A phenotypic expansion of TRNT1 associated sideroblastic anemia with immunodeficiency, fevers, and developmental delay

Am J Med Genet A. 2022 Jan;188(1):259-268. doi: 10.1002/ajmg.a.62482. Epub 2021 Sep 12.


Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD; MIM #616084) is an autosomal recessive disorder of mitochondrial and cytosolic tRNA processing caused by pathogenic, biallelic variants in TRNT1. Other features of this disorder include central nervous system, renal, cardiac, ophthalmological features, and sensorineural hearing impairment. SIFD was first described in 2013 and to date, it has been reported in 46 patients. Herein, we review the literature and describe two siblings with SIFD and note the novel phenotype of hypoglycemia in the context of growth hormone (GH) deficiency. GH deficiency without hypoglycemia has previously been reported in three patients with SIFD, but GH deficiency had not been firmly ascribed to SIFD. We propose to expand the phenotype to include GH deficiency, hypoglycemia, and previously unreported dysmorphic features. Furthermore, we highlight the intrafamilial variability of the disease by the discordance of our patients' clinical phenotypes and biochemical profiles measured by untargeted metabolomics analysis. Several metabolomic abnormalities were observed in both patients, and these may represent a potential biochemical signature for SIFD.

Keywords: SIFD; TRNT1; growth hormone deficiency; metabolomics; mitochondrial disorder.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Anemia, Sideroblastic* / genetics
  • Fever / complications
  • Fever / genetics
  • Humans
  • Mutation
  • Nucleotidyltransferases / genetics
  • Phenotype


  • Nucleotidyltransferases
  • TRNT1 protein, human