Debilitating hip degeneration in trichothiodystrophy: Association with ERCC2/XPD mutations, osteosclerosis, osteopenia, coxa valga, contractures, and osteonecrosis

Am J Med Genet A. 2022 Dec;188(12):3448-3462. doi: 10.1002/ajmg.a.62962. Epub 2022 Sep 14.


Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder of DNA repair and transcription with developmental delay and abnormalities in brain, eye, skin, nervous, and musculoskeletal systems. We followed a cohort of 37 patients with TTD at the National Institutes of Health (NIH) from 2001 to 2019 with a median age at last observation of 12 years (range 2-36). Some children with TTD developed rapidly debilitating hip degeneration (DHD): a distinctive pattern of hip pain, inability to walk, and avascular necrosis on imaging. Ten (27%) of the 37 patients had DHD at median age 8 years (range 5-12), followed by onset of imaging findings at median age 9 years (range 5-13). All 10 had mutations in the ERCC2/XPD gene. In 7 of the 10 affected patients, DHD rapidly became bilateral. DHD was associated with coxa valga, central osteosclerosis with peripheral osteopenia of the skeleton, and contractures/tightness of the lower limbs. Except for one patient, surgical interventions were generally not effective at preventing DHD. Four patients with DHD died at a median age of 11 years (range 9-15). TTD patients with ERCC2/XPD gene mutations have a high risk of musculoskeletal abnormalities and DHD leading to poor outcomes. Monitoring by history, physical examination, imaging, and by physical medicine and rehabilitation specialists may be warranted.

Keywords: DNA repair diseases; avascular necrosis of the hip; developmental abnormalities; osteonecrosis; skeletal abnormalities; trichothiodystrophy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Bone Diseases, Metabolic* / genetics
  • Child
  • Child, Preschool
  • Contracture* / complications
  • Contracture* / genetics
  • Coxa Valga* / complications
  • Humans
  • Mutation
  • Osteonecrosis*
  • Osteosclerosis*
  • Trichothiodystrophy Syndromes* / diagnosis
  • Trichothiodystrophy Syndromes* / genetics
  • Xeroderma Pigmentosum Group D Protein / genetics
  • Young Adult


  • ERCC2 protein, human
  • Xeroderma Pigmentosum Group D Protein