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Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A.

ABSTRACT: Vitamin D dependent rickets is a rare autosomal recessive disorder secondary to mutation in 1 ? hydroxylase enzyme gene. We are presenting a case of a two-year-old boy with vitamin D dependent rickets type 1A whose diagnosis was missed for a long period and he was treated as nutritional rickets. He suffered with severe hypotonia and regressing milestones. Severe hypotonia with proximal muscle weakness caused respiratory failure which required intensive care admission and mechanical ventilation. DNA analysis revealed previously reported homozygous mutation in CYP27B1 gene (p.Arg429Pro (R429P) at exon c.1286 G?>?C). Rare genetic disorders of rickets are not considered in early course of disease in regions with high prevalence of vitamin D deficiency. This severe presentation of rickets highlights the need of close monitoring of treatment response and consideration of other differential diagnosis in children who are not responding to vitamin D supplements. There is a high prevalence of genetic disorders particularly autosomal recessive conditions in societies having high rate of inter-family and consanguineous marriages.

SUBMITTER: Ahmad N

PROVIDER: S-EPMC6363249 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A.

Ahmad Noman N Mohamed Sobaihi Mrouge M Al-Jabri Mona M Al-Esaei Nabil Abdulrahman NA Al Zaydi Abdullah M AM

International journal of pediatrics & adolescent medicine 20180607 2

Vitamin D dependent rickets is a rare autosomal recessive disorder secondary to mutation in 1 α hydroxylase enzyme gene. We are presenting a case of a two-year-old boy with vitamin D dependent rickets type 1A whose diagnosis was missed for a long period and he was treated as nutritional rickets. He suffered with severe hypotonia and regressing milestones. Severe hypotonia with proximal muscle weakness caused respiratory failure which required intensive care admission and mechanical ventilation. ...[more]

PMID: 30805538

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Project description:ContextVitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessively inherited disorder due to loss-of-function mutations in the CYP27B1 gene. CYP27B1 encodes an enzyme of 25-hydroxyvitamin D-1?-hydroxylase for converting inactive 25-OHD to biologically active 1,25-(OH)2D.ObjectiveTo identify underlying genetic defects in patients with VDDR1A.MethodsTwelve patients from 7 Turkish and 2 Saudi families were investigated. The coding exons and intron-exon boundaries of the CYP27B1 gene were amplified by Polymerase Chain Reaction (PCR) from peripheral lymphocyte DNA. PCR products were directly sequenced. The consequences of c.590G > A mutation were analyzed by in silico and functional analysis.ResultsCYP27B1 mutations were identified in all the patients. Two novel mutations were identified in two separate families: c.171delG (family 7) and c.398_400dupAAT (family 8). The intra-exon deletion of c.171delG resulted in a frameshift and premature stop codon 20 amino acids downstream from the mutation (p.L58Cfs?20). The intra-exon duplication of c.398_400dupAAT generated a premature stop codon at the mutation site (p.W134?). A missense c.590G > A (p.G197D) mutation was found in a patient from family 4 and caused a defect in pre-mRNA splicing. As a result, two populations of transcripts were detected: the majority of them with intron 3 retention (83%), and the minority (17%) being properly spliced transcripts with about 16% of wild-type enzymatic activity. The remaining nine patients from six families carried a previously reported c.1319_1325dupCCCACCC (F443Pfs?24) mutation. Clinically, all the patients need continued calcitriol treatment, which was consistent with inactivation of 25-hydroxy vitamin D1?-hydroxylase activity.ConclusionTwo novel frameshift CYP27B1 mutations were identified and predicted to inactivate 25-hydroxyvitamin D-1?-hydroxylase. The loss of enzymatic activity by c.590G > A missense mutation was mainly caused by aberrant pre-mRNA splicing.

Project description:Acute respiratory distress syndrome (ARDS) continues to have significant mortality and morbidity. The only intervention proven to reduce mortality is the use of lung-protective mechanical ventilation strategies, although such a strategy may lead to problematic hypercapnia. Extracorporeal carbon dioxide removal (ECCO?R) devices allow uncoupling of ventilation from oxygenation, thereby removing carbon dioxide and facilitating lower tidal volume ventilation. We performed a systematic review to assess efficacy, complication rates, and utility of ECCO?R devices. We included randomised controlled trials (RCTs), case-control studies and case series with 10 or more patients. We searched MEDLINE, Embase, LILACS (Literatura Latino Americana em Ciências da Saúde), and ISI Web of Science, in addition to grey literature and clinical trials registries. Data were independently extracted by two reviewers against predefined criteria and agreement was reached by consensus. Outcomes of interest included mortality, intensive care and hospital lengths of stay, respiratory parameters and complications. The review included 14 studies with 495 patients (two RCTs and 12 observational studies). Arteriovenous ECCO?R was used in seven studies, and venovenous ECCO?R in seven studies. Available evidence suggests no mortality benefit to ECCO?R, although post hoc analysis of data from the most recent RCT showed an improvement in ventilator-free days in more severe ARDS. Organ failure-free days or ICU stay have not been shown to decrease with ECCOvR. Carbon dioxide removal was widely demonstrated as feasible, facilitating the use of lower tidal volume ventilation. Complication rates varied greatly across the included studies, representing technological advances. There was a general paucity of high-quality data and significant variation in both practice and technology used among studies, which confounded analysis. ECCO?R is a rapidly evolving technology and is an efficacious treatment to enable protective lung ventilation. Evidence for a positive effect on mortality and other important clinical outcomes is lacking. Rapid technological advances have led to major changes in these devices and together with variation in study design have limited applicability of analysis. Further well-designed adequately powered RCTs are needed.

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Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A.

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Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A.

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