Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.

Cristina Bertulli, Antonio Marzollo, Margherita Doria, Silvia Di Cesare, Claudio La Scola, Francesca Mencarelli, Andrea Pasini, Maria Carmen Affinita, Enrico Vidal, Pamela Magini, Paola Dimartino, Riccardo Masetti, Laura Greco, Patrizia Palomba, Francesca Conti, Andra Pession

Journal: International journal of molecular sciences 2021;21(22):8604

PMID: 33203071

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Abstract

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in . A phenotype-genotype correlation has been attempted and variable expressivity of biallelic variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

Address: Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.; Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.; Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens' Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy.; Dialysis and Transplantation Unit, Pediatric Nephrology, Department of Woman's and Child's Health, University Hospital of Padua, 35128 Padua, Italy.; Medical Genetics Unit, Department of Medical and Surgical Science, S. Orsola-Malpighi Hospital_Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.; Medical Genetics Unit, DIMEC, University of Bologna, 40138 Bologna, Italy.; "Lalla Seràgnoli", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.; Pediatric Radiology Unit, Department of Diagnostic and Preventive Medicine, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy.; Immunology Research Area-Unit of Diagnostic Immunology, Unit of B-cell Pathophysiology, Department of Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy.; Pediatric Unit, Department of Woman, Child and Urologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.; "Lalla Seràgnoli", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.; Pediatric Unit, Department of Woman, Child and Urologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

DOI: 10.3390/ijms21228604

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MeSH Terms: Amino Acid Substitution, Arteriosclerosis, DNA Helicases, Female, Humans, Interleukin-7 Receptor alpha Subunit, Kidney, Killer Cells, Natural, Male, Mutation, Missense, Nephroma, Mesoblastic, Nephrotic Syndrome, Osteochondrodysplasias, Phenotype, Primary Immunodeficiency Diseases, Pulmonary Embolism, Urinary Tract, Whole Genome Sequencing