Trichothiodystrophy in a child with occult learning disorder.

Trichothiodystrophy (TTD) is an autosomal recessive condition characterized by brittle and sparse sulfur deficient hair. The disorder is due to a known genetic mutation in DNA nucleotide excision repair (NER) in up to 83% of cases. We describe a 13-month-old girl presenting with hair fragility and hair loss since age 3 months, and discuss the overlap between TTD and other NER diseases. This case report highlights the importance of early diagnosis of occult learning disorder in young children with TTD and the need for early assessment and involvement of multidisciplinary team to target the child's educational needs.

INTRODUCTION

Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder with brittle, sulphur deficient hair. Tay's syndrome was coined in 1971,[1] after a kindred with brittle hair, trichorrhexis nodosa, ichthyosiform erythroderma, mental, and growth retardation. We discuss the overlap between TTD and nucleotide excision repair (NER) diseases such as xeroderma pigmentosa. This case report highlights the previously lesser known but now recognized clinical features and advances in management of TTD.

CASE REPORT

A 13-month-old girl presented with hair fragility and hair loss since age of 3 months. The mother had an uncomplicated antenatal history with first trimester vaginal bleeding. She was born at term, of non-consanguineous parents. At birth, she was encased in a collodion membrane, which was shed after 2 weeks. There was no photosensitivity and sweating was normal. An initial impression of self-healing collodion baby was made.

Physical examination revealed a prematurely aged appearance, frontal bossing [Figure 1a], sparse scalp hair [Figure 1b], knotted area on right scalp, absent eyebrows, brittle finger and toe nails with onychoschizia [Figure 1c], and normal sweating. The skin showed mild xerosis with eczema on the trunk.

Figure 1

(a) Frontal bossing, and absent eyebrows, (b) sparse scalp hair, (c) onychoschizia of distal nail

Light microscopy of haircuts showed trichorrhexis nodosa, trichoschisis [Figure 2a]. On polarized microscopy, the hair shafts exhibited light and dark banding in a tiger-tail pattern [Figure 2b]. Karyotype was 46XX. Full blood count, electrolytes, renal, liver function, serum immunoglobulin, and lymphocyte subsets were normal.

Figure 2

(a) Trichorrhexis nodosa (black arrow) and trichoschisis (red arrow) on light microscopy, (b) polarized microscopy showing alternating dark (black arrow) and light (red arrow) “tiger tail” pattern

2D echocardiogram revealed a moderate atrial septal defect, mild pulmonary valve stenosis, and tricuspid valve regurgitation. Ultrasound of the head was performed to investigate macrocephaly. This showed asymmetry of the lateral ventricles with left frontal horn dilatation. She was found to have global developmental delay, particularly in the gross motor skills. She started rolling on her stomach at 8 months, and by 14 months, she was not crawling, showed poor dynamic sitting balance and oro-motor delay with poor chewing and feeding skills.

The clinical features and hair microscopy findings were consistent with a diagnosis of TTD. The patient was followed up closely with dermatologists, cardiologists, and neurologists. She received physiotherapy for motor skill improvement, and was enrolled in “Rainbow Centre,” a school with special facilities catering to children with learning disability.

DISCUSSION

The term TTD was first coined by Price et al. in 1980.[2] It is a rare, autosomal recessive disorder with clinical heterogenous manifestation but the common appearance of brittle, sulfur-deficient hair. TTD is a marker of neuroectodermal symptom complex with features ranging from milde.st spectrum of an isolated disorder of hair,[3] to combination of photosensitivity, itchthyosis, brittle hair, infertility, developmental delay, and short stature. Van Neste et al. proposed a classification using letters alphabetically to denote the main symptoms,[4] this was later updated by Petrin et al.[5] However, not all patients fit into this uniform sequence. For example, although the Van Neste classification lists photosensitivity as a more severe case of TTD, some patients may have photosensitivity without ichthyosis or short stature. When hair from a patient with TTD is examined under the polarizing microscopy, there is a diagnostic alternating bright and dark pattern termed tiger-tail banding.

In approximately 83% of cases, TTD is found to arise from a known genetic mutation[6] in one of three DNA NER subunit genes, xeroderma pigmentosum complementation group B (XPB),[7] xeroderma pigmentosum complementation group D (XPD),[8] or TTD complementation group A (TTD-A).[9] They encode helicases of the basal transcription factor IIH (TFIIH), a multisubunit protein complex which is involved in RNA polymerase II transcription, NER and removes ultraviolet-induced photoproducts. Mutations in the TFIIH, XPB, XPD, Zeroderma pigmentosum complementation group A (XPA), are associated with TTD, xeroderma pigmentosum (XP), and Cockayne syndrome.

Patients with TTD, XP, and Cockayne syndrome have different mutations in the affecting NER system. It has been hypothesized that the non-XP features in TTD, such as brittle hair and nails, growth retardation and neurological impairment are predominantly due to the transcription activities of these genes rather than their repair activities, while photosensitivity is a consequence of disruption of DNA function. Nonphotosensitive subtypes of TTD follow a “repair/transcription” syndrome model in which a mutation impairs the transcription function of TFIIH but leaves the repair function intact. In normal dividing cells in a TTD patient, the abnormal TFIIH factor will be renewed sufficiently rapidly to compensate for its reduced stability. In terminally differentiated cells, such as hair or in the process of neuromyelination, TFIIH levels may be insufficient and give rise to depressed basal transcription of genes. Lack of skin cancers in TTD may also attributed to a more efficient immunosurveillance system compared to that of XP.[1011]

A recent systemic review of 112 cases of TTD in the literature[6] found a worldwide incidence affecting both males and females similarly. Clinical features were remarkably varied and ranged from isolated hair involvement to severe neurological and developmental abnormalities. Important findings included sparse, dry, and easily broken scalp hair associated with low sulfur and cysteine content. Noteworthy were the pregnancy complications, seen in 28% cases, which included a 4-fold increase in preeclampsia and a 36-fold increase in hemolysis, elevated liver enzymes, and low platelets syndrome. Many patients were born prematurely or are small for gestational age, suggesting that mortality with TTD begins in utero. The most common clinical features were brittle hair or hair shaft abnormalities, intellectual impairment or developmental delay (86%), short stature (73%), and ichthyosis (65%). Patients with TTD reported brittle hair, often not requiring haircuts. Ignoring gonadal dysgenesis due to its difficulty in assessing children, 64% of patients had clinical features to fit into the category of either photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature (PIBIDS), ichthyosis, intellectual impairment, brittle hair, decreased fertility, and short stature (IBIDS) or brittle hair, intellectual impairment, decreased fertility and short stature (BIDS). Several features were found to be more common than photosensitivity (present in 42%) and these included abnormal characteristics at birth (53%) ocular abnormalities (51%), and infections (46%). The authors propose that these characteristics could perhaps be considered major clinical features of TTD.

The physical appearance of an infant with brittle hair and ichthyosis should spark a differential diagnosis of TTD. Education of parents regarding genetic testing and mode of inheritance is essential. Our patient's parents declined further hair analysis. It is crucial to be vigilant in monitoring the developmental progress, as up to 86% of TTD patients experience learning disability or developmental delay. Early intervention with multidisciplinary approach involving pediatrician, neurologist, and other medical specialties, with physiotherapists and psychologists would benefit development of the infant and quality of life. Consideration of enrollment into special needs school to allow focus and improvement of a child's individual needs.

CONCLUSION

This case report highlights the disease recognition of TTD. Management should include a multidisciplinary team approach as the disease involves many organ systems, and allied health professionals including speech, occupational, physiotherapy and social workers in the future care of the affected child. Early disease recognition, screening, intervention, as well as identification of families who will benefit from genetic counseling is vital in the treatment of TTD.