Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Hip arthroplasty fatality related to dabigatran induced gastrointestinal haemorrhage.

We report a fatality due to massive gastrointestinal haemorrhage in a patient receiving prophylactic dabigatran etexilate following a total hip replacement. A 79-year-old woman was commenced on dabigatran for venous thromboembolic prophylaxis following a total hip replacement. She presented again four days after surgery with haematemesis and hypotension but her coagulopathy could not be corrected, leading to her death. This case highlights the lack of reversal agent for dabigatran etexilate that resulted in this fatal complication.

Tranexamic acid in total knee replacement: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of randomised controlled trials evaluating the effect of tranexamic acid (TXA) upon blood loss and transfusion in primary total knee replacement. The review used the generic evaluation tool designed by the Cochrane Bone, Joint and Muscle Trauma Group. A total of 19 trials were eligible: 18 used intravenous administration, one also evaluated oral dosing and one trial evaluated topical use. TXA led to a significant reduction in the proportion of patients requiring blood transfusion (risk ratio (RR) 2.56, 95% confidence interval (CI) 2.1 to 3.1, p < 0.001; heterogeneity I(2) = 75%; 14 trials, 824 patients). Using TXA also reduced total blood loss by a mean of 591 ml (95% CI 536 to 647, p < 0.001; I(2) = 78%; nine trials, 763 patients). The clinical interpretation of these findings is limited by substantial heterogeneity. However, subgroup analysis of high-dose (> 4 g) TXA showed a plausible consistent reduction in blood transfusion requirements (RR 5.33; 95% CI 2.44 to 11.65, p < 0.001; I(2) = 0%), a finding that should be confirmed by a further well-designed trial. The current evidence from trials does not support an increased risk of deep-vein thrombosis (13 trials, 801 patients) or pulmonary embolism (18 trials, 971 patients) due to TXA administration.

[Genetic syndromes that mimic congenital infections: report of 2 cases]. / Syndromes génétiques mimant les infections congénitales : à propos de 2 cas.

Genetic syndromes that mimic congenital infections must be recognized because of the associated risk of recurrence. We describe a male infant who was born with the association of intra-uterine growth retardation, microcephaly, intracranial calcifications, white matter abnormalities, microphtalmy, bilateral cataract, and hearing loss. Congenital cytomegalovirus (CMV) infection was suspected, but serologic CMV markers were not decisive (IgG+/IgM-). His half-sister (same father) presented a similar phenotype. Therefore, the diagnosis of congenital CMV infection was questioned and a genetic hypothesis was suggested. In 1983, Baraitser et al. first described two brothers with microcephaly and intracranial calcifications and negative TORCH analysis. Later, a number of authors reported children in whom detailed investigation failed to objectively confirm an intra-uterine infective agent. Clinical features include severe postnatal microcephaly, seizures, and pronounced developmental arrest. These cases have been considered to define a distinct autosomal recessive disorder first named pseudo-Torch syndrome. The family described herein is different from the cases previously described with a suspected autosomal dominant inheritance, severe ophtalmological abnormalities, and unusual brain imaging.

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.

Mutations in cytokine receptor-like factor 1 (CRLF1) account for both Crisponi and cold-induced sweating syndromes.

Crisponi syndrome is a rare autosomal recessive disorder characterized by congenital muscular contractions of facial muscles, with trismus in response to stimuli, dysmorphic features, bilateral camptodactyly, major feeding and respiratory difficulties, and access of hyperthermia leading to death in the first months of life. The overlap with Stuve-Wiedemann syndrome (SWS) is striking, but the two conditions differ in that congenital lower limb bowing is absent in Crisponi syndrome, whereas it is a cardinal feature of SWS. We report here the exclusion of the leukemia inhibitory factor receptor gene in Crisponi syndrome and the identification of homozygote or compound heterozygote cytokine receptor-like factor 1 (CRLF1) mutations in four children from three unrelated families. The four mutations were located in the immunoglobulin-like and type III fibronectin domains, and three of them predicted premature termination of translation. Using real-time quantitative polymerase chain reaction, we found a significant decrease in CRLF1 mRNA expression in patient fibroblasts, which is suggestive of a mutation-mediated decay of the abnormal transcript. CRLF1 forms a heterodimer complex with cardiotrophin-like cytokine factor 1, and this heterodimer competes with ciliary neurotrophic factor for binding to the ciliary neurotrophic factor receptor (CNTFR) complex. The identification of CRLF1 mutations in Crisponi syndrome supports the key role of the CNTFR pathway in the function of the autonomic nervous system.

Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis.

Iron overload is associated with free radical generation and tissue damage. Our main objective was to ascertain the frequency and severity of iron overload in a group of 59 patients who died after conventional-intensity autologous (n=24) or allogeneic (n=35) haematopoietic stem cell transplantation (HSCT). A second objective was to investigate associations between liver-iron concentration and causes of transplant-related mortality. The median age was 41 years (range, 19-66), 41 were males and 18 females. In total, 26 patients had acute leukaemia or MDS, 10 CML, 17 lymphoma, four myeloma and two aplastic anaemia. The median hepatic iron concentration (HIC) was 138 micromol/g dry weight (7.7 mg/g; range 31-631 micromol/g). In total, 4/32 (12%) patients with HIC <150 micromol/g and 10/27 (37%) with hepatic iron > or =150 micromol/g showed invasive aspergillosis at autopsy (P=0.035). This was significant in multivariate analysis (RR 9.0; 95% CI 1.6-50.3, P=0.012). In conclusion, severe iron overload is frequent in patients who die following HSCT and is associated with invasive aspergillosis.

Measurement of liver iron overload by magnetic induction using a planar gradiometer: preliminary human results.

The measurement of hepatic iron overload is of particular interest in cases of hereditary hemochromatosis or in patients subject to periodic blood transfusion. The measurement of plasma ferritin provides an indirect estimate but the usefulness of this method is limited by many common clinical conditions (inflammation, infection, etc). Liver biopsy provides the most quantitative direct measurement of iron content in the liver but the risk of the procedure limits its acceptability. This work studies the feasibility of a magnetic induction (MI) low-cost system to measure liver iron overload. The excitation magnetic field (B0, frequency: 28 kHz) was produced by a coil, the perturbation produced by the object (deltaB) was detected using a planar gradiometer. We measured ten patients and seven volunteers in supine and prone positions. Each subject was moved in a plane parallel to the gradiometer several times to estimate measurement repeatability. The real and imaginary parts of deltaB/B0 were measured. Plastic tanks filled with water, saline and ferric solutions were measured for calibration purposes. We used a finite element model to evaluate the experimental results. To estimate the iron content we used the ratio between the maximum values for real and imaginary parts of deltaB/B0 and the area formed by the Nyquist plot divided by the maximum imaginary part. Measurements in humans showed that the contribution of the permittivity is stronger than the contribution of the permeability produced by iron stores in the liver. Defined iron estimators show a limited correlation with expected iron content in patients (R < or = 0.56). A more precise control of geometry and position of the subjects and measurements at multiple frequencies would improve the method.

First preimplantation genetic diagnosis of hereditary retinoblastoma using informative microsatellite markers.

Retinoblastoma is a malignant intra-ocular tumour of developing retina initiated by inactivation of both alleles of the retinoblastoma susceptibility (RB1) gene. This paper reports the first clinical experience of preimplantation genetic diagnosis (PGD) for hereditary retinoblastoma using two highly polymorphic microsatellite markers RB1.20 and D13S284, located within and close to the RB1 gene respectively. Duplex PCRs were tested on more than 300 single lymphocytes from heterozygous individuals at both loci, in order to test the accuracy and reliability of the single-cell protocol. This procedure requires a nested PCR and the analysis of fluorescently labelled PCR products on an automatic DNA sequencer. Amplification efficiency and allele drop-out rates ranged from 96.7 to 98.4%, and 3.7 to 5.4% respectively. This test was found to be accurate and reliable enough to be applied to the study of human blastomeres. Subsequently, this approach was used in a PGD treatment cycle for a couple who already had a child affected with hereditary retinoblastoma and found to be informative for both microsatellite markers.

[Clinical manifestations of familial hypercholesterolemia in Mediterranean population]. / Manifestaciones clínicas de la hipercolesterolemia familiar en una población mediterránea.

BACKGROUND: Familial hypercholesterolemia is defined by a genetically elevated concentration of plasma cholesterol. This is a descriptive and retrospective study to evaluate the prevalence of clinical manifestations of FH clinically diagnosed in our setting. PATIENTS AND METHODS: 114 non-related patients, from lipid clinics, entered into the study. Analytical criteria were total cholesterol over 7.8 mmol/l (300 mg/dl), triglycerides under 2.8 mmol/l (250 mg/dl), and at least one first-degree relative bearing the same lipid profile. Clinical history, antropometric measurements, lipid deposits and profile, treatment and its effects on lipid levels were recorded. Lipoprotein (a) concentration, apolipoprotein E (apo E) genotype and the presence of apo B-3500 mutations were analysed. RESULTS: Mean total cholesterol was 9.05 (1.58) mmol/l, LDL-cholesterol 7.09 (1.64) mmol/l, HDL-cholesterol 1.33 (0.45) mmol/l and triglyceride 1.38 (0.59) mmol/l. Xanthomas were found in 11.4% of the participants, 12.2% showed xanthelasmas and corneal arch was present in 27.1% of them. The 16.8% of the patients were suffering from ischaemic cardiopathy. Patients with corneal arch had higher concentrations of total and LDL-cholesterol (7.6 [1.9] vs 6.8 [1.5] mmol/l [p = 0.04]). A 57.9% of the patients with ischaemic heart disease had at least one first degree relative with the same complaint (p < 0.05). The apo B-3500 mutation was not found in this population. The apo E3/E4 genotype was present in 16.1% of the patients and total and LDL cholesterol concentrations were higher in them than in patients with the apo E3/E3 genotype (p < 0.05). In the multivariate analysis, the most important risk factors associated with ischaemic cardiopathy were the smoking habit (odds ratio [OR] = 20.59; CI: 3.3-111.2), corneal arch (OR = 7.27; 95% CI: 1.08-27.1). HDL-cholesterol concentrations were negatively associated with the existence of ischaemic heart disease (OR = 0.21; 95% CI: 0.03-1.15). CONCLUSIONS: The presence of ischaemic heart disease and lipids deposits in clinically diagnosed patients of familial hypercholesterolemia in our country is lower than description from others non Mediterranean, being the corneal arch the most prevalent sign. The smoking habit, corneal arch and the presence of familial antecessors with ischaemic heart disease were associated with ischaemic myocardiopathy in our patients.

Taxa de lotaçäo e manejo de pastagens de braquiária (Brachiaria decumbens) e soja perene (Neonotonia wightii). I.- Efeito sobre a disponibilidade de forragem e produçäo de proteína bruta das diferentes fraçöes da planta / Grazing pressure and pasture management of brachiaria (Brachiaria decumbens) and soya (Neonotomia wightii). I.- Effect on forage availability and crude protein production of different parts of plant

Avaliaram-se os efeitos da lotaçäo e do manejo sobre a qualidade e a disponibilidade da braquiária (Brachiaria decumbens), e seus diversos componentes. Foram usados quatro a seis bovinos azebuados por piquete, dependendo da taxa de lotaçäo e da área da pastagem. As lotaçöes usadas com pastejo contínuo foram: 1,43; 2,14 e 3,00 cabeças/hectare, envolvendo 45 bovinos e três manejos, A = braquiária, B = braquiária mais pastejo de soja na época seca e C = braquiária mais feno de soja na seca. As avaliaçöes da braquiária foram realizadas durante 315 dias, sendo a quantidade de forragem no pasto representada pela média ponderada de 15 estimativas visuais do melhor observador e mais 10 observaçöes reais de cada piquete. Utilizou-se análise de variância e teste "t" para comparaçäo entre médias. A maior disponibilidade de forragem foi verificada nos piquetes com as menores cargas. Houve diferença significativa entre os três manejos empregados, com maior disponibilidade no manejo A. A medida que se aumentou a lotaçäo, as quantidades de folha e talo da braquiária em todos os manejos diminuíram. As porcentagens de proteína bruta da folha de braquiária foram superiores aos outros componentes da planta. A partir de outubro, com o início das chuvas, essas porcentagens aumentaram em todos os componentes da braquiária

Taxa de lotaçäo e manejo de pastagens de braquiária (Brachiaria decumbens) e soja perene (Neonotonia wightii). II.- Efeito sobre a digestibilidade in vitro, teores de parede celular das diferentes fraçöes da planta e desempenho animal nas pastagens / Grazing pressure and pasture management of brachiaria (Brachiaria decumbens) and soya (Neonotonia wightii). II.- In vitro digestibility, cell wall conten of different parts of the plant and animal performance on pastures

Avaliaram-se os efeitos da lotaçäo e do manejo sobre o ganho de peso de animais, assim como sobre a qualidade e a disponibilidade da braquiária (Brachiaria decumbens), e suas diferentes fraçöes. Foram usados quatro a seis bovinos azebuados por piquete, dependendo da taxa de lotaçäo e da área da pastagem. As lotaçöes usadas com pastejo contínuo foram: 1,43; 2,14 e 3,00 cabeças/hectare, envolvendo 45 bovinos e três manejos, A = brachiaria, B = brachiaria mais pastejo de soja na época seca e C = brachiaria mais feno de soja na seca. As avaliaçöes da braquiária foram realizadas durante 315 dias, sendo a quantidade de forragem no pasto representada pela média ponderada de 15 estimativas visuais do melhor observador e mais 10 observaçöes reais de cada piquete. Utilizou-se análise de variância e teste "t" para a comparaçäo entre médias. A soja usada para pastejo era avaliada a cada 15 dias, através de gaiolas, durante quatro meses. Em março, os piquetes A, B e C de soja foram fenados para suplementar os animais do manejo C durante o inverno. A medida que se aumentou a lotaçäo, o ganho de peso diminuiu. Os ganhos de peso por hectare, no entanto, foram maiores com o aumento da lotaçäo. As porcentagens de digestibilidade in vitro da matéria orgânica e de conteúdo celular da folha de braquiária foram superiores aos outros componentes da planta. A partir de outubro, com o início das chuvas, essas porcentagens aumentaram em todas as fraçöes da braquiária

[Congenital adenomatoid cystic malformation of the lung and renal polycystosis. A fetal case report and review of the literature]. / Malformation congénitale adénomatoïde kystique du poumon et polykystose rénale. A propos d'une observation chez un foetus et revue de la littérature.

We observed a plurifocal cystic adenomatoid malformation of the lung, Stocker class II, in a 21-week gestation fetus in association with polycystosis of a solitary medial kidney. There was no other notable abnormally. The caryotype could not be obtained. The association of these two congenital malformations is exceptional, only three similar cases have been reported in the literature. Two other cases of pulmonary adenomatoid malformations associated with nephromegaly with renal hyperlobulation have also been described. Whether this is a fortuitous association or not remains to be determined.

Mobilization of peripheral blood progenitor cells by cyclophosphamide and rhGM-CSF in multiple myeloma.

Fifteen consecutive patients with multiple myeloma (MM) scheduled for peripheral blood progenitor cell (PBPC) transplantation, were randomly selected to receive cyclophosphamide (CY) (4 g/m2) alone (group I) or associated with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (5 micrograms/kg/day) (group II). The mean time of neutropenia after CY administration was 9.8 +/- 4.3 days in group I and 6.4 +/- 1.2 days in group II (P = 0.0228). One hundred and eight aphereses were performed (7.1 +/- 1.8 aphereses per patient in group I and 6.4 +/- 2.8 aphereses per patient in group II). rhGM-CSF administration after CY allowed a higher collection of CD34+ cells in apheresis products (1.42 +/- 1.68 x 10(6) CD34+ cells/kg) in comparison to without factor administration (0.47 +/- 0.52 x 10(6) CD34+ cells/kg) (P = 0.0165). The mean number of cells infused per patient was 6.56 +/- 4.02 x 10(8) MNC/kg and 7.64 +/- 3.00 x 10(4) CFU-GM/kg in group I and 6.25 +/- 4.03 x 10(8) MNC/kg and 8.16 +/- 9.73 x 10(4) CFU-GM/kg in group II. The mean time to recover 0.5 x 10(9) granulocytes/I, 20 and 50 x 10(9) platelets/I in peripheral blood (PB) was 17.2 +/- 7.4, 13.4 +/- 3.7 and 16.5 +/- 6.9 days respectively, in group I and 13.3 +/- 1.7, 11.6 +/- 1.6 and 15 +/- 6.3 days, in group II. rhGM-CSF administration after CY treatment for PBPC mobilization in MM patients reduces the neutropenic period after CY and enhances apheresis CD34+ cell collection.

[Erythroblastopenia during recurrence of a thymoma associated with myasthenia gravis. Apropos of a new case]. / Eritroblastopenia en el curso de un timoma recidivante asociado a miastenia gravis: a propósito de un nuevo caso.

A new case of thymoma, myasthenia gravis and pure red cell aplasia is presented. Pure red cell aplasia came out 10 years after the diagnosis of the two other diseases in one of several relapses of metastatic thymoma with clinical signs of myasthenia. Surgery, chemotherapy and radiotherapy besides pyridostigmine treatment were used in the clinical course of the patient. A phenotypical change of medullary T lymphocytes (CD4 to CD8) was observed at the same time of pure red cell aplasia diagnosis. A dual role of medullary CD2+ T cell lymphocytes, stimulant and suppressive, over erythroid progenitor cells (BFU-E and CFU-E) was suggested by in vitro cultures.