Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.206G > A), a gene previously associated with Sensenbrenner Syndrome, Ellis-van Creveld syndrome and Short-rib polydactyly syndrome type V. The genetic findings in this family led to the re-evaluation of the initial diagnosis and a differential diagnosis of Sensenbrenner Syndrome was made after cautious re-examination of the patient. Cell culture studies revealed normal subcellular localization of the mutant WDR35 protein in comparison to wildtype protein, pointing towards impaired protein-protein interaction and/or altered cell signaling pathways as a consequence of the mutated allele. This research study highlights the importance of including pathogenic variant identification in the diagnosis pipeline of ciliary chondrodysplasias, especially for clinically not fully defined phenotypes.
Data on the treatment and outcome of Kuwaiti children with steroid refractory idiopathic glomerulonephritis (SRIGN), i.e. nephrotic syndrome who failed an eight-week course of prednisone, were collected retrospectively from the records of children attending the two renal centers of Kuwait between January 1, 1990 to December 31, 1996. During those seven years, a total of 34 Kuwaiti children were diagnosed to have SRIGN. Histologically, 22 (65%) of those patients had minimal change, 5 (15%) focal segmental GN, 2 (6%) non-IgA mesangioproliferative GN and one membranous GN. Twenty-two patients had manifested frequent relapses, six were steroid-dependent and six were steroid-resistant. Treatment options were in the following order: (a) small maintenance-dose of corticosteroids (< 0.5 mg/kg/alternate days); (b) cyclophosphamide and or chlorambucil for a single eight week-course or eight then 12 week courses (c) cyclosporin A for three months. The response to therapy was as follows: nine children were cured with low-dose corticosteroids; 17 with chlorambucil and/or cyclophosphamide; and five with cyclosporin A. At the end of study, only three children failed such drug therapy, two of who had focal segmental glomerulosclerosis.
Primary hyperoxaluria type-1 (PH-1) is a rare autosomal recessive metabolic disorder leading to excessive oxalate production, deposition of calcium oxalate crystals in the kidney, nephrocalcinosis, progressive renal failure and systemic deposition of oxalate (oxalosis). Combined liver and kidney transplantation (LKT), which has been accepted as the treatment of choice for PH-1, has considerably improved patient and graft survival. Herein, we report our experience of three children with PH-1 who underwent combined LKT, with a review of the literature.
Focal segmental glomerulosclerosis is a common cause of end-stage renal disease in children. Focal segmental glomerulosclerosis recurrence in renal transplants is a challenging disease, and can cause graft dysfunction and loss. Different therapies exist with varying responses, from complete remission to resistance to all modes of treatment. Abatacept was recently introduced as a treatment for primary focal segmental glomerulosclerosis in native kidneys and in recurrent disease after transplant. We present a pediatric case with immunosuppression-resistant primary NPHS2-negative focal segmental glomerulosclerosis recur-rence after renal transplant. The standard therapy for recurrent focal segmental glomerulosclerosis (rituximab, plasmapheresis, highdose cyclosporine, and corticosteroids) was tried but failed to induce remission. Abatacept (10 mg/kg) was given at 0, 2, and 4 weeks (total, 3 doses) with no good response. We conclude that abatacept may work in patients with B7-1-positive focal segmental glomerulosclerosis recurrence and its efficacy is uncertain in disease with B7-1-negative or unknown staining status.
A retrospective analysis is described to assess the effects of using recombinant activated factor VII to control bleeding in a series of patients who had failed to respond to conventional hemostatic measures. In all, 18 patients (aged 16-65 years) with a range of conditions resulting in bleeding refractory to conventional methods of control were treated with recombinant activated factor VII (60-120 Amicrog/kg; 1-4 doses). The effects of recombinant activated factor VII on bleeding were noted together with the patients' transfusion requirements and hematological parameters. Administration of recombinant activated factor VII successfully stopped bleeding in 17 of the 18 patients. Therapy with recombinant activated factor VII significantly decreased transfusion requirements for packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate compared with pretreatment values along with significant improvement in hemostasis. In various serious bleeding situations, treatment with recombinant activated factor VII may effectively arrest bleeding, which has remained refractory to conventional methods of control.
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