title: Atypical hematologic and renal manifestations in neurofibromatosis type I: coincidence or pathophysiological link?
abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors with a birth incidence rate of 1 in 2500-3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as café-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots café-au -lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C > A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin, Service de Génétique Médicale, Centre de Référence des Anomalies du Développement Embryonnaire, 33076 Bordeaux Cedex, France. Electronic address: julien.vangils@gmail.com.
authors.forename: Julien
authors.initials: J
authors.lastname: Van-Gils
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin-Enfants, Centre de référence maladies rénales rares du Sud-Ouest (SORARE), Service de Pédiatrie, 33076 Bordeaux Cedex, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Harambat
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin-Enfants, Unité d'Hématologie Oncologie Pédiatrique, 33076 Bordeaux Cedex, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jubert
authors.affiliation: Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Service de biochimie et génétique moléculaire, 75679 Paris Cedex 14, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin-Enfants, Centre de référence maladies rénales rares du Sud-Ouest (SORARE), Service de Pédiatrie, 33076 Bordeaux Cedex, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Llanas
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin-Enfants, Unité d'Hématologie Oncologie Pédiatrique, 33076 Bordeaux Cedex, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Perel
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin, Service de Génétique Médicale, Centre de Référence des Anomalies du Développement Embryonnaire, 33076 Bordeaux Cedex, France; Université Bordeaux, Laboratoire Maladies Rares, Génétique et Métabolisme (MRGM), EA4576, 33076 Bordeaux Cedex, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: CHU Bordeaux, Hôpital Pellegrin, Service de Génétique Médicale, Centre de Référence des Anomalies du Développement Embryonnaire, 33076 Bordeaux Cedex, France; Université Bordeaux, Laboratoire Maladies Rares, Génétique et Métabolisme (MRGM), EA4576, 33076 Bordeaux Cedex, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
mesh_terms: D000293:Adolescent; D000328:Adult; D019080:Cafe-au-Lait Spots / Q000175:diagnosis / Q000235:genetics; D002648:Child; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000175:diagnosis* / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000175:diagnosis* / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics; D010375:Pedigree; D000090063:Proto-Oncogene Mas
chemical_list: C000715470:MAS1 protein, human; D025542:Neurofibromin 1; D000090063:Proto-Oncogene Mas
keywords: Acute myeloid leukemia; Blood disease; Nephrotic syndrome; Neurofibromatosis type 1; Proto-oncogene protein ras; Von Recklinghausen disease; mTOR serine threonine kinases