A case of otocephaly with anencephaly and meningomyelocele

A case of otocephaly with anencephaly and meningomyelocele: Otocephaly is a rare lethal syndrome with microstomia, aglossia, agnathia, and synotia as major clinical features due to arrest in development of the first branchial arch. Some associated anomalies may be present as cyclopia, holoprosencephaly, cerebellar hypoplasia, situs inversus, and other visceral anomalies. We describe a case of fetus, spontaneously aborted in the 14th week of gestation with otocephaly complex (agnathia, synotia, microstomia) and associated anencephaly and meningomyelocele.     

Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options

Electrical storm occurring in a patient with the Brugada syndrome is an exceptional but malignant and potentially lethal event. Efficient therapeutic solutions should be known and urgently applied because of the inability of usual antiarrhythmic means in preventing multiple recurrences of ventricular arrhythmias. Isoproterenol should be immediately infused while oral quinidine should be further administrated when isoproterenol is not effective. In case of failure of these therapeutic options, ablation of the triggering ventricular ectopies should be attempted.     

The fetal akinesia deformation sequence. A fetopathological approach

In this paper we review the present knowledge on the etiological factors and pathogenetic mechanisms of the fetal akinesia deformation sequence, based on a fetopathological approach. Special attention is given to two sever, lethal subgroups i.e. the Pena-Shokeir I syndrome and the lethal multiple pterygium syndrome.     

DSCR1 (ADAPT78) lethality: evidence for a protective effect of trisomy 21 genes?

Over the last several years, suggestive evidence has accrued supporting a possible involvement for DSCR1 (ADAPT78) in Down syndrome. Toward testing this, we attempted to generate DSCR1 transgenic mice. Surprisingly, in almost every case, embryonic lethality was observed. In C57Bl/6 mice, DSCR1 human transgene was identified in developing embryos prior to lethality and up to day 9.5. Its mRNA expression was also observed and varied relative to control. In rare instances (twice) where transgenics survived to term, no mRNA expression was observed, suggesting that expression is required for lethality. This lethal phenotype contrasted with, and was surprising in light of, mouse models of Down syndrome where multiple chromosome 21 genes including Dscr1 are overexpressed and survive to term. To explain the seemingly contradictory lethal effect of DSCR1 by itself but not in combination with other trisomy genes, we propose that some trisomy genes (including DSCR1) confer lethality, but others suppress it.     

Delayed presentation of pacemaker Reel Syndrome and lead damage: Coincidence or consequence?

Reel syndrome is a pacemaker lead early dislodgment, characterized by reeling-in of the lead(s) without being damaged. We herein present a case of an 86-year-old woman, with medical history of single chamber pacemaker implantation two years ago, admitted in cardiology department with complete AV block. Chest-Xray revealed ventricular lead coiling around and behind the pacemaker device. Urgent extraction of the previous pacemaker was performed; however, the lead damage made its repositioning unfeasible. Successful implantation of single-chamber pacemaker has been made. This clinical case highlights the importance of adequate follow-up to timely identify lead dislodgement, avoid lethal complications and lead fracture.     

Heritable syndrome of skeletal defects in a family of Australian shepherd dogs

A syndrome of multiple defects including cleft palate, polydactyly, and often syndactyly, shortened tibia-fibula, brachygnathism and scoliosis lethal to males is described in a family of Australian shepherd dogs. Female pups lack the cleft palate and survive, but may exhibit the other defects to a lesser degree than do males. Litter data suggest that the trait is inherited as an X-linked lethal gene, but the possibility of a sex-influenced autosomal allele cannot be ruled out. The syndrome may have arisen in conjunction with instability of the merle locus.     

Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders

Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.     

Preliminary investigation of lethally toxic sera of sudden infant death syndrome victims and neutralisation by commercially available immunoglobulins and adult sera

The aim of the study was to test the hypotheses (i) that sudden infant death syndrome sera are toxic to 11-day old chick embryos and (ii) that such a toxicity can be counteracted by immunoglobulin or adult sera. Serum samples from 11 SIDS victims and five controls were tested for lethal toxicity in the chick embryo bioassay. Five serum samples were used to challenge chick embryos injected with the following: sudden infant death syndrome serum plus Hank's balanced salt solution; Hank's balanced salt solution alone; sudden infant death syndrome serum plus 3% w/v commercial immunoglobulin; sudden infant death syndrome serum plus 6% w/v immunoglobulin; sudden infant death syndrome serum plus pooled sera of 40 healthy adults. Results obtained revealed that Hank's balanced salt solution, the pooled adult serum and the commercial immunoglobulin were all non-lethal, in the chick embryo test system. By contrast. 10 sudden infant death syndrome victims yielded sera containing lethal levels of toxin(s) compared to 2/5 controls which was statistically significant (P < 0.05, Fischer's exact test). In the tests of sudden infant death syndrome serum plus immunoglobulin or pooled adult serum, the lethality of sudden infant death syndrome serum was abolished in all cases. The reduction in toxicity of individual sudden infant death syndrome serum plus immunoglobulin or pooled adult serum was often statistically significant (P<0.05-P<0.00005, Fischer's exact test). We conclude that lethal levels of toxin are present in sudden infant death syndrome sera and that they can be neutralised by normal immune serum. These results indicate that passive immunisation is a potential treatment to protect babies considered at risk from sudden infant death syndrome.     

Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous.

Mice deficient for the expression of CTLA-4 develop a lethal lymphoproliferative syndrome and multiorgan inflammation leading to death at about 4 wk of age. Here we show that RAG2-deficient mice reconstituted with CTLA-4-deficient bone marrow do not develop a lymphoproliferative syndrome despite lymphocyte infiltration mainly into pericardium and liver. Moreover, RAG2-deficient mice reconstituted with a mixture of normal and CTLA-4-deficient bone marrow remain healthy and do not develop any disease. Thus, the lethal disease observed in CTLA-4-deficient mice is not T cell autonomous and can be prevented by factors produced by normal T cells.     

A short rib polydactyly syndrome overlapping both lethal and nonlethal types

Short rib polydactyly syndrome (SRPS) type II is a rare, autosomal recessively inherited, lethal skeletal dysplasia characterized by polydactyly, short limbs, short and horizontal ribs, a short ovoid tibia and major organ anomalies. We report a patient with a fetus with SRPS type II that presented at the 19th week of pregnancy for amniocentesis because of maternal age. During ultrasound pre-axial synpolydacytly, a short and ovoid tibia, nuchal edema, vertebral irregularities, hypoplastic thorax with short ribs and talipes were detected. All of the extremities were under the 5th percentile. Thorax-abdomen ratio was 0,56. The family was counselled for a diagnosis of lethal SRPS. After termination of pregnancy, radiological and histopathological examination allowed us to reach the diagnosis ofMajewski syndrome (SRPS type II). SRPSs are a continuous spectrum of both lethal and nonlethal forms. Prenatal diagnosis and termination depending on ultrasound findings should be done very precociously considering different phenotypic expressions, even in families previously affected by a lethal SRPS.     

Lethal factor to mice produced by Escherichia coli isolated from chickens with swollen head syndrome

A lethal toxin similar to Bacillus cererus lethal toxin was detected in the culture supernatants of Escherichia coli isolated from chickens with swollen head syndrome. The lethal activity was heat-labile, protease-sensitive and killed mice within 10 min. The light microscopy of the histopathological studies revealed that the principal organ affected by this toxin was the lung but the liver and kidneys also showed lesions. The relevance of this lethal activity from E. coli remains to be determined.     

The common bacterial toxins hypothesis of sudden infant death syndrome

The background to the common bacterial toxin hypothesis of sudden infant death syndrome is presented. The idea is that some cases of sudden infant death syndrome are due to the lethal effects of nasopharyngeal bacterial toxins which can act synergistically to trigger the events leading to death. The concept is consistent with the age distribution of sudden infant death syndrome, the winter excess of cases and the role of prone sleeping and passive exposure to cigarette smoke. A number of laboratory-based investigations are described. There is an increased isolation of staphylococci and Gram-negative bacilli from sudden infant death syndrome infants compared with age- and season-matched healthy infants. Bacteria from sudden infant death syndrome infants interact synergistically to cause sudden death in gnotobiotic weanling rats. Bacterial toxins implicated in sudden infant death syndrome interact synergistically to cause death in chick embryos. Nicotine in very low doses potentiates the lethal effect of toxin combinations in chick embryos. Staphylococcal toxins and endotoxins have been demonstrated in sudden infant death syndrome tissues, antibodies to endotoxins are low in sudden infant death syndrome cases and the prone sleeping position leads to pooling of secretions in the upper airways, increasing the risk of bacterial growth and toxin production. If the hypothesis is correct, then there is the possibility of a further reduction in the incidence of sudden infant death syndrome based on immunisation against the toxins involved.     

Proteus syndrome: a case with clonal chromosome aberration

Proteus syndrome is a disorder characterized by overgrowth of multiple tissues, connective tissue nevi, epidermal nevi and hyperostoses with asymmetric involvement. The clinical expression of the disorder is extremely variable. Molecular pathogenesis of the syndrome is unknown but it is hypothesized that it resulted from a somatic alteration of a gene leading to mosaic effects that would be lethal if the mutation was carried in nonmosaic fashion, and this may explain the variability among patients. We report a new case who presented at birth with asymmetric hypertrophy of the bones and soft tissues of fingers and a tumor of the chest. Cytogenetic analysis of the excised tumor revealed clonal chromosome aberration: mos46, XY, add(9)(p13) [5]/46,XY[30]. During follow up tumors of the rectum and urinary bladder were diagnosed.     

One more case of a severe lethal condition resembling the Smith-Lemli-Opitz, type II syndrome.

A male child with a lethal multiple congenital anomaly syndrome of facial dysmorphism, ambiguous genitalia, syndactyly and postaxial polydactyly is presented. He had findings consistent with the diagnosis of Smith-Lemli-Opitz type II syndrome. Similar changes were observed in his elder sister, who died when she was 2 months old. On the basis of this familial observation the nosology of Smith-Lemli-Opitz syndrome is discussed.     

Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome

Aicardi syndrome is a rare disorder characterized by absent corpus callosum, infantile spasms, and chorioretinal lacunae. It is sporadic in nature and affects only females, resulting in severe mental and physical handicap. It has been suggested that the disease is caused by a dominant X-linked mutation which occurs de novo in females, and is lethal in hemizygous male embryos. This mode of inheritance has been observed in a number of other rare syndromes. In these syndromes, when X inactivation is studied, a non-random pattern is usually found. We have studied the X inactivation pattern in ten female patients with Aicardi syndrome and their parents using the highly polymorphic, differentially methylated androgen receptor gene. The results showed an unexpected random X-inactivation pattern in these patients. Previous clinical and cytogenetic evidence suggests that Aicardi syndrome is caused by an X-linked dominant mutation, de novo in females and lethal in males. However, unlike most other known X-linked disorders inherited in this fashion, Aicardi syndrome patients have a normal (i.e., random) X-inactivation pattern. A number of possible explanations is proposed for this apparently contradictory evidence. Received: 20 December 1996 / Accepted: 30 April 1997     

Lethal toxin is a critical determinant of rapid mortality in rodent models of Clostridium sordellii endometritis

The toxigenic anaerobe Clostridium sordellii is an uncommon but highly lethal cause of human infection and toxic shock syndrome, yet few studies have addressed its pathogenetic mechanisms. To better characterize the microbial determinants of rapid death from infection both in vitro and in vivo studies were performed to compare a clinical strain of C. sordellii (DA-108), isolated from a patient who survived a disseminated infection unaccompanied by toxic shock syndrome, to a virulent reference strain (ATCC9714). Rodent models of endometrial and peritoneal infection with C. sordellii ATCC9714 were rapidly lethal, while infections with DA-108 were not. Extensive genetic and functional comparisons of virulence factor and toxin expression between these two bacterial strains yielded many similarities, with the noted exception that strain DA-108 lacked the tcsL gene, which encodes the large clostridial glucosyltransferase enzyme lethal toxin (TcsL). The targeted removal by immunoprecipitation of TcsL protected animals from death following injection of crude culture supernatants from strain ATCC9714. Injections of a monoclonal anti-TcsL IgG protected animals from death during C. sordellii ATCC9714 infection, suggesting that such an approach might improve the treatment of patients with C. sordellii-induced toxic shock syndrome.     

X-linked hydrocephalus: another two families with an L1 mutation

X-linked hydrocephalus is a variable condition caused by mutations in the gene encoding for L1CAM. This gene is located at Xq28. Clinically the spectrum ranges from males with lethal congenital hydrocephalus to mild/moderate mental retardation and spastic paraplegia. Few carrier females show minimal signs of the syndrome. Although most cases are familial, de novo situations have been reported. We report two new families with the syndrome and a L1 mutation. Family 1 has two patients and family 2 a single patient. Clinical diagnosis in all three affected boys was beyond doubt. Prenatal testing through chorionic villus biopsy is possible only with a demonstrated L1 mutation. In lethal sporadic cases neuropathology is very important in order to evaluate for features of the syndrome. We stress the importance of further clinical reports including data on neuropathology and DNA analysis in order to further understand the mechanisms involved in this disorder.     

Mortality of monkeys after exposure to fission neutrons and the effect of autologous bone marrow transplantation.

In order to assess the risk of exposure to ionizing radiation in man, and to evaluate the results of therapeutic measures, the mortality of rhesus monkeys irradiated with X-rays and fission neutrons and the effect of autologous bone marrow transplantation have been investigated. The LD50/30d values for X- and neutron-irradiated monkeys amount to 525 and 260 rad respectively, resulting in an r.b.e. of approximately 2 for the occurrence of the bone marrow syndrome. Protection of the animals by autologous bone marrow transplantation was observed up to doses of 860 rad of X-rays and 440 rad of fission neutrons. After both fission-neutron irradiation and X-irradiation in the lowest range of lethal doses, the bone marrow syndrome was found to occur without the concurrent incidence of the intestinal syndrome. The studies indicate that, for humans accidentally exposed to what would otherwise be lethal doses of fast neutrons, bone marrow transplantation may be beneficial.     

S2 subunit of SARS-nCoV-2 interacts with tumor suppressor protein p53 and BRCA: an in silico study

Novel coronavirus disease 2019 (COVID-19) is the biggest threat to human being globally. The first case was identified in a patient with flu symptoms along with severe acute respiratory syndrome in Wuhan, China in December 2019 and now it has spread in more than 200 countries. COVID-19 is more lethal in the elderly and people with an underlying condition such as asthma, cancer, diabetes. Here we performed bioinformatic analysis to investigate the interaction of S2 subunit protein of SARS-nCoV-2 of novel coronavirus with tumor suppressor proteins p53 and BRCA-1/2. In this short communication we report the interaction between S2 subunit proteins with tumor suppressor proteins for the first time. This preliminary result will open up a new direction to investigate the effect of a novel coronavirus in cancer patients.     

An unrecognized etiology of sexual ambiguity: Smith-Lemli-Opitz syndrome or a new entity?

The authors report three cases of a new syndrome which characteristic anomalies are facial dysmorphism with anteverted nose, down slanting palpebral fissures, ptosis, severe microretrognatia, polydactyly. The authors insist on the particular severe genital anomalies, the failure to thrive and the constant lethal issue. The authors discuss the diagnosis of Smith-Lemli-Opitz syndrome and suggest the possibility of a new entity always confounded with others associations characterized by a polydactyly and a sexual reversion in male.