title: Hoyeraal-Hreidarsson Syndrome due to PARN Mutations: Fourteen Years of Follow-Up.
abstract: BACKGROUND
  Hoyeraal-Hreidarsson syndrome is a dyskeratosis congenita-related telomere biology disorder that presents in infancy with intrauterine growth retardation, immunodeficiency, and cerebellar hypoplasia in addition to the triad of nail dysplasia, skin pigmentation, and oral leukoplakia. Individuals with Hoyeraal-Hreidarsson syndrome often develop bone marrow failure in early childhood. Germline mutations in DKC1, TERT, TINF2, RTEL1, ACD, or PARN cause about 60% of individuals with Hoyeraal-Hreidarsson syndrome.
  
  
  METHODS
  We describe 14 years of follow-up of an individual with Hoyeraal-Hreidarsson syndrome who initially presented as an infant with intrauterine growth retardation, microcephaly, and central nervous system calcifications. He was diagnosed with Hoyeraal-Hreidarsson syndrome at age 6 years and had a complicated medical history including severe developmental delay, cerebellar hypoplasia, esophageal and urethral stenosis, hip avascular necrosis, immunodeficiency, and bone marrow failure evolving to myelodysplastic syndrome requiring hematopoietic cell transplantation at age 14 years. He had progressive skin pigmentation, oral leukoplakia, and nail dysplasia leading to anonychia. Whole exome sequencing identified novel biallelic variants in PARN.
  
  
  CONCLUSIONS
  This patient illustrates that the constellation of intrauterine growth retardation, central nervous system calcifications, and cerebellar hypoplasia, esophageal or urethral stenosis, and cytopenias, in the absence of congenital infection, may be due to Hoyeraal-Hreidarsson syndrome. Early diagnosis of Hoyeraal-Hreidarsson syndrome is important to optimize medical management and provide genetic counseling.
authors.affiliation: San Antonio Military Medical Center, San Antonio, Texas.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Burris
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Bari J
authors.initials: BJ
authors.lastname: Ballew
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Kentosh
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Clesson E
authors.initials: CE
authors.lastname: Turner
authors.affiliation: Children's National Medical Center, Washington, District of Columbia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Norton
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, NCI-Frederick, Rockville, Maryland.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Neelam
authors.initials: N
authors.lastname: Giri
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.affiliation: Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Anandani
authors.initials: A
authors.lastname: Nellan
authors.affiliation: Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gamper
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Kip R
authors.initials: KR
authors.lastname: Hartman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. Electronic address: savagesh@mail.nih.gov.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D004252:DNA Mutational Analysis; D019871:Dyskeratosis Congenita / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D059472:Exome; D005095:Exoribonucleases / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008137:Longitudinal Studies; D008297:Male; D008831:Microcephaly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009154:Mutation / Q000235:genetics*; D055815:Young Adult
chemical_list: D005095:Exoribonucleases
keywords: CNS calcification; Hoyeraal-Hreidarsson syndrome; PARN; dyskeratosis congenita; microcephaly; telomere
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