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 .
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 .
Who gets trichothiodystrophy?
The estimated incidence of trichothiodystrophy is one per million live births. Both sexes 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 carry a copy of the mutated gene that causes trichothiodystrophy for a child to inherit the condition.
- Photosensitive trichothiodystrophy usually results from mutations in the DNA repair genes ERCC2 (XPD), ERCC3 (XPB) 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 that seen in patients with xeroderma pigmentosa).
Other non-dermatological-associated abnormalities may include:
- Pregnancy-related complications, which present in around 30% of cases (eg, intrauterine growth retardation, pre-eclampsia and eclampsia, premature birth < 37 weeks' gestation, and low birth weight)
- Intellectual impairment or developmental delay (85% of cases)
- Short stature (73% of cases)
- Ocular abnormalities including congenital cataracts, strabismus (horizontal and vertical eye deviations), and nystagmus (involuntary eye movements) approximately 50% of cases
- Rheumatological abnormalities including joint contractures and dislocations, axial osteosclerosis (abnormal hardening of bone), and distal osteopenia (bone weakening)
- Haematological abnormalities such as anaemia, neutropenia, and features of beta-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 only hair abnormalities to severe disease with recurrent infections and severe developmental defects. A number of acronyms have been created to describe some of the different clinical phenotypes seen :
- PIBIDS: photosensitivity–ichthyosis–brittle hair–intellectual impairment–decrease fertility–short stature.
- In non-photosensitive trichothiodystrophy, IBIDS and BIDS represent the initials of the same words :
- IBIDS: ichthyosis-brittle hair-intellectual impairment-decreased fertility-short stature
- BIDS: brittle hair–intellectual impairment–decreased fertility–short stature.
What are the complications of trichothiodystrophy?
Complications of trichothiodystrophy are mostly related to the high risk of acquiring severe and potentially life-threatening infections .
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 called 'tiger-tail banding', in the hair shaft, found by polarised light microscopy or trichoscopy
- A severely damaged or absent hair cuticle by scanning electron microscopy.
What is the differential diagnosis for trichothiodystrophy?
Differential diagnoses of trichothiodystrophy can include those below.
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 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 (the atrophy and loss of functions of neurons) (30%).
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 is a rare autosomal-recessive condition of cornification (squamous epithelial cells hardening into hair and nails) characterised by a triad of inflammatory and scaly skin lesions, the characteristic hair-shaft abnormality 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 based around managing clinical manifestations, symptoms, and complications. Patients who are photosensitive should be provided with sun protection advice. Infections should be treated early and aggressively .
What is the outcome 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 .