Fetal Skeletal Dysplasias: Radiologic-Pathologic Classification of 72 Cases.

ObjectiveThe aim of this study was to classify the fetal skeletal dysplasias (FSD) in a series of affected fetuses based on radio-pathologic criteria. Materials and methods: We gathered clinicopathologic data of 72 cases which were diagnosed among 5995 autopsies performed over a 8-year period. Results: The prevalence of FSD was 1.2:100 autopsies. The overall sex ratio (M:F) was 1.25. Gestational age was between 17 and 24 weeks in 60% of cases. The FSD were classified into 13 distinct pathologic groups. Four major groups were identified: (1) Osteogenesis imperfecta (21 cases, 29%); (2) FGFR3 chondrodysplasia (18 cases, 25%); (3) Ciliopathies (9 cases, 12%); and (4) Sulfation disorders (7 cases, 10%). Thanatophoric dysplasia type 1 and lethal osteogenesis imperfecta were the most common skeletal dysplasias. Conclusion: Our study demonstrates the usefulness of the radio-pathologic examination in the diagnosis and accurate classification of the FSD, thus enabling better targeting of genetic counseling.

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Maternal 25-hydroxyvitamin D level and the occurrence of neural tube defects in Tunisia.

OBJECTIVE: To determine whether low vitamin D levels in pregnant women are associated with the occurrence of neural tube defects (NTDs) in Tunisia. METHODS: In a prospective study, pregnant women were recruited at a center in Tunis between January 1, 2012, and December 30, 2013. Women carrying a fetus with a severe NTD were recruited before elective termination. Matched, healthy pregnancy women were enrolled into a control group. Plasma levels of 25-hydroxyvitamin D were measured by a competitive chemiluminescence immunoassay. RESULTS: Overall, 68 women formed the NTD group and 64 the control group. The mean maternal vitamin D level was significantly lower in the NTD group (20.65±10.25nmol/L) than in the control group (28.30±13.82nmol/L; P<0.001). Vitamin D deficiency was recorded for 53 (78%) women in the NTD group and 39 (61%) in the control group. Vitamin D insufficiency was recorded for 15 (22%) women in the NTD group and 20 (31%) in the control group. Vitamin D sufficiency was found only in the control group (n=5 [8%]; P<0.001). CONCLUSION: The findings confirm an association between a decreased vitamin D level in pregnant women and the risk of fetal NTDs.

Association of maternal homocysteine and vitamins status with the risk of neural tube defects in Tunisia: A case-control study.

BACKGROUND: This study was conducted to determine whether low folate and vitamin B12 levels, as well as high homocysteine levels in pregnant women are associated with neural tube defects (NTDs) in Tunisia. METHODS: A total of 75 NTDs pregnancies and 75 matched controls were included in the study. Their vitamin B12, folate, and red blood cell folate concentrations were measured using a radio-immunoassay kit and total homocysteine concentrations were determined using a fluorescent polarization immunoassay. RESULTS: Vitamin B12 and folate concentrations were lower in NTD-affected pregnant women than in controls (respectively, p = 0.009 and p < 0.001). Total homocysteine concentration was significantly higher in the NTDs group than in controls (p = 0.008). In the case group, the folate levels were positively related with vitamin B12 levels (r = 0.54; p < 0.001) and negatively correlated with total homocysteine levels (r = -0.19; p = 0.04). Besides, red blood cell folate levels were positively correlated with folate levels (r = 0.24; p = 0.02) and negatively correlated with total homocysteine levels (r = -0.37; p = 0.001). CONCLUSION: Lower concentrations of folate and vitamin B12 are related to the increased risk of NTDs. Both folate and vitamin B12 intake insufficiency could contribute to the increased risk of NTDs. A dietary supplement, combining folate and vitamin B12, might be an effective measure to decrease the NTDs incidence in Tunisia.

[Antenatal diagnosis of multicystic renal dysplsia. Report of 11 cases]. / Diagnostic antenatal des dysplasies renales multikystiques. A propos de 11 cas.

BACKGROUND: Multicystic dysplastic of the kidney (UCDK) in the most common cause of an abdominal man in the new born period and is the most common cystic malformation of the kidney in infancy. The increasingly widespread use of prenatal diagnostic techniques has revealed that UCDK is apparently even more prevalent than had been assumed. THE AIM: of this study was to assess the utility of antenatal ultra ecography for in utero diagnosid of UCDK and its management. METHODS: A retrospective study of 11 UCDK cases diagnosed by antenatal ultra echography performed between the 4th and 6th monts of pregnancy. The outcome measure was radiographic imaginy It acts of a retrospective study of the 11 cases of DRMK diagnosed in anténatal by an echography obstétricale of the second quarter. A diagnostic confirmation was obtained by radiological examinations in post native for the pregnancies carried. RESULT: Patients with UCDK have significant associated urological and/or non urological malformations. In certain cases of non lethal anomalies, antenatal detection may influence both obstetric and postnatal management. Conservative management requires appropriate investigation of urinary tract tract and long-term follow-up.

[Retrocervical cystic hygroma: about 35 cases]. / Hygroma kystique du cou: à propos de 35 cas.

Retrocervical cystic hygroma is a congenital defect associated to chromosomic anomalies. We report a retrospective study about 35 cystic hygroma autopsies colliged in C.M.N.T in 10 years. Antenatal sonography has a sensibility 94.5%. Genetic abnormalities dominated by trisomie 13 Turner syndrome dad found in 11.5%. Medical abortion has done in 48.5%. A multidisciplinary management autorized to understand etiopathogeny of this defect.