Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins.

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

Hyperhomocysteinemia in stable pediatric, adolescents, and young adult renal transplant recipients.

BACKGROUND: High total plasma homocysteine (tHcy) levels are accompanied by an increased risk for premature development of atherosclerosis and atherothrombosis. Adult renal transplant recipients have elevated tHcy levels. Corresponding data in pediatric, adolescent, and young adult renal transplant recipients are scarce. We investigated whether tHcy levels were elevated in stable renal transplant recipients who received kidney grafts before age 18. METHODS: This cross-sectional study was conducted during routine posttransplantation follow-up. Fasting tHcy levels, serum creatinine, and lipoprotein profile were measured in 38 clinically stable renal transplant recipients with different degrees of renal function. No patient was receiving B vitamin or folic acid supplementation. Estimated glomerular filtration rate (GFR) was assessed according to Schwartz's formula. All patients followed a triple-drug immunosuppressive regimen, with the exception of three patients (deflazacort and azathioprine). Forty-one apparently healthy subjects constituted the control group. tHcy levels were determined by fluorescence polarization immunoassay in an IMx analyzer. RESULTS: Mean tHcy levels in transplant recipients were significantly higher than in controls (16.8+/-8.7 micromol/L and 9.5+/-2.3 micromol/L, respectively; P<0.01). A significant positive correlation between tHcy and serum creatinine levels was observed for both transplant recipients (rS=0.70, P<0.01) and controls (rS=0.54, P<0.01). In transplant recipients, tHcy correlated negatively with estimated GFR (rS=[minus]0.47, P<0.05). Fasting tHcy levels in excess of 14.6 micromol/L (>95th percentile in controls) were present in 19 (50%) patients; 14 of these patients had an estimated GFR<60 ml/min per 1.73 m2. When the renal transplant recipients were analyzed by renal function, mean tHcy was significantly higher in patients with an estimated GFR<60 ml/min per 1.73 m2 compared with patients with an estimated GFR> or =60 ml/min per 1.73 m2 (20.5+/-9.9 vs. 13.2+/-5.8 micromol/L, P<0.01). Both groups were significantly different from controls (P<0.01). No relationship was found between tHcy level and either cumulative cyclosporine or cumulative methylprednisone doses. No differences were observed in tHcy levels or lipoprotein profile between patients who were receiving deflazacort and those on methylprednisone. CONCLUSIONS: Hyperhomocysteinemia in renal transplant recipients is a common condition. Testing for fasting tHcy level might be a useful tool to identify patients at increased risk for development of vascular disease.

Plasmatic homocysteine response to vitamin supplementation in elderly people.

Homocysteine (Hcy) increase is now widely accepted as a risk factor for vascular disease. The effects of folic acid (FA) and vitamins B12 and B6 in lowering Hcy have been extensively studied, but there is still little data on the response to FA dietary administration. Our purpose was to evaluate the impact of the diet and the degree of response to different doses of pharmacological FA supplementation. In a prospective, randomized, and simple blind study, 50 elderly subjects were given a 400-microg/day FA diet and were randomly assigned to one of the following treatments: Group I = placebo tablet; Group II = tablet containing 1-mg folic acid, 1-mg B12, and 25-mg B6; and Group III = tablet containing 2.5-mg folic acid and same B6 and B12 doses as Group II. Forty-four subjects completed the study, and their plasmas were evaluated. Hcy concentration significantly decreased even in patients with normal basal values, and there were no differences in the response between individuals receiving diet plus placebo and those receiving diet plus pharmacological supplementation. After the treatment, the mean decrease of plasmatic Hcy levels was 10.8 (9.4, 12.5) micromol/l, geometric mean [95% confidence interval (95% CI)], and particularly, the values for Group I were 10.6 (7.4, 14.8) micromol/l. In 31% of the subjects, the post-treatment Hcy levels were less than or = 5 micromol/l. These results show that a special diet, with or without pharmacological FA and B12 and B6 supplementation, significantly decreases the Hcy levels in elderly people. Therefore, a diet with high contents of FA might have an enormous impact on the morbidity and mortality of atherothrombosis.

[Epidemiology of delirium in elderly inpatients]. / Epidemiología del delirio en ancianos hospitalizados.

Our objective was to determine delirium incidence and risk factors in a cohort of elderly inpatients. We randomly selected 149 patients, aged 65 years or older, from admission to general wards, without evidence of delirium. They were evaluated daily with the Confusion Assessment Method, an instrument validated for the diagnosis of delirium. We obtained relative risks for delirium and those independently associated were included in a logistic regression model. We used the chi-square test with Yate's corrections for univariate analysis, and t-test for comparisons of means. We observed that 51 patients (20.5%) developed delirium during their hospital stay. Severity of disease (RR 1.28, 1.14-1.43), having chronic diseases (RR 3.45, 2.4-4.96), and having fever at admission (RR 1.84, 1.33-2.56) were found independently associated with delirium. Patients who developed delirium had longer hospital stay (9.87 days +/- 3.48 vs 6.95 days +/- 2.45, p < 0.05) and higher mortality (RR 2.19, CI 1.26-3.79). We conclude that delirium in our setting is very frequent and has negative effects on resource utilization and mortality in elderly inpatients. Its association with the severity of the disease seems interesting. Appropriate prospective identification of patients at risk for delirium may allow the implementation of preventive strategies in order to minimize the impact of this complication.

Epidemiología del delirio en ancianos hospitalizados. / [Epidemiology of delirium in elderly inpatients]

Our objective was to determine delirium incidence and risk factors in a cohort of elderly inpatients. We randomly selected 149 patients, aged 65 years or older, from admission to general wards, without evidence of delirium. They were evaluated daily with the Confusion Assessment Method, an instrument validated for the diagnosis of delirium. We obtained relative risks for delirium and those independently associated were included in a logistic regression model. We used the chi-square test with Yates corrections for univariate analysis, and t-test for comparisons of means. We observed that 51 patients (20.5

) developed delirium during their hospital stay. Severity of disease (RR 1.28, 1.14-1.43), having chronic diseases (RR 3.45, 2.4-4.96), and having fever at admission (RR 1.84, 1.33-2.56) were found independently associated with delirium. Patients who developed delirium had longer hospital stay (9.87 days +/- 3.48 vs 6.95 days +/- 2.45, p < 0.05) and higher mortality (RR 2.19, CI 1.26-3.79). We conclude that delirium in our setting is very frequent and has negative effects on resource utilization and mortality in elderly inpatients. Its association with the severity of the disease seems interesting. Appropriate prospective identification of patients at risk for delirium may allow the implementation of preventive strategies in order to minimize the impact of this complication.

Lack of effective blood pressure control among an elder hypertensive population in Buenos Aires.

Our purpose was to determine the level of awareness, treatment, and control of hypertension in a population of subjects aged 65 or more. We studied a random sample from the national health care program in Buenos Aires. Letters were mailed to 1000 selected individuals. Among those eligible, 41.4% (n = 414) were enrolled. The mean age was 73.8 years and 68% were women. Prevalence of hypertension in our sample was 77.5% (n = 321). Awareness of hypertension was 60.7% (n = 195). Fifty-four percent (n = 173) of the hypertensive subjects were receiving pharmacologic treatment and only 18.5% (n = 32) of them were controlled. These results show that there is a low level of awareness, pharmacologic treatment, and control of hypertension in the studied elderly subjects.