Maria F. Soares

Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis

Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling.

Optic nerve infiltration by acute lymphoblastic leukemia: MRI contribution

We describe the clinical presentation and imaging features of a patient with acute lymphoblastic leukemia (ALL) that was complicated by optic nerve infiltration. The clinical and diagnostic characteristics of this complication must be recognized so that optimal therapy can be started to prevent blindness. MR imaging is useful in early detection and should be performed in any leukemic patient with ocular complaints, even during remission.

Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families.

Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed.

Radiografia simples de abdome no diagnóstico da impactação fecal em crianças com constipação intestinal: comparação entre três escores radiológicos

OBJECTIVES To compare three radiological scores in the study of fecal impaction in children with constipation. To investigate whether these radiological scores are useful in the assessment of fecal disimpaction therapy and if they present a relation with total colonic transit time. METHODS The Barr, Blethyn and Leech scores were measured by three observers, independently, in 123 abdominal radiographs. Interobserver agreement in the diagnosis of fecal impaction was calculated for the three scores. In 30 radiographs, the analysis of the scores was performed before and after fecal disimpaction. Total colonic transit time was calculated in 59 radiographs with the use of radiopaque markers. RESULTS The agreement between pairs of observers was assessed by the kappa coefficient and was good for the Barr (0.56, 0.59 and 0.69) and Leech scores (0.53, 0.58 and 0.61). The Blethyn score presented lower kappa coefficients (0.26, 0.32 and 0.36). In the comparison of methods, Leech and Barr showed a good correlation. After fecal disimpaction, there was a statistically significant reduction (p < 0.001) of scores, most significantly with the Barr score. There was no relation between radiographic scores and colonic transit time. CONCLUSIONS There is no relation between fecal impaction assessed by radiography of the abdomen and total colonic transit time. Plain radiographs may be a useful tool for the diagnosis of fecal impaction. The Barr score can be considered a good method of analysis, especially to assess the response to treatment of fecal impaction.OBJECTIVES: To compare three radiological scores in the study of fecal impaction in children with constipation. To investigate whether these radiological scores are useful in the assessment of fecal disimpaction therapy and if they present a relation with total colonic transit time. METHODS: The Barr, Blethyn and Leech scores were measured by three observers, independently, in 123 abdominal radiographs. Interobserver agreement in the diagnosis of fecal impaction was calculated for the three scores. In 30 radiographs, the analysis of the scores was performed before and after fecal disimpaction. Total colonic transit time was calculated in 59 radiographs with the use of radiopaque markers. RESULTS: The agreement between pairs of observers was assessed by the kappa coefficient and was good for the Barr (0.56, 0.59 and 0.69) and Leech scores (0.53, 0.58 and 0.61). The Blethyn score presented lower kappa coefficients (0.26, 0.32 and 0.36). In the comparison of methods, Leech and Barr showed a good correlation. After fecal disimpaction, there was a statistically significant reduction (p < 0.001) of scores, most significantly with the Barr score. There was no relation between radiographic scores and colonic transit time. CONCLUSIONS: There is no relation between fecal impaction assessed by radiography of the abdomen and total colonic transit time. Plain radiographs may be a useful tool for the diagnosis of fecal impaction. The Barr score can be considered a good method of analysis, especially to assess the response to treatment of fecal impaction.

Atypical 581-kb 22q11.21 Deletion in a Patient with Oculo-Auriculo-Vertebral Spectrum Phenotype.

The oculo-auriculo-vertebral spectrum (OAVS) is defined as a group of malformations involving the ears, mouth, mandible, eyes, and cervical spine. Establishing an accurate clinical diagnosis of OAVS is a challenge for clinical geneticists, not only because these patients display heterogeneous phenotypes, but also because its etiology encompasses environmental factors, unknown genetic factors and different chromosome aberrations. To date, several chromosomal abnormalities have been associated with the syndrome, most frequently involving chromosome 22. In the literature, six 22q11.2 microdeletions have been described within the same region, suggesting possible OAVS candidate genes in this segment. Here, we report on a patient with an ∼581-kb 22q11.21 deletion, detected by genomic array and MLPA. This is the 7th case described with OAVS and 22q deletion, suggesting that the 22q11.2 region may be related to the regulation of body symmetry and facial development.

Cytogenomic delineation and clinical follow‐up of two siblings with an 8.5 Mb 6q24.2‐q25.2 deletion inherited from a paternal insertion

The chromosomal segment 6q24‐q25 comprises a contiguous gene microdeletion syndrome characterized by intrauterine growth retardation, growth delay, intellectual disability, cardiac anomalies, and a dysmorphic facial phenotype. We describe here a 10‐year follow‐up with detailed clinical, neuropsychological, and cytomolecular data of two siblings, male and female, who presented with developmental delay, microcephaly, short stature, characteristic facial dysmorphisms, multiple organ anomalies, and intellectual disability. Microarray analysis showed an 8.5 Mb 6q24.2‐q25.2 interstitial deletion. Fluorescence in situ hybridization analyses confirmed the deletions and identified an insertion of 6q into 8q13 in their father, resulting in a high recurrence risk. This is the first report in sibs with distinct neuropsychological involvement, one of them with stenosis of the descending branch of the aorta.

Cytogenomic characterization of an unexpected 17.6 Mb 9p deletion associated to a 14.8 Mb 20p duplication in a dysmorphic patient with multiple congenital anomalies presenting a normal G-banding karyotype.

We describe a female patient with developmental delay, dysmorphic features and multiple congenital anomalies who presented a normal G-banded karyotype at the 550-band resolution. Array and multiplex-ligation probe amplification (MLPA) techniques identified an unexpected large unbalanced genomic aberration: a 17.6Mb deletion of 9p associated to a 14.8 Mb duplication of 20p. The deleted 9p genes, especially CER1 and FREM1, seem to be more relevant to the phenotype than the duplicated 20p genes. This study also shows the relevance of using molecular techniques to make an accurate diagnosis in patients with dysmorphic features and multiple anomalies suggestive of chromosome aberration, even if on G-banding their karyotype appears to be normal. Fluorescence in situ hybridization (FISH) was necessary to identify a masked balanced translocation in the patients mother, indicating the importance of associating cytogenetic and molecular techniques in clinical genetics, given the implications for patient management and genetic counseling.

Urinary CD20 mRNA as a surrogate of CD20-positive cells infiltration during allograft dysfunction in renal transplant patients

B lymphocyte infiltration in renal acute allograft rejection has been associated with steroid resistance and poor outcomes. We aimed to measure CD20 mRNA in urine of renal transplant patients with graft dysfunction and correlate with the histological diagnosis and immunohistochemical (IH) staining for CD20. A total of 48 urine samples were analyzed (21 with acute rejection, 10 with chronic allograft nephropathy, 11 with unspecific tubular lesions, 3 with acute pyelonephritis and 3 with polyomavirus nephropathy). Higher urinary CD20 levels associated with a positive IH staining for CD20 (>50 positive cells/HPF) in renal tissue (p=0.04), with a sensitivity of 83.3% and a specificity of 51.6%. Within the acute rejection group, a positive staining for CD20 was not associated with graft loss, steroid resistance or lack of return to basal creatinine after treatment, but was associated with higher serum creatinine at 3 and 6 months, 1 and 2 years after the acute episode (p<0.05). In conclusion, we showed that urinary levels of CD20 detected by RT-PCR had a high sensitivity for CD20+ staining in the corresponding renal tissue, but with a low specificity. Patients with clusters of CD20+ cells >50/HPF had higher serum creatinine after 2 years of follow up.

Inactivation of AMMECR1 is associated with growth, bone and heart alterations

We report five individuals with loss‐of‐function of the X‐linked AMMECR1: a girl with a balanced X‐autosome translocation and inactivation of the normal X‐chromosome; two boys with maternally inherited and de novo nonsense variants; and two half‐brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients’ features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patients cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid‐binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.

Untreated Congenital Hypothyroidism Mimicking Hirschsprung Disease: A Puzzling Case in a One-Year-Old Child

Congenital hypothyroidism is a clinical emergency due to its potential risk of mental retardation. Constipation might be present in hypothyroid children. However, Hirschsprung disease is rarely associated with congenital hypothyroidism. Herein, a case of congenital hypothyroidism in a one-year-old child mimicking Hirschsprung disease is described. Adequate treatment with levothyroxine sodium tablets controlled intestinal dysmotility that mimicked congenital intestinal aganglionosis due to the critical influence of thyroid hormones on bowel motility.