Trichothiodystrophy

Author: Jacqueline Deen, Principal House Officer, Dermatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia. DermNet New Zealand Editor in Chief: Hon A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. September 2019.


What is trichothiodystrophy?

Trichothiodystrophy is a rare, multisystem, autosomal recessive disorder characterised by sulphur-deficient, short, brittle hair. Other clinical features may include photosensitivity, ichthyosis, intellectual impairment, haematological abnormalities, decreased fertility, and short stature [1].

The name trichothiodystrophy was coined by Price et al in 1979, and is derived from Greek: tricho (hair), thio (sulphur), dys (faulty), trophy (nourishment).

Trichothiodystrophy is classified into photosensitive and non-photosensitive sub-types [2].

Who gets trichothiodystrophy?

The estimated incidence of trichothiodystrophy is one per million live births. Males and females are affected equally. Trichothiodystrophy has been described in various ethnic groups worldwide, although it occurs more commonly amongst populations where consanguinity is frequent [1,3].

What causes trichothiodystrophy?

Trichothiodystrophy is caused by defective DNA repair and transcription and is inherited in an autosomal recessive pattern, meaning both parents must have the mutated gene that causes trichothiodystrophy for the child to inherit it.

  • Photosensitive trichothiodystrophy usually results from mutations in the DNA repair genes ERCC2 (XPD), ERCC3 (XPD) or GTF2H (p8/TTDA), with the former (ERCC2/XPD) gene mutation being most common.
  • A few cases of non-photosensitive trichothiodystrophy have been linked to mutations in MPLKIP (TTDN1), a gene of unknown function [2–4].

What are the clinical features of trichothiodystrophy?

Trichothiodystrophy is characterised by sulphur-deficient, short, brittle hair, which is sparse and easily broken. Other clinical features are highly variable in expression. Approximately 50% of patients have associated photosensitivity, although this does not confer an increased risk of future skin cancer (unlike patients with xeroderma pigmentosa).

Additional cutaneous features may include xerosis, ichthyosis and collodion membrane at birth. It may also be associated with onychodystrophy (brittle nails) [1–3].

Other non-dermatological-associated abnormalities may include:

  • Pregnancy-related complications, which present in around 30% of cases (intrauterine growth retardation, pre-eclampsia and eclampsia, premature birth [< 37 weeks gestation] and low birth weight)
  • Intellectual impairment/developmental delay (85% of cases)
  • Short stature (73% of cases)
  • Ocular abnormalities including congenital cataracts, strabismus, and nystagmus (approximately 50% of cases)
  • Rheumatological abnormalities (joint contractures and dislocations, axial osteosclerosis, and distal osteopenia)
  • Haematological abnormalities (anaemia, neutropenia, and features of β-thalassaemia trait)
  • Recurrent infections, particularly respiratory, which develop in the first year of life [1,5].

The clinical phenotype of trichothiodystrophy varies from mild disease with hair abnormalities to severe disease with recurrent infections and severe developmental defects. A number of acronyms have been created to describe the different clinical phenotypes seen.

  • PIBIDS: P (photosensitivity), I (ichthyosis), B (brittle hair), I (intellectual impairment with low IQ), D (decreased fertility), and S (short stature).
  • In non-photosensitive trichothiodystrophy, IBIDS and BIDS represent the initials of the same words [3].

What are the complications of trichothiodystrophy?

Complications of trichothiodystrophy are mostly related to the high risk of acquiring severe and potentially life-threatening infections [5].

How is trichothiodystrophy diagnosed?

Trichothiodystrophy may be diagnosed by demonstrating low sulphur content on biochemical analysis of hair shafts, in addition to one of the following findings:

  • Trichoschisis (broken or split hairs)
  • Alternating light and dark bands or ‘tiger-tail’ bands in the hair shaft, found by polarised light microscopy or trichoscopy
  • A severely damaged or absent hair cuticle by scanning electron microscopy [3].

What is the differential diagnosis for trichothiodystrophy?

Differential diagnoses of trichothiodystrophy can include:

Cockayne syndrome

Cockayne syndrome is a rare autosomal recessive disorder of DNA repair, characterised by photosensitivity, a distinctive facial appearance, short stature, ocular abnormalities, premature ageing, and neurological dysfunction.

Xeroderma pigmentosum

Xeroderma pigmentosum is a rare autosomal recessive condition of DNA repair, typified by the early development of pigmentary changes, an increased risk of ultraviolet radiation-induced skin and mucous membrane cancer, severe photosensitivity (50%), and in some individuals, progressive neurodegeneration (30%).

Menkes disease

Menkes disease (also known as Menkes kinky hair syndrome) is a congenital X-linked genetic disorder where copper deficiency causes peculiar ‘kinked' (sharply bent) hair, neurodegeneration and connective tissue abnormalities.

Netherton syndrome

Netherton syndrome is a rare autosomal recessive condition of cornification characterised by a triad of inflammatory and scaly skin lesions, a characteristic hair-shaft abnormality labelled trichorrhexis invaginata (‘bamboo hair’) and an increased incidence of allergic diseases such as food allergy, urticaria, and atopic dermatitis [2,3].

What is the treatment for trichothiodystrophy?

Patients with trichothiodystrophy typically have complex health care needs and benefit from a multidisciplinary approach, with input from paediatrics, genetics, ophthalmology, neurology, obstetrics, orthopaedics, infectious diseases, dermatology, and radiology. Appropriate genetic counselling should be offered to affected patients and their families.

Given there is no cure for trichothiodystrophy, treatment is largely based on managing clinical manifestations, symptoms, and complications. Patients who are photosensitive should be provided with sun protection advice. Infections should be treated early and aggressively [1].

What is the outcome for trichothiodystrophy?

Given there is no cure for trichothiodystrophy, the prognosis is typically poor for children with severe disease and the median age of death is reported as 3 years. During the neonatal and childhood period, there is substantial morbidity and mortality, with pneumonia and other infections (particularly sepsis) being the leading causes of death [1].

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References

  1. Faghri S, Tamura D, Kraemer KH, et al. Trichothiodystrophy: a systematic review of 112 published cases characterizes a wide spectrum of clinical manifestations. J Med Genet 2008; 45: 609–621. PubMed
  2. Stefanini M, Botta E, Lanzafame M, et al. Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amst). 2010; 9: 2–10. PubMed
  3. Hashimoto S, Egly JM. Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Hum Mol Genet. 2009; 18: R224–30. PubMed
  4. Moslehi R, Signore C, Tamura D, et al. Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development. Clin Genet 2010; 77: 365–73. PubMed Central
  5. Price VH, Odom RB, Ward WH, et al. Trichothiodystrophy: sulfur‐deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol 1980; 116: 1375–84. PubMed

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