title: A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature.
abstract: Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15-29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative.
  
  
  CONCLUSIONS
  We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals.
  
  
  BACKGROUND
  • Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies. What is new: • We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable pathogenicity was detected.
authors.affiliation: Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic. michaela.nemcikova@fnmotol.cz.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nemcikova
authors.affiliation: Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Vejvalkova
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic.
authors.forename: Filip
authors.initials: F
authors.lastname: Fencl
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Sukova
authors.affiliation: Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Krepelova
mesh_terms: D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006801:Humans; D007970:Leukopenia / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000235:genetics*; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D018631:ras Proteins / Q000235:genetics*
chemical_list: C486776:RIT1 protein, human; D018631:ras Proteins
keywords: Leukopenia; Myeloproliferative; Noonan syndrome; RASopathies; RIT1