Visceral Malformations Research Articles

Recognition and management of vascular lesions in von Willebrand disease

Recognition and management of vascular lesions in von Willebrand disease

Determination of Extra Craniofacial Abnormalities in Patients With Craniofacial Microsomia

Craniofacial microsomia (CFM) is caused by abnormalities in the development of the first and second pharyngeal arches. One-third to half of the patients with CFM also present with extra craniofacial (ECF) malformations. The knowledge of the visceral alteration related to CFM is vital for optimized care and a better prognosis. To describe the incidence of ECF malformations in patients with CFM and to infer if there was a correlation between CFM and ECF malformations. The authors analyzed medical records of patients diagnosed with CFM from 1996 to 2006. The data collected included age, gender, category of craniofacial alteration, and the type of ECF malformation when present. The sample was inspected to find possible correlations between craniofacial abnormalities and ECF malformations. The sample included 102 patients, with a mean age of 7 years and a predominance of males (61.8%). Ear malformations (93.1%) followed by mandible (59.8%) and facial nerve (10.8%) abnormalities were the most common CFM. Among patients with CFM, 37.2% had ECF involvement, mainly in vertebrae (20%), heart (11%), and limbs (9.8%). Multivariate analysis revealed that the presence of ear malformations was related to a higher incidence of nonspecific visceral malformations (P = 0.034) and that mandible malformation was related to an increased incidence of vertebral malformations (P = 0.008). A significant percentage of patients with CFM presented associated ECF impairment. Ear and mandible involvement may be predictors of nonspecific visceral malformation and vertebral malformations, respectively.

Influence of Swimming Program on the Blood Pressure of Pregnant Hypertensive Rats and Their Fetuses.

The hypertension incidence and its complication on pregnant women are growing and can lead to adverse consequences on their fetuses. However, it is known that regular exercise practice can be healthful to hypertensive pregnant women but harmful to fetal growth. So, the objective of this study was to evaluate the effects of exercise beginning before pregnancy or during pregnancy on the maternal blood pressure and reproductive outcome and on the fetal development of spontaneously hypertensive rats (SHR). Pregnant SHR were randomly distributed into three experimental groups: (1) SHR-Control, non-exercised; (2) SHR-Ex0, rats submitted to physical exercise (swimming program) from day zero to 20 of pregnancy; (3) and SHR-ExPr, rats submitted to swimming program before and during pregnancy. At end of pregnancy (day 21), the rats were anesthetized, and reproductive parameters and fetal development were assessed. Blood pressure was reduced at the end of pregnancy in all the groups. Regardless of swimming exposure time, there was reduced maternal weight gain. The exercise decreased fetal weight at term pregnancy, with a higher percentage of small for gestational age (SGA) fetuses and lower number ossification sites, indicating intrauterine growth restriction (IUGR). In conclusion, our findings provide insight to support that swimming exercise in pregnant SHR impairs fetal development, causing IUGR and visceral malformations. Therefore, the indication of physical exercise must be defined very carefully, as it can compromise fetal development.

Perosomus Elumbis in Piglets: Pathological, Radiological and Cytogenetic Findings.

Simple SummaryPerosomus elumbis (PE) is a rare congenital condition characterized by malformations localized mainly at the lumbo-sacral column. PE is reported in the literature as a description of single or very few cases. Although some authors have suggested a possible genetic etiology, the cause of PE has been poorly investigated. Here we report the first extensive pathological, radiological and cytogenetical description of eight cases of PE detected in two consecutive births of a Casertana pig sow, bred in an extensive farm located in Campania region, southern Italy. In this study, we also performed an epidemiological investigation to assess the rate of piglets born dead and malformations in the farm. The gross and radiological examination showed a broad range of malformations, such as skeletal and visceral abnormalities, but cytogenetic investigation did not show chromosome alterations. Finally, the retrospective data from the farm showed a low frequency of malformations in newborn pigs in the year of PE cases observation. These findings, taken together, suggest a specific genetic etiological basis as cause of PE in pigs but exclude chromosomal abnormalities. Perosomus elumbis (PE) is a rare congenital condition characterized by agenesis of the lumbar, sacral and coccygeal vertebrae. Perosomus elumbis has rarely been reported in literature as morphological description of singles or few cases. Here we report the first extensive description of eight cases of PE detected in two consecutive litters from the same parents of Casertana pig breed. In August 2018, eight piglets were investigated for multiple malformations. All malformed animals, but one, died in the first day of life. The survivor piglet died at 23 days of age. Pathological, radiological and cytogenetic examination was performed. Furthermore, a farm epidemiological investigation was carried out to investigate the percentage of piglets born dead or with malformations in 2018. The radiological and pathological exams showed skeletal abnormalities at the spinal cord level and visceral malformations. Cytogenetic investigations showed a normal chromosome arrangement. Finally, epidemiological investigation revealed a low prevalence of malformations in newborn pigs, equal to 0.5% of the total birth rate of the farm. Our findings report the first extensive description of PE cases in pigs and suggest an underestimation of this malformation in veterinary medicine. Our findings also suggest a specific genetic etiological basis as cause of PE in pigs and exclude chromosomal abnormalities. Further studies will be performed to confirm this hypothesis.

The Potential Teratogenic Effect of Tilmicosin in Rats: Visceral Malformations and Histomorphological Alterations in Fetal Internal Organs

Potential fetal adverse effects are well-known for several antibacterial classes. The present study was performed to evaluate the potential teratogenic effect of Tilmicosin (TMS) antibiotic in Sprague Dawley rats. TMS was daily administered orally to pregnant rats at two dose levels, 250 or 500 mg/kg bw, on 6-15 days of gestation. The morphological or skeletal malformations were non-significantly different from control values. However, visceral examination revealed elevation in the percentage of intrathoracic and intracranial haemorrhages, and kidney hypoplasia (unilateral or bilateral) in fetuses from dams treated with the high dose. In addition, both dose levels produced fetuses with increased percentages of dilated brain ventricles, heart ventricles and renal pelvis. Histopathologically, both TMS doses induced pathological changes in fetal liver and kidney, in a dose-dependent manner. Liver showed hepatocyte hydropic degeneration, congestion of hepatic blood vessels, engorgement of bile canaliculi and dilatation of hepatic lymphatic vessels. Kidney revealed coagulative necrosis of renal tubules and glomerular tuft, adhesion between the parietal and visceral layers of Bowman’s capsule and the glomerular tuft became ring shape with the presence of multiple layer glomerular tufts. In conclusion, TMS antibiotic has the potential to induce teratogenic effects (mainly visceral) and pathological changes in liver and kidneys tissues of rat fetuses when administered during the organogenesis period. This result demonstrated the ability of TMS to pass the placental barrier.

Simulated gastric hydrolysis and developmental toxicity of dibutyltin bis(2-ethylhexyl thioglycolate) in rats.

Previously, dibutyltin dichloride (DBTC) was the putative toxophore for dibutyltin bis-alkyl and bis-thio esters. Recent chemical and toxicological data on dioctyltin bis(2-ethylhexyl thioglycolate) suggest the thioglycolate esters of alkyltins do not generate the dichloride toxophore. Our results, using 119 Sn-nuclear magnetic resonance (NMR) spectroscopy, demonstrated that dibutyltin bis(2-ethylhexyl thioglycolate) (DBTE) is hydrolyzed to dibutyltin chloro-(2-ethylhexyl thioglycolate) (DBTEC) under simulated gastric conditions. No DBTC was detected. DBTE was administered orally to presumed-pregnant Sprague-Dawley rats in a corn oil vehicle at 2.5, 8.5, and 25.0 mg/kg/day (Gestation Day 5 [GD5] through GD19). There were no maternal deaths, no treatment-related statistically significant reductions in feed consumption, maternal body weight or weight gain, or adverse gestational outcomes. Maternal thymus weight was significantly reduced in rats at 25 mg/kg. There were no effects on fetal growth, no dose-dependent pattern of external, visceral, or skeletal malformations, and no increase in anatomical variations. Based on the obtained experimental data, it is concluded here that DBTE forms DBTEC, not DBTC, in the stomach, and DBTE was not teratogenic nor fetotoxic in rats, a species sensitive to DBTC. The maternal no-observed-adverse-effect level (NOAEL) was 8.5 mg/kg/day, and the developmental NOAEL was 25 mg/kg/day, the high dose. The maternal LOAEL was 25 mg/kg/day based on reduced maternal thymus weight.

Prenatal developmental toxicity of alkyl dimethyl benzyl ammonium chloride and didecyl dimethyl ammonium chloride in CD rats and New Zealand White rabbits.

The prenatal developmental toxicity potential of alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC) was evaluated in regulatory‐compliant studies. Pregnant female CD rats (25/group) and New Zealand White rabbits (16/group) were administered ADBAC (0, 10, 30, or 100 mg/kg/day and 0, 1, 3, or 9 mg/kg/day, respectively), or DDAC (0, 1, 10, or 20 mg/kg/day and 0, 1, 3, or 10 mg/kg/day, respectively), by oral gavage on gestation days (GD) 6–15 for rats and GD 6–18 for rabbits. At scheduled termination (GD 21 for rats; GD 29 for rabbits), maternal necropsies were conducted and live fetuses were weighed and examined for external, visceral, and skeletal malformations and variations. Clinical signs of maternal toxicity were observed in rats and rabbits dosed with ADBAC, resulting in no‐observed‐adverse‐effect levels (NOAELs) of 10 and 3 mg/kg/day, respectively. Despite the treatment‐related maternal toxicity of ADBAC, the NOAEL for prenatal developmental toxicity was 100 and 9 mg/kg/day for rats and rabbits, respectively, the highest doses evaluated. Repeated oral doses of DDAC resulted in maternal toxicity in both species at the top two doses, with 25% mortality noted in rabbits at 10 mg/kg/day. No teratogenic effects were observed at any dose for either species. However, increased incidence of dead fetuses per litter and decreased fetal body weights were observed in rabbits at the maternally lethal dose of 10 mg/kg/day. The NOAEL for maternal toxicity of DDAC was 1 mg/kg/day for both species and the NOAEL for prenatal developmental toxicity was 20 and 3 mg/kg/day, for rats and rabbits, respectively.

Absence of arterial duct in fetus: an autopsy analysis

Objective: To analyze the absence of congenital arterial duct in fetus and to improve the diagnostic accuracy. Methods: Four hundred cases of congenital heart disease diagnosed by echocardiography during pregnancy were examined the fetal cardiovascular malformation and visceral malformation, and the absence of arterial duct was analyzed. Results: There were 24(6%)cases of absence of arterial duct, including 19 cases of left aortic arch and five cases of right aortic arch. There were 21 cases with main pulmonary arteries and 3 cases without main pulmonary arteries and branches. There were 15 cases of pulmonary artery stenosis with absence of arterial duct and the major cardiovascular malformations included six cases of single ventricle, six cases of atrial septal defect, four cases of single atrium, four cases of right atrium isomerism, four cases of double outlet right ventricle, four cases of anomalous pulmonary venous drainage, three cases of tetralogy of Fallot, and three cases of persistent left superior vena cava. There were seven cases of pulmonary atresia with absence of arterial duct and with systemic-pulmonary collateral circulation. There was one case of tetralogy of Fallot with absent pulmonary valve and absent arterial duct and the pulmonary artery was dilated. There was one case of aortopulmonary septal defect with absent arterial duct, with normal pulmonary artery. There were also seven cases of asplenia, seven cases of pulmonary abnormality and seven cases of visceral inversion. Conclusions: The absence of arterial duct is often associated with congenital heart disease. Pulmonary atresia is often associated with systemic-pulmonary collateral circulation. The visceral malformations are related to the accompanying congenital cardiovascular malformations.

Genetic Variants and Clinical Phenotypes in Korean Patients With Hereditary Hemorrhagic Telangiectasia.

ObjectivesHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients.MethodsSeventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated.ResultsIn the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms.ConclusionOnly approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

Thalidomide and unilateral limb defects: the Italian chapter of a neverending story

Fifty years after the event, Italy introduced legislation to compensate malformations in children - now in their sixties - born to mothers who had been prescribed the antiemetic drug thalidomide for morning sickness. However, compensation has been denied to people 'only' damaged in one half of their body as opposed to those with bilateral malformations. The present study reviews the papers describing case series of children born with 'thalidomide embryopathy' in the UK, Germany, and other countries around 1960. Most clinical series were not organized on the basis of inclusion/exclusion criteria, thus allowing for probable selection and information biases on maternal use of thalidomide. In any case, they included a sizable number of children with a unilateral limb defect born from mothers certainly exposed to thalidomide during the relevant pregnancy. In many of these children, limb defects were associated with visceral malformations, as frequently observed following exposure to thalidomide in utero. Similarly, later literature reviews were not bias-free in their choice of articles, as is the case of a recently proposed 'diagnostic algorithm' for thalidomide-caused specific malformations and of the advice by the Italian National Institute of Health ruling out the possibility of thalidomide producing unilateral limb defects. Overall, the scientific evidence suggests that thalidomide can cause unilateral limb defects.

A study of the genetic and prenatal developmental toxicity potential of lithothamnion sp

Due to its calcium-rich and diverse multimineral profile, Aquamin (derived from the red seaweed Lithothamnion sp.) is used globally as a dietary food supplement. Published reports on the genetic and prenatal developmental toxicity of Lithothamnion sp. do not exist. In accordance with the standardized protocols set by the Ministry of Health of the People’s Republic of China (GB-15193), the following studies were performed: the Ames test, the mammalian erythrocyte micronucleus test, the mammalian spermatocyte chromosome test, and prenatal developmental toxicity testing. The results showed that Lithothamnion sp. did not induce a significant increase in the following: revertant colony numbers for Salmonella typhimurium strains TA 97, 98, 100, 102 and 1535; frequency of micronucleated polychromatic erythrocytes (MNPCE); spermatocyte chromosomal aberration rate. In the prenatal developmental toxicity study, no mortality, no abnormal changes in behavior and activities, and the absence of toxic symptoms and abnormalities in macroscopic autopsy were observed in each dam/all pups. Compared to the negative control group, Lithothamnion sp. at all tested doses had no effects on body weight gain, number of corpora lutea and implantations, fetal body weight and length, external, visceral and skeletal malformations. In conclusion, Lithothamnion sp. did not cause genetic toxicity. Furthermore, the prenatal developmental toxicity no observed adverse effect level (NOAEL) was determined to be greater than 2000 mg/kg.bw.

Assessing the safety of using the dry extract of Justicia pectoralis Jacq. (Acanthaceae) during pregnancy of Wistar rats

Ethnopharmacological relevanceJusticia pectoralis Jacq. (Acanthaceae), popularly known as tilo, chambá and anador, is widely used in folk medicine in Latin American countries as a sedative, anti-anxiety, reducing menopause symptoms and in the treatment of pathologies of the respiratory tract. Although J. pectoralis is widely used by the female population, there are no studies on the safety of using this species during pregnancy. Aim of this studyTo evaluate the effects of prenatal treatment with dry extract from the aerial parts of J. pectoralis on maternal and developmental toxicity in Wistar rats. Material and methodsPregnant Wistar rats (n = 10/group) were treated from gestational day (GD) 0–20 with the vehicle (control group) or with the dry extract of J. pectoralis at doses of 300, 600 or 1200 mg/kg. During pregnancy, clinical signs of toxicity, maternal weight, feed and water intake were evaluated. On GD 21, rats were anesthetized and intracardiac blood was collected to evaluate biochemical parameters. During cesarean section, reproductive performance parameters were recorded. The liver, kidneys, uterus and ovaries were removed for histopathological analysis. Fetuses were examined for possible malformations and/or skeletal and visceral variations. ResultsTreatment with dry extract of J. pectoralis did not alter weight gain, feed intake or biochemical and maternal reproductive performance parameters There were also no significant histopathological changes in the maternal organs, as well as external, skeletal and visceral malformations in the fetuses. ConclusionOral administration of J. pectoralis dry extract during pregnancy did not induce maternal toxicity or embryotoxic and teratogenic effects.

The effect of Ipomoea carnea on maternal reproductive outcomes and fetal and postnatal development in rats

Ipomoea carnea is a toxic plant found in Brazil and other tropical countries. The plant contains the alkaloids calystegines and swainsonine, which inhibit key cellular enzymes and cause systematic cell death. It is known that swainsonine is excreted in the amniotic fluid of dams exposed to the plant. Thus, the aim of this study was to verify whether the toxic effect of I. carnea on fetuses is due to exclusively the passage of the active principle of the plant through the placenta, or if the placentotoxic effect of swainsonine could collaborate in the adverse effects observed in the fetus. The teratogenic effects of exposure to the toxic principles of I. carnea were evaluated not only using the conventional protocol but also at later stages in the postnatal developmental period. Females were treated, from gestation day (GD) 6 until GD19, with 0.0, 1.0, 3.0 or 7.0 g/kg body weight of I. carnea dry leaves. The plant did not induce changes in reproductive performance or biochemical profile of the dams. Dams that received the highest dose of I. carnea showed cytoplasmic vacuolization in the liver, kidney and placental tissue. I. carnea promoted different lectin binding patterns in different areas of placental tissue. No fetal skeletal or visceral malformations was observed. The postnatal evaluation revealed a lower litter weight and a lower pup body weight one day after birth in the group that received the highest dose of I. carnea. Physical milestones were unaffected by the treatments. Female pups from all experimental groups exhibited a delay in achieving a negative geotaxis response. The results show that the toxic principle of I. carnea produces injury in utero in mothers and fetuses, but these deleterious effects were better demonstrated using postnatal evaluation.

The Role of Liver Imaging in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by spontaneous epistaxis, telangiectasia, and visceral vascular malformations. Hepatic vascular malformations are common, though a minority are symptomatic. Symptoms are dependent on the severity and exact type of shunting caused by the hepatic malformation: Arteriosystemic shunting leads to manifestations of high output cardiac failure, and arterioportal shunting leads to portal hypertension. Radiologic imaging, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), is an important tool for assessing liver involvement. Doppler ultrasonography is the first-line screening modality for HHT-related liver disease, and it has a standardized scale. Imaging can determine whether shunting is principally to the hepatic vein or the portal vein, which can be a key determinant of patients’ symptoms. Liver-related complications can be detected, including manifestations of portal hypertension, focal liver masses as well as ischemic cholangiopathy. Ultrasound and MRI also have the ability to quantify blood flow through the liver, which in the future may be used to determine prognosis and direct antiangiogenic therapy.

Prenatal developmental toxicity study of an alkaloid-free Ageratum conyzoides extract powder in rats by oral administration

A prenatal developmental toxicological study was conducted to evaluate the safety of an alkaloid-free Ageratum conyzoides extract powder administration on pregnant female Wistar rats and on the development of the conceptus in accordance with OECD test guideline (no. 414). Pyrrolizidine alkaloids (PAs) naturally present in A. conyzoides have been shown to induce toxicity in past studies, particularly towards hepatic cells. Therefore our test item preparation of A.conyzoides extract (aerial part of the plant) consisted of the removal of PAs. There were no treatment related adverse effects found during maternal examinations (body weights, food consumption, numbers of pregnant and non-pregnant female rats, endocrine evaluation, gravid uterine weights, and number of corpora lutea), maternal/fetal examinations (numbers of implantation sites, pre-and post-implantation loss (%), dead and live fetuses (%), resorption sites), or fetal examinations (litter size and weights, number of fetuses, sex ratio, or external, visceral, and skeletal variations and malformations) in the Ageratum conyzoides extract powder groups at doses of 500, 1000 and 2000 mg/kw bw/day compared to vehicle control group. The no observed adverse effect level (NOAEL) determined for both maternal and developmental toxicity was 2000 mg/kg bw/day, which was the highest dose tested.

Pregnancy Outcome in Female Rats Exposed to Bispyribac Sodium and Ameliorative Effect of Nigella Sativa Oil

Bispyribac sodium is commonly used as a herbicide worldwide. Few studies had investigated the health impact of exposure to it. Redox homeostasis has a great role during organogenesis through in cell growth, differentiation, and death. The aim of this study is to investigate the redox homeostasis imbalance and teratogenic effect of BPS in female rats exposed to bispyribac sodium (BPS) during organogenesis and evaluates the protective role of Nigella Sativa Oil (NSO). Pregnant female rats were grouped into four groups, negative and positive (NSO) control groups. While the others, BPS with and without NSO treatment groups. Results showed that BPS exposure during the pregnancy led to maternal and fetotoxicity as evidenced by preimplantation, post-implantation loss, reduction in placenta weight, reduction in fetal weight, fetal length, skeletal anomalies (incomplete ossification, misaligned sternbrae), visceral malformation (anophthalmia, microphthalmia, internal hydrocephaly, and microcephaly) and oxidative stress in dams serum. NSO treatment exhibited amelioration in the aforementioned maternal and fetotoxicity against BPS exposure.

Abcès cérébral et maladie de Rendu-Osler-Weber : pensez à rechercher des malformations artério-veineuses pulmonaires

IntroductionOsler-Rendu-Weber syndrome or hereditary hemorrhagic telangiectasia affects between 1/5000 and 1/8000 people. It is characterized by presence of recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations. It is a genetic disease with autosomal dominant transmission inducing an endothelial cells hyper-proliferation. Case reportA 68-year-old women with Osler-Rendu-Weber syndrome was referred for management of general impairment with confusional syndrome and hyperthermia. Various examinations have allowed us to conclude at diagnosis of brain abscess with ventriculitis probably favored by right–left shunt secondary to pulmonary arteriovenous malformations. Evolution was favorable after antibiotic treatment and endovascular embolization. ConclusionIn case of brain abscess without obvious promoting factor, don't forget to looking for a right–left shunt providing septic or aseptic emboli. Furthermore, diagnosis of Rendu-Osler-Weber syndrome should be considered presence of telangiectasias and/or epistaxis.

Integration of clinical parameters, genotype and epistaxis severity score to guide treatment for hereditary hemorrhagic telangiectasia associated bleeding

BackgroundHereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT.MethodologyWe conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS.ResultsOne hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p < 0.05). Neither ESS nor genotype was predictive of pulmonary or brain AVMs. Twenty-four HHT patients with ESS > 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months.ConclusionsWe demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.

Unusual context of CENPJ variants and primary microcephaly: compound heterozygosity and nonconsanguinity in an Argentinian patient

Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual disability, with normal brain structure in most patients, or with a small brain and gyri without visceral malformations. We present the case of an adult patient born from Argentinian nonconsanguineous healthy parents. He had a head circumference >5 SD below the mean, cerebral neuroimaging showing hypoplasia of the corpus callosum, bilateral migration disorder with heterotopia of the sylvian fissure and colpocephaly. The patient was compound heterozygous for pathogenic variants in the CENPJ gene (c.289dupA inherited from his mother and c.1132 C > T inherited from his father). Our patient represents an uncommon situation for the usual known context of CENPJ and MCPH, including family origin (Argentinian), pedigree (nonconsanguineous), and genotype (a compound heterozygous case with two variants predicting a truncated protein). Next-generation sequencing studies applied in a broader spectrum of clinical presentations of MCPH syndromes may discover additional similar patients and families.

Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a rare congenital anomaly syndrome characterized by intellectual disability, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and some visceral malformations is caused by de novo heterozygous mutations of the SON gene. The nuclear protein SON is involved in gene transcription and RNA splicing; however, the roles of SON in neural development remain undetermined. We investigated the effects of Son knockdown on neural development in mice and found that Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons. The induction of human wild-type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. We also applied truncated SON proteins encoded by disease-associated mutant SON genes for rescue experiments and found that a truncated SON protein encoded by the most prevalent SON mutant found in ZTTK syndrome rescued the neural abnormalities while another much shorter mutant SON protein did not. These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine abnormalities, which seem neuropathological bases of the neural symptoms of ZTTK syndrome. In addition, the results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.