Atypical fibrodysplasia ossificans progressiva diagnosed by whole-exome sequencing.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of connective tissue that begins during the first decade of life. Our patient presented with intrauterine growth retardation, respiratory distress, neonatal onset soft tissue masses, bilateral hallux valgus, and congenital anomalies of the thyroid and uterus. She was initially diagnosed with atypical infantile myofibromatosis based on clinical and pathological findings. She underwent whole-exome sequencing (WES) as part of the FORGE study to identify the gene for infantile myofibromatosis; however a de novo dominant mutation in ACVR1 (NM_001105.4:c.617G>A) revised the diagnosis to FOP. This patient highlights the utility of WES as an early diagnostic tool in the investigation of patients with unusual presentations of rare diseases, thereby providing clinicians with accurate molecular diagnoses and the opportunity to tailor clinical management to improve patient care.

Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation.

BACKGROUND: Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. METHODS: We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. RESULTS: In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. INTERPRETATION: We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea.

Evaluating Curricular Modules in the Care of Children With Medical Complexity: A Mixed-Methods Randomized Controlled Trial.

OBJECTIVE: Children with medical complexity (CMC) are a growing population, yet training in complex care varies across pediatric residency programs. The purpose of this study was 1) to evaluate the effectiveness of a curriculum for pediatric residents in improving performance in a simulated clinical scenario, and 2) to explore residents' perceived self-efficacy in caring for CMC. METHODS: A randomized controlled trial was conducted supplemented by qualitative inquiry. Pediatric residents from 2 residency programs were randomly assigned to participate in interactive modules on: 1) clinical assessment, care planning, and technological dependency or 2) noncomplex care topics. The primary outcome was mean score on an Observed Structured Clinical Examination (OSCE) of tracheostomy care. Semistructured interviews were conducted postintervention and analyzed using qualitative content analysis. RESULTS: Ninety-four eligible residents were randomized. Residents who attended all modules and the OSCE and consented to participate (intervention [n = 20] and control [n=24]) were included in the final analysis. At baseline, few (9%) reported being comfortable caring for CMC. There was no significant difference in mean OSCE score between intervention and control groups (39.0 ± 1.1 vs 38.0 ± 1.0, P = .48). Qualitative analysis revealed 3 emerging themes related to resident self-efficacy: building a system of care, navigating uncertainty, and professional identity formation. CONCLUSIONS: A standardized complex care curriculum delivered in a classroom setting did not lead to improved performance in an OSCE station despite increased resident-reported self-efficacy in approaching care for CMC. These findings highlight the need for multidimensional educational interventions and assessments in complex care.