proposed, thus highlighting the importance of a healthy lifestyle during pregnancy (Müller‐Schulte, Kurlemann, Harder, & Edition, ).…”