title: Identification of a novel nonsense mutation in the FOXP3 gene in a fetus with hydrops--Expanding the phenotype of IPEX syndrome.
abstract: IPEX Syndrome is a well-characterized, however rare, autoimmune condition primarily affecting males presenting with neonatal onset of severe diarrhea, diabetes, dermatitis, and other autoimmune symptoms. The gene responsible for this condition, FOXP3, is important in the function of T-regulatory cells which maintain tolerance to self-antigens and are implicated in many autoimmune conditions. While females who carry FOXP3 mutations are typically asymptomatic, pregnancy loss of male fetuses in families with a history of IPEX syndrome has been noted. This loss is likely unrelated to the maternal carrier status, and rather related to pathogenic fetal autoimmunity. Fetal presentation of IPEX Syndrome has been recently reported in two families. Of the two reported probands, one had onset of severe intrauterine growth restriction and the second involved monochorionic diamniotic twins affected with fetal hydrops. Loss of male fetuses was noted in both families. We present a third family who suffered the loss of two male fetuses as a result of fetal hydrops of an unknown etiology. Whole Exome Sequencing on fetal remains following the second loss identified a novel nonsense mutation in the FOXP3 gene, which was inherited from the mother and subsequently confirmed in saved cells from the first pregnancy. These two cases further expand the fetal phenotype of IPEX Syndrome. While rare, IPEX syndrome should be another potential differential when considering the onset of unexplained hydrops in a male fetus.
authors.affiliation: Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Reichert
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: McKay
authors.affiliation: Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Moldenhauer
mesh_terms: D000328:Adult; D003025:Clubfoot / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital* / Q000235:genetics; D003967:Diarrhea / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics*; D007154:Immune System Diseases / Q000151:congenital* / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods
chemical_list: D018389:Codon, Nonsense; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
keywords: FOXP3 mutations; IPEX syndrome; fetal hydrops; prenatal diagnosis; whole exome sequencing