Down syndrome and pulmonary hemosiderosis: an under-recognized association

International audienc

Premature ovarian insufficiency in CLPB deficiency: transcriptomic, proteomic and phenotypic insights

International audienceABSTRACT Context Premature ovarian insufficiency (POI) is a common form of female infertility that most often presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimise co-morbidity and improve health outcomes. Objective To determine the genetic cause of premature ovarian insufficiency (POI), intellectual disability, neutropenia and cataracts. Methods We performed whole exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq and quantitative proteomics, as well as clinical update of previously reported patients with variants in the CaseinoLytic Peptidase B (CLPB) gene. Results We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts and neutropenia that is often fatal in childhood, however, there is likely a reporting bias towards severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common post-pubertal ailment. Conclusions A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of post-pubertal females with CLPB deficiency. Patients with CLPB deficiency should be referred to paediatric gynaecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimise associated co-morbidities

Additional file 1: of Pulmonary hemosiderosis in children with Down syndrome: a national experience

Table S1. Detailed characteristics of the 34 included patients. (DOCX 24 kb

Orphanet J Rare Dis

BACKGROUND: Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare(R) network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS. METHODS: Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare(R) database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients' data were compared. RESULTS: A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 +/- 3.27 years old for non-DS and 2.9 +/- 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution. CONCLUSIONS: DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease