Anodontia as the sole clinical sign of the ectrodactyly-ectodermal dysplasia-cleft lip (EEC) syndrome

In this report we present another family with oligosymptomatic expression of the EEC syndrome. A mother with complete absence of the permanent teeth had two children with split hand/split foot deformity, as typically seen in the EEC syndrome. Cleft lip/cleft palate was also present in one of them. The great variability in expression of this autosomal dominant syndrome is discussed and the difficulties in genetic counseling are emphasized.     

Tetrasomy 12p (Pallister-Killian syndrome): possible diagnosis before the age of a year

In this short report we present a 1 year old female child with tetrasomy 12p (Pallister-Killian syndrome) and emphasize the importance of the recognition of the dysmorphic stigmata of this MR/MCA syndrome.     

Management of elderly patients with a non-ST-segment-elevation acute coronary syndrome

Elderly patients with an acute coronary syndrome are underrepresented in randomised controlled trials. Neither the European Society of Cardiology nor the American Heart Association/American College of Cardiology acute coronary syndrome guidelines provide specific recommendations for elderly patients. However, elderly patients are at higher thrombotic and bleeding risk compared with younger patients leading to difficulties in choosing the optimal treatment. In this review, we discuss the uncertainties we encounter in treating elderly patients with non-ST-elevation acute coronary syndrome and suggest treatment options based on the existing literature.     

Pierre-Robin综合征的遗传调控机制

Pierre-Robin综合征（Pierre-Robin syndrome，PRS）是一种能引起颅面器官异常的遗传性疾病，主要表现为下颌发育不全、舌后坠和腭裂等，进而导致新生儿喂食困难，甚至危及个体生命的阻塞性呼吸暂停，是先天性颅面畸形中较为常见的一种综合征。该综合征在全球的发病率为1/8 500~1/14 000，不仅影响个体的生长发育还影响其受教育程度，对患者造成巨大影响，受到社会的广泛关注。虽然Pierre-Robin综合征的临床特征明显，易于诊断，但不同患者间高相似性的表型很容易掩盖患病个体之间的病理学异质性，从而很难确定每例Pierre-Robin综合征的具体病因。因此，了解Pierre-Robin综合征的发病原理及其遗传机制，对于防治Pierre-Robin综合征尤为重要。由基于此，本文结合新近几年在Pierre-Robin综合征发病机制方面的相关研究，主要对引起该综合征的关键信号通路及其相关分子机制，特别是不同信号通路间的相互作用机制进行综述，从而进一步理解Pierre-Robin综合征发生的遗传调控机制。     

Pseudotrisomy 13 syndrome: use of homozygosity mapping to target candidate genes

Pseudotrisomy 13 syndrome is characterised by holoprosencephaly with or without polydactyly, but with a normal karyotype. The genetic cause of this syndrome remains unclear, but it is thought to be autosomal recessive. In order to identify possible candidate genes, we identified regions of homozygosity in the DNA of an affected foetus, which was the seventh pregnancy of a healthy non-consanguineous Cook Island Maori couple; this ethnic group derives from a small founder population. Several large regions of homozygosity were identified using a high density array. We excluded two candidate genes that lay within these regions, and suggest that Pseudotrisomy 13 syndrome might not be monogenic and that a larger cohort of patients should be analysed using high density dosage/SNP arrays as well as whole exome sequencing in order to clarify the genetic underpinning of this rare syndrome.     

Portal vein thrombosis and high factor VIII in Turner syndrome

BACKGROUNDS/AIMS: Turner syndrome is not usually associated with thrombotic events. The aim of this study is to report 3 Turner syndrome patients with portal vein thrombosis and, in 2 of them, high factor VIII. These findings are compared to values in Turner syndrome patients without thrombosis and controls. METHODS: In different years, 3 patients with Turner syndrome were initially seen at the Gastroenterology Clinic of Hospital de Clínicas de Porto Alegre, Brazil, for portal vein thrombosis. After the most common causes of portal vein thrombosis and thrombophilias had been excluded, the 2 surviving patients were studied for clotting factors VIII, IX and von Willebrand factor. The same factors were also assessed in 25 Turner syndrome patients without thrombosis and 25 normal girls. RESULTS: One of the patients with portal vein thrombosis died before the study. In the 2 surviving patients, factors VIII and von Willebrand levels were >150 IU/dl, which is considered to be high. In Turner syndrome patients without thrombosis, the mean factor VIII level was 127.2 +/- 41.1 IU/dl and for von Willebrand factor 101.2 +/- 26.9 IU/dl, while in control girls these were 116.0 +/- 27.6 and 94.28 +/- 27.5 IU/dl, respectively. Factor VIII and von Willebrand factor were not different between these 2 groups. When non-O blood group Turner syndrome patients and normal girls were compared, the former had significantly higher levels of factor VIII. CONCLUSIONS: This is the first report on the unusual finding of portal thrombosis in patients with Turner syndrome in whom high levels of factor VIII and von Willebrand factor were found. Factor VIII is higher in the non-O blood group Turner syndrome patients without thrombosis when compared to normal girls.     

Mitotic recombination and segregation of satellites in Bloom's syndrome

Mitotic recombination in satellite stalks — a phenomenon often difficult to distinguish from satellite association — was studied in a sister and a brother with Bloom's syndrome. Segregation after recombination was analyzed in the lymphocytes of the sister who had Q-bright satellites. Her cells varied greatly both in regard to the acrocentrics which displayed Q-bright satellites and the number of such satellites per cell. In 58 cells a total of 31 different patterns were seen. In 83 cells of 6 controls who also had Q-bright satellites on at least one acrocentric chromosome, not one cell was found in which the pattern differed from that characteristic of the person. Obviously exchanges between satellite stalks in patients with Bloom's syndrome are fairly frequent (estimated lower limit 6/1000) and very rare in persons who do not have this syndrome (estimated 0.1/1000).     

Smoking dose modifies the association between C242T polymorphism and prevalence of metabolic syndrome in a Chinese population

Background

The C242T polymorphism of the CYBA gene that encodes p22phox, a component of NADPH oxidase, has been found to modulate superoxide production. Oxidase is a major source of the superoxide anion that contributes to individual components of metabolic syndrome. We examined the relationship of the C242T polymorphism with the prevalence of metabolic syndrome in a Chinese population, taking account of consumed cigarette amounts.

Methodology/Principal Findings

In 870 participants, we collected biomarkers related to metabolic syndrome and detailed history of smoking and genotyped the C242T polymorphisms. After adjustment for covariates, the CT/TT genotypes were associated with a lower risk of metabolic syndrome (P = 0.0008). The odds of having metabolic syndrome in the CT/TT participants were 0.439 (95%CI: 0.265, 0.726), while for CC participants the odds were 1.110 (95%CI: 0.904, 1.362). There was significant (P = 0.014) interaction between the C242T polymorphism and smoking status in relation to the prevalence of metabolic syndrome. For smokers who smoke no less than 25 pack-years, those with CT/TT genotypes had lower risk of metabolic syndrome as compared with CC polymorphism carriers (P = 0.015). In the multiple regression analysis, the CT/TT genotypes were significantly associated with lower serum concentration of triglycerides both in all subjects and smokers; furthermore, the CT/TT genotypes were also related to smaller waist circumference in smokers.

Conclusions

Our study suggests that the C242T gene polymorphism is indeed related to the prevalence of metabolic syndrome and smoking dose might modify this association.     

Probable case of Binder syndrome in a skeleton from Quarai,New Mexico

Binder syndrome (maxillonasal dysplasia) is a not uncommon disorder reported in the clinical literature and is characterized by hypoplastic development of the midface. An extensive review of the paleopathology literature did not reveal any examples of Binder syndrome. In this paper, a probable case of Binder syndrome in a female skeleton, 16-17 years at age of death, from Quarai, New Mexico (ca. AD 1375-1450) is presented. This case was identified during standard documentation prior to repatriation at the National Museum of Natural History, Smithsonian Institution.The skull of this individual (381243) exhibits unusual facial features, including an underdeveloped midface, flattened glabella, absent nasal spine, and apparent alveolar prognathism, in addition to a vertebral anomaly. All of these characteristics are consistent with skeletal dysmorphologies associated with Binder syndrome. Measurements of the Quarai skull are compared with published data on Binder patients and normal control groups in order to quantify the nature of the observed morphology. Univariate analysis of craniometric/cephalometric data provides further support for a diagnosis of Binder syndrome, as critical measurements on the Quarai skull are consistent with those reported in Binder patients and significantly different from those reported for normal control groups. In addition to presenting a probable prehistoric case of Binder syndrome, this paper demonstrates the applicability of using direct comparisons of clinical data to help identify unusual conditions in skeletal remains.     

Normal male chromosome complement and a lack of the SRY and SOX9 gene mutations in a male pseudohermaphrodite dog

In this report we present a case of the male-to-female sex reversal syndrome in a Dachshund bitch. The animal was subjected for examination due to the enlargement of clitoris and male-type behaviour. The cytogenetic analysis (Giemsa staining and FISH with sex chromosome specific probes) revealed a normal male chromosome complement (78,XY). The molecular analysis of the SRY and SOX9 genes with the use of SSCP technique did not reveal any polymorphism. Blood testosterone concentration was low (0.75 ng/ml), thus the androgen insensitivity syndrome could be excluded. We suggest that this case may represent a persistent Müllerian duct syndrome.     

Cholesteryl ester transfer protein (CETP) ?629C/A polymorphism and it,s effects on the serum lipid levels in metabolic syndrome patients

Metabolic syndrome is a relatively common disorder with significant morbidity worldwide. Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of lipoproteins. In this study the effect of -629C/A polymorphism on the concentration of CETP and plasma lipids pattern was elicited in metabolic syndrome patients and control subjects. For this, a sample of 200 patients diagnosed with metabolic syndrome disorder was studied in comparison with 200 healthy controls. This study was performed by using polymerase chain reaction and restriction fragment length polymorphisms. Genotype distribution and allelic frequencies were determined and compared in metabolic syndrome and healthy controls. To determine the relationship between -629C/A polymorphism and lipid levels, lipids and CETP concentration were measured in metabolic syndrome and normal subjects. The results showed a significant difference between two groups in terms of FBS, cholesterol, TG, HDL-C, LDL-C levels as well as BMI, waist circumference, systolic and diastolic blood pressure. The genotype frequencies for this polymorphism differed significantly between metabolic syndrome patients and controls (in control group: CC%?20.5, CA%?76, AA%?3.5 and in patient group: CC%?28.5, CA%?53.5, AA%?18) (p?相似文献   

Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype.     

Zinc and Homocysteine Levels in Polycystic Ovarian Syndrome Patients with Insulin Resistance

In this study, our objective was to evaluating the value of serum zinc levels as an etiologic and prognostic marker in patients with polycystic ovarian syndrome. We conducted a prospective study, including 53 women with polycystic ovarian syndrome and 33 healthy controls. We compared serum zinc levels, as well as clinical and metabolic features, of the cases. We also compared serum zinc levels between patients with polycystic ovarian syndrome with insulin resistance. Mean zinc levels were found to be significantly lower in patients with polycystic ovarian syndrome than healthy controls. Multiple logistic regression analysis of significant metabolic variables between polycystic ovarian syndrome and control groups (serum zinc level, body mass index, the ratio of triglyceride/high-density lipoprotein cholesterol, and homocysteine) revealed that zinc level was the most significant variable to predict polycystic ovarian syndrome. Mean serum zinc levels tended to be lower in patients with polycystic ovarian syndrome with impaired glucose tolerance than patients with normal glucose tolerance, but the difference was not statistically significant. In conclusion, zinc deficiency may play a role in the pathogenesis of polycystic ovarian syndrome and may be related with its long-term metabolic complications.     

Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome

Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G0/G1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.     

Elevated circulating levels of markers of oxidative-nitrative stress and inflammation in a genetic rat model of metabolic syndrome

Metabolic syndrome is a cluster of metabolic diseases that in essence greatly promotes progression of atherosclerosis. We used a genetic model of the metabolic syndrome, the SHR/NDmcr-cp (SHR/cp) rat, from 6 to 40 weeks of age to investigate whether systemic oxidative stress, a major cause of atherosclerosis, increases in this syndrome. Nine-week-old male rats already showed manifestations of metabolic syndrome, including heavier body weight, higher blood pressure and higher levels of serum glucose, insulin and various lipids compared to the age-matched Wistar Kyoto (WKY) rats used as a genetic control. These metabolic parameters gradually progressed with age. Likewise, the serum levels of oxidative stress markers, including lipid peroxides, which oxidatively modify low-density lipoprotein (LDL) and 8-hydroxydeoxyguanosine (8-OHdG), gradually increased in SHR/cp rats. The serum levels of 3-nitrotyrosine and 3-chlorotyrosine also persistently increased, indicating the involvement of peroxynitrite or myeloperoxidase-catalyzed oxidation. In addition, high-sensitivity C-reactive protein (hsCRP), an early marker of inflammation, temporarily increased in SHR/cp rats compared to WKY rats. These findings suggest that oxidative stress, as well as nitrative stress and inflammation, increases in the metabolic syndrome, which may contribute to the development of atherosclerosis.     

Exploring the behavioral and cognitive phenotype of KBG syndrome

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD‐symptoms and social‐emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age‐appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.     

Mislocalization of K channels causes the renal salt wasting in EAST/SeSAME syndrome

The Kir4.1/Kir5.1 channel mediates basolateral K⁺ recycling in renal distal tubules; this process is critical for Na⁺ reabsorption at the tubules. Mutations in Kir4.1 are associated with EAST/SeSAME syndrome, a genetic disorder characterized by renal salt wasting. In this study, we found that MAGI-1 anchors Kir4.1 channels (Kir4.1 homomer and Kir4.1/Kir5.1 heteromer) and contributes to basolateral K⁺ recycling. The Kir4.1 A167V mutation associated with EAST/SeSAME syndrome caused mistrafficking of the mutant channels and inhibited their expression on the basolateral surface of tubular cells. These findings suggest mislocalization of the Kir4.1 channels contributes to renal salt wasting.     

Ubiquitination of Ro52 autoantigen

Anti-Ro/SSA antibodies are antinuclear antibodies most commonly found in patients with Sj?gren's syndrome, a chronic autoimmune disease characterized by dryness of the eyes and mouth. The autoantibodies recognize a RING-finger protein, Ro52/SSA (52 kDa), whose function is still unknown. In this study, the ubiquitination of Ro52 was investigated. We found that Ro52 was strongly conjugated by a single molecule of ubiquitin in cells. Although the biological relevance of this mono-ubiquitination was not defined, the function of Ro52 might be modified by the mono-ubiquitination. We also found that Ro52 was conjugated with poly-ubiquitin chain in cells (poly-ubiquitination), suggesting that Ro52 may be downregulated by the ubiquitin-proteasome pathway in vivo. Interestingly, sera from patients with Sj?gren's syndrome showed heterogeneity in their reactivity to poly-ubiquitinated Ro52, probably because of their differing antigenic determinants. This heterogeneity of the reactivity might be associated with the varying clinical features found in patients with Sj?gren's syndrome.     

PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype

Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.     

Transgenic isolation of skeletal muscle and kidney defects in laminin beta2 mutant mice: implications for Pierson syndrome

Pierson syndrome is a recently defined disease usually lethal within the first postnatal months and caused by mutations in the gene encoding laminin beta2 (LAMB2). The hallmarks of Pierson syndrome are congenital nephrotic syndrome accompanied by ocular abnormalities, including microcoria (small pupils), with muscular and neurological developmental defects also present. Lamb2(-/-) mice are a model for Pierson syndrome; they exhibit defects in the kidney glomerular barrier, in the development and organization of the neuromuscular junction, and in the retina. Lamb2(-/-) mice fail to thrive and die very small at 3 weeks of age, but to what extent the kidney and neuromuscular defects each contribute to this severe phenotype has been obscure, though highly relevant to understanding Pierson syndrome. To investigate this, we generated transgenic mouse lines expressing rat laminin beta2 either in muscle or in glomerular epithelial cells (podocytes) and crossed them onto the Lamb2(-/-) background. Rat beta2 was confined in skeletal muscle to synapses and myotendinous junctions, and in kidney to the glomerular basement membrane. In transgenic Lamb2(-/-) mice, beta2 deposition in only glomeruli prevented proteinuria but did not ameliorate the severe phenotype. By contrast, beta2 expression in only muscle restored synaptic architecture and led to greatly improved health, but the mice died from kidney disease at 1 month. Rescue of both glomeruli and synapses was associated with normal weight gain, fertility and lifespan. We conclude that muscle defects in Lamb2(-/-) mice are responsible for the severe failure to thrive phenotype, and that renal replacement therapy alone will be an inadequate treatment for Pierson syndrome.