Abstract
Corpus callosum defects are frequent congenital cerebral disorders caused by mutations in more than 300 genes. These include genes implicated in corpus callosum development or function, as ...well as genes essential for mitochondrial physiology. However, in utero corpus callosum anomalies rarely raise a suspicion of mitochondrial disease and are characterized by a very large clinical heterogeneity.
Here, we report a detailed pathological and neuro-histopathological investigation of nine foetuses from four unrelated families with prenatal onset of corpus callosum anomalies, sometimes associated with other cerebral or extra-cerebral defects. Next generation sequencing allowed the identification of novel pathogenic variants in three different nuclear genes previously reported in mitochondrial diseases: TIMMDC1, encoding a Complex I assembly factor never involved before in corpus callosum defect; MRPS22, a protein of the small mitoribosomal subunit; and EARS2, the mitochondrial tRNA-glutamyl synthetase. The present report describes the antenatal histopathological findings in mitochondrial diseases and expands the genetic spectrum of antenatal corpus callosum anomalies establishing OXPHOS function as an important factor for corpus callosum biogenesis.
We propose that, when observed, antenatal corpus callosum anomalies should raise suspicion of mitochondrial disease and prenatal genetic counselling should be considered.
Boutaud et al. present findings from a pathological and neuro-histopathological investigation of foetuses with prenatal onset of corpus callosum anomalies and mitochondrial disorders caused by pathogenic variants in nuclear genes encoding mitochondrial proteins: TIMMDC1, EARS2 and MRPS22.
Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different ...mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.
Basal cell carcinoma (BCC) is the most frequent skin cancer but <1% of the cases develop in the vulva. Histoprognostic features of vulvar BCCs are not recognized and, consequently, the treatment of ...the disease is not well codified. To overcome this lack of knowledge, we have performed a retrospective analysis of vulvar BBCs to assess the value of various histological features regarding the disease outcome. In all, 19 patients surgically treated for a vulvar BCC in the Centre Hospitalier Intercommunal de Créteil from March 1, 2000 to September 26, 2019 were retrieved. Clinical and histologic features were reviewed in all cases and analyzed in comparison with disease recurrence and patient's survival. The median age of the patients was 74 (range 54-99) yr. Tumor location on the labium majus was the most frequent (68%). None presented with a medical condition related to BCC. All the patients were treated by surgery alone, except one who benefited from additional radiotherapy. We found a significant association between tumor size and recurrences (P=0.031). Other features associated with disease outcome were tumor thickness, treatment type, and surgical margins. Recurrence was observed for tumors larger than 20 mm with a surgical margin of less than 3 mm. A combination of tumor size, thickness, and surgical margin are histoprognostic factors more significant than tumor subtype.
Background
Bainbridge‐Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo ...dominant loss of function mutation in the ASXL3 gene.
Case
We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation. We review 29 previous published cases.
Discussion
The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights ASXL3 as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous ASXL3 mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.
Background
Bainbridge‐Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo ...dominant loss of function mutation in the
ASXL3
gene.
Case
We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo
ASXL3
mutation. We review 29 previous published cases.
Discussion
The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights
ASXL3
as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous
ASXL3
mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.
Fetal heterotaxy: Should we still categorize? Houyel, Lucile; Bessières, Bettina; Gonzales, Marie ...
Archives of Cardiovascular Diseases Supplements,
September 2021, 2021-09-00, Volume:
13, Issue:
4
Journal Article
Peer reviewed
Heterotaxy (HTX) is usually stratified in right (RI) and left isomerism (LI).
We analyzed 61 fetal specimens with HTX divided in 5 groups: classic LI CLI: bronchopulmonary LI, bilaterally absent ...pectinate muscles (PM), polysplenia, n=22, non-classic LI (NCLI: one discordant feature, n=13), classic RI (CRI: bronchopulmonary RI, bilateral extent of PM to the crux, asplenia, n=12), non-classic RI (NCRI: one discordant feature, n=6, totally discordant features, n=8).
Non-classic patterns were found in 44% (33% RI, 37% LI). Among those, the status of the spleen was highly variable (NCLI with asplenia 38%, NCRI with single spleen 66%), while the bronchial status was almost always concordant. Intestinal malrotation was present in 83% CRI, 64% CLI, 50% NCLI, 50% NCRI.
Extent of PM was highly variable in NCLI (bilaterally left 46%, normal 46%, bilaterally right 8%), and bilaterally right in 83% of NCRI only. Interrupted inferior caval vein was seen in LI only; total extracardiac anomalous pulmonary venous connection (APVC) was seen only in RI, ipsilateral APVC only in LI. A common atrioventricular (AV) junction was constant in RI vs. 66% in LI, with a complete AV canal in 100% RI, 75% LI. Functionally univentricular hearts were found in 67% RI, 46% LI, right in 62.5%. Ventriculo-arterial (VA) connections were abnormal in 100% RI, 59% LI, double outlet right ventricle (DORV) being the most frequent type in all categories. Pulmonary atresia and stenosis were frequent in RI (77%), rare in LI. Aortic arch hypoplasia and coarctation were found almost exclusively in LI (57%). Right-sided aortic arch was found in 67% RI, 6% LI.
HTX and isomerism are not synonymous. Extent of PM is not always symmetrical (15%) and cannot therefore be considered the hallmark of HTX. Because HTX includes both abnormal symmetry and random organization of organs, each anatomic feature should be analysed individually rather than trying to categorize.
