Hoyeraal-Hreidarsson Syndrome due to PARN Mutations: Fourteen Years of Follow-Up

Abstract

Introduction 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. Patients with Hoyeraal-Hreidarsson syndrome often develop bone marrow failure in early childhood. Germline mutations in DKC1, TERT, TINF2, RTEL1, ACD, and PARN cause about 60% of Hoyeraal-Hreidarsson syndrome cases. Case Report We report 14 years of follow-up for a patient 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 six 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. He had progressive skin pigmentation changes, oral leukoplakia, and nail dysplasia leading to anonychia. Whole exome sequencing identified novel biallelic variants in PARN. Conclusions This case illustrates that the constellation of IUGR, 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.

Impaired telomere integrity and rRNA biogenesis in PARN‐deficient patients and knock‐out models

“…In P1, the combined analyses of whole genome homozygosity mapping (WGHM) and whole exome sequencing (WES) focused on homozygous genetic variants absent from dbSNPs, EVS, 1,000 genome and from our in‐house databases (8,319 individuals) and located in chromosomal regions co‐segregating with the disease identified homozygous mutations in the Titin‐encoding gene (NM_001267550.1:c.9413C>A; Chr2(GRCh37):g.179632544G>T; p.Ala3138Glu) and in the PARN‐encoding gene (NM_002582.2:c.204G>T; Chr16(GRCh37):g.14721167C>A; p.Gln68His). We considered PARN gene as the strongest candidate because biallelic PARN mutations had been recently reported in HH (Dhanraj et al , ; Moon et al , ; Tummala et al , ; Burris et al , ). Sanger sequencing confirmed the homozygous c.204G>T PARN mutation in P1, with both parents being heterozygous for the mutation (Fig B).…”

“…We first assessed whether PARN deficiency in patients was accompanied by a telomere length defect as previously reported (Dhanraj et al , ; Moon et al , ; Tummala et al , ; Burris et al , ). Telomere restriction fragment (TRF) measurement revealed abnormally short telomeres in peripheral blood mononuclear cells from P1 and P2 as compared to their parents (Fig A).…”

“…Disease resulting from biallelic PARN mutations has been reported in only 9 patients so far (Dhanraj et al , ; Moon et al , ; Tummala et al , ; Burris et al , ). We here describe two unrelated patients carrying novel biallelic PARN mutations and exhibiting a phenotype corresponding to Høyeraal–Hreidarsson syndrome.…”

Advances in the gene therapy of monogenic blood cell diseases

“…Dyskeratosis congenita (DC) constitutes another IBMFS associated with mutations in any of the 15 genes related with the maintenance of telomere length . Three inherited forms of the disease have been described: X‐linked, autosomal dominant and autosomal recessive.…”

“…Dyskeratosis congenita (DC) constitutes another IBMFS associated with mutations in any of the 15 genes related with the maintenance of telomere length. [137][138][139][140] Three inherited forms of the disease have been described: X-linked, autosomal dominant and autosomal recessive. The main manifestations of the disease are ungual dystrophy, leukoplakia, cutaneous hyperpigmentation, as well as BMF, which appears in 80% of DC patients before the age of 30.…”