ABSTRACT
Cenani Lenz syndrome is a rare autosomal recessive disorder associated with variable degree of limb malformations, dysmorphism, and renal agenesis. It is caused due to pathogenic variants in the LRP4 gene, which plays an important role in limb and renal development. Mutations in the APC gene have also been occasionally associated with CLS. The phenotypic spectrum ranges from mild to very severe perinatal lethal type depending on the type of variant. We report a pathogenic variant, c.2710 del T (p.Trp904GlyfsTer5) in theLRP4 gene, in a fetus with lethal Cenani Lenz syndrome with antenatal presentation of tetraphocomelia and symmetrical involvement of hands and feet.
Subject(s)
Congenital Abnormalities/genetics , Kidney Diseases/congenital , Kidney/abnormalities , LDL-Receptor Related Proteins/genetics , Limb Deformities, Congenital/genetics , Syndactyly/genetics , Aborted Fetus/pathology , Adenomatous Polyposis Coli Protein/genetics , Congenital Abnormalities/mortality , Congenital Abnormalities/pathology , Female , Genes, Lethal/genetics , Genetic Predisposition to Disease , Homozygote , Humans , Indian Ocean Islands/epidemiology , Kidney/pathology , Kidney Diseases/genetics , Kidney Diseases/mortality , Kidney Diseases/pathology , Limb Deformities, Congenital/mortality , Limb Deformities, Congenital/pathology , Male , Mutation/genetics , Pedigree , Phenotype , Pregnancy , Syndactyly/mortality , Syndactyly/pathologyABSTRACT
OBJECTIVES: The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations. BACKGROUND: TS is an extremely rare genetic disorder of the L-type cardiac channel Cav1.2 encoded by CACNA1C. The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms. METHODS: Patients diagnosed with TS between January 1, 1994, and April 1, 2016, from 12 international tertiary care pediatric centers were included in this retrospective study. Data were gathered via survey from the patients' electrophysiologists. RESULTS: Seventeen patients diagnosed with TS were identified. Length of follow-up was 4.9 years (range 3.0 to 19.0 years). Mean QTc was 640 ms (range 500 to 976 ms). All patients were treated with beta-blockers; 13 patients (76%) were also treated with an implantable defibrillator. Eleven patients experienced an episode of aborted cardiac arrest, 6 associated with general anesthesia and 2 with hypoglycemia. Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia. CONCLUSIONS: This study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.