A novel 2q14.1q14.3 deletion involving GLI2 and RNU4ATAC genes associated with partial corpus callosum agenesis and severe intrauterine growth retardation.

BACKGROUND: Microdeletions encompassing chromosome bands 2q14.1q14.3 are rare. To date, eight reports of relatively large deletions of this region (∼20 Mb) but only two small deletions (<6 Mb) have been reported. These deletions can cause a variable phenotype depending on the size and location of the deletion. Cognitive disability, facial dysmorphism, and postnatal growth retardation are the most common phenotypic features. CASE: We report on a novel 5.8 Mb deletion of 2q14.1q14.3 identified by array comparative genomic hybridization in a fetus with severe intrauterine growth retardation and partial agenesis of the corpus callosum. The deletion contained 24 coding genes including STEAP3, GLI2, and RNU4ATAC and was inherited from the mild affected mother. A sibling developmental delay and similar dysmorphic facial features was found to have inherited the same deletion. CONCLUSION: This case emphasizes the variable expressivity of the 2q14 microdeletion and reinforces the hypothesis that agenesis of corpus callosum, microcephaly, developmental delay, and distinctive craniofacial features may be part of the phenotypic spectrum characterizing the affected patients. We suggest that GLI2 is a dosage-sensitive gene that may be responsible for the agenesis of corpus callosum observed in the proband. Birth Defects Research (Part A) 106:793-797, 2016. © 2016 Wiley Periodicals, Inc.

Fatal subacute myocarditis associated with human bocavirus 2 in a 13-month-old child.

Human bocavirus has rarely been incriminated in fatal or life-threatening respiratory infections. We report a case of fatal disseminated infection with subacute lymphocytic myocarditis in a 13-month-old child. The human bocavirus 2 genome was detected by PCR analysis in nasal swab, plasma, urine, ascitic fluid, and mesenteric node, skeletal muscle, and lung tissue specimens.

The changes in angiogenic gene expression in recurrent multiple chorioangiomas.

OBJECTIVES: To assess the messenger ribonucleic acid expression in placental tissue of growth factors, cytokines, angiogenic and anti-angiogenic factors in one case of recurrent multiple chorioangiomas. METHODS: Complementary deoxyribonucleic acid array analysis was performed on the affected placentae and on normal placentaes (controls) to compare messenger ribonucleic acid levels of 96 genes involved in angiogenesis. RESULTS: Eleven genes presented more than two-fold alteration in expression levels: undetectable (angiopoietin 1, osteonectin, tyrosine kinase endothelial, neuropilin 1), decreased (transcription growth factor beta receptor 3, tissue inhibitor of metalloproteinase type 2, EGF receptor, integrin-alpha V, tyrosine kinase vascular endothelial growth factor receptor 2), increased (angiopoietin 2, osteopontin). CONCLUSIONS: We illustrated the complexity of angiogenic disruption in recurrent multiple chorioangiomas leading to the difficulty to propose a single candidate gene to explain this pathology.

Antenatal detection and impact on outcome of congenital diaphragmatic hernia: a 12-year experience in Auvergne, France.

OBJECTIVE: To evaluate the detection rate of prenatal diagnosis and its impact on outcome in congenital diaphragmatic hernia (CDH). STUDY DESIGN: We retrospectively studied 51 cases of CDH registered in the Auvergne area from January 1992 to December 2003 (Birth Defect Registry of Auvergne, Institut Européen des Génomutations). Our main outcome measurements were the detection rate of prenatal diagnosis, the incidence and types of associated anomalies and outcome (termination of pregnancy, in utero fetal demise, neonatal death, survival at the time of registration). RESULTS: Twenty-nine cases of isolated CDH were identified of which 13 were detected prenatally (45%) at a mean gestational age of 26.1 weeks and 22 cases of CDH with associated anomalies with prenatal diagnosis of CDH or any associated anomaly in 16 (73%; p=0.03) at a mean gestational age of 23.9 weeks. In the prenatally detected group (29 cases), there was 1 (3%) in utero fetal death (IUFD), 17 (59%) terminations of pregnancy (TOP) and 11 (38%) live births with early neonatal death in 7 (24%) cases despite delivery in a tertiary care centre in 10/11 cases (four survivors=14%). Most of the undetected cases were isolated CDH (16/22=73%) of which 1 (5%) was a stillborn and 21 (95%) live births with 17 survivors (77%) although 15/21 (71%) were not born at the tertiary care centre (p=0.001). The overall survival rate was 41% with a large variability depending on associated anomalies and prenatal diagnosis (p<0.0001) (prenatally detected cases: 3/13 (23%) isolated CDH and 1/16 (6%) CDH with associated anomalies; undetected cases: 13/16 (81%) isolated CDH and 4/6 (67%) CDH with associated anomalies). CONCLUSION: Prenatal diagnosis of CDH leads to the delivery of affected babies in tertiary care centres but it remains a challenge in particular for isolated CDH cases and it is associated with a lower survival rate. Associated anomalies contribute to prenatal detection, are related to a higher TOP rate but do not facilitate the detection of diaphragmatic defect per se.

Anti-HPA-9bw (Maxa) fetomaternal alloimmunization, a clinically severe neonatal thrombocytopenia: difficulties in diagnosis and therapy and report on eight families.

BACKGROUND: Fetal or neonatal alloimmune thrombocytopenia (FMAIT) results from a maternal alloimmunization against fetal platelet (PLT) antigens. In Caucasian persons, HPA-1a is the most frequently implicated antigen. During the past few years, FMAIT has been reported associated with rare or private antigens. STUDY DESIGN AND METHODS: Since the first documented case of FMAIT due to anti-HPA-9bw (Max(a)), no additional cases have been reported. Here a retrospective analysis is presented of the cases referred to our laboratories in recent years. The diagnosis was performed by genotyping and identification of the maternal alloantibody by the monoclonal antibody-specific immobilization of PLT antigens (MAIPA) technique. RESULTS: Parental genotyping showed HPA-9bw (Max(a)) mismatch as the sole antigenic incompatibility in seven of eight families. Because the father was found to be HPA-9bw (Max(a)) heterozygous in all the cases, the infant or fetus was genotyped to ascertain the diagnosis. The maternal alloantibody was identified in the MAIPA technique. These data strongly suggest, however, that recognition of the HPA-9bw (Max(a)) epitope is not uniform. The neonatal thrombocytopenia was severe in most cases with bleeding. The outcome was good in all the cases but one. CONCLUSION: This analysis confirms that anti-HPA-9bw (Max(a)) FMAIT is not uncommon and was found to be approximately 2 percent of our confirmed FMAIT cases. It is a clinically severe syndrome that requires prompt diagnosis, albeit difficult, and maternal PLT transfusion therapy. Laboratory investigation of a suspected FMAIT case should be carried out in a specialist laboratory well-experienced in optimal testing. Appropriate management and antenatal therapy should be considered for successive pregnancies to prevent fetal bleeding.

Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.

Comparison of different treatment regimens in a case of homozygous familial hypercholesterolemia.

The laboratory results of five periods of different treatment regimens were compared in a 19-year-old girl with homozygous familial hypercholesterolemia (FH): weekly low-density lipoprotein (LDL) apheresis sessions with dextran sulfate columns (LA 15, Kaneka Corporation, Osaka, Japan) without statin administration; weekly LDL apheresis with polyacrylate columns (DALI, Fresenius Adsorber Technology, Bad Homburg, Germany) without statin; LDL apheresis as in Period 2 with 40 mg atorvastatin daily; LDL apheresis as in Period 2 with 80 mg atorvastatin daily; and fortnightly LDL apheresis sessions with polyacrilate and administration of 80 mg atorvastatin daily. The five treatments were given in the above order, and each lasted at least 2 months. To compare the effectiveness of the different methods, the blood levels of total cholesterol, LDL-cholesterol and high-density lipoprotein (HDL)-cholesterol were measured before each session, and the percentage decreases in the blood levels of total cholesterol and LDL-cholesterol were recorded during sessions in Periods 1 and 2. In Periods 1 and 2, the biological effectiveness of LDL apheresis was comparable. Atorvastatin (40 mg daily) improved the blood levels of total cholesterol and LDL-cholesterol, but lowered HDL-cholesterol values. Increasing the daily dose of atorvastatin from 40 mg to 80 mg did not significantly improve LDL-cholesterol levels. When the time between two sessions was longer (Period 5), the total cholesterol and LDL-cholesterol values worsened and were comparable to those of Period 2 during which there was no atorvastatin treatment. In this case of homozygous FH, weekly sessions of LDL apheresis in association with atorvastatin at dose of 40 mg per day gave the best results.