Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations

Abstract

Trichothiodystrophy (TTD) is a rare, autosomal recessive disease, characterised by brittle, sulfur deficient hair and multisystem abnormalities. A systematic literature review identified 112 patients ranging from 12 weeks to 47 years of age (median 6 years). In addition to hair abnormalities, common features reported were developmental delay/intellectual impairment (86%), short stature (73%), ichthyosis (65%), abnormal characteristics at birth (55%), ocular abnormalities (51%), infections (46%), photosensitivity (42%), maternal pregnancy complications (28%) and defective DNA repair (37%). There was high mortality, with 19 deaths under the age of 10 years (13 infection related), which is 20-fold higher compared to the US population. The spectrum of clinical features varied from mild disease with only hair involvement to severe disease with profound developmental defects, recurrent infections and a high mortality at a young age. Abnormal characteristics at birth and pregnancy complications, unrecognised but common features of TTD, suggest a role for DNA repair genes in normal fetal development.

Figure 1

Microscopic diagnosis of trichothiodystrophy. (Left) Routine microscopic examination of hair from a patient with trichothiodystrophy shows shaft abnormalities of trichoschisis (arrows) and trichorrhexis nodosa-like fraying (arrows). (Right) Under polarising microscopy the hair shafts show a striking alternating dark and light (tiger tail) banding pattern.

Figure 2

Age at last report in trichothiodystrophy (TTD) patients (n = 110). The number in each bar indicates the number of patients reported in the indicated age group among the 90 reported living TTD patients. The shaded portion of the bar indicates the number of patients who died in the indicated age range among the 20 reported deceased TTD patients.

Figure 3

Infections reported (n = 51) in trichothiodystrophy patients. The number in each bar indicates the number of patients reported with the indicated type of infection among the 51 reported patients. A patient may have more than one reported infection. The shaded portion of the bar indicates the number of patients with the indicated type of infection as the cause of death among the 13 cases who died of infection. Aetiologies of infections included bacterial, fungal and viral. GI, gastrointestinal.

Figure 4

A clinical array of features reported in the literature on 112 trichothiodystrophy patients. Each column of rectangles represents clinical features of one reported patient. Presence or absence of each feature is indicated in each rectangle of a column. Abnormal clinical features reported are indicated by “1” in a coloured rectangle. Normal reported features are indicated by “0” in a tan rectangle. Unreported features are blank. The rows represent P (yellow)—photosensitivity (n = 47 cases); I (orange)—ichthyosis (n = 73 cases); B (powder blue)—brittle hair or hair shaft abnormality (n = 108); II (pink) —intellectual impairment (n = 96 cases); GD (grey) —gonadal dysgenesis (n = 16 cases); BC (light green) —abnormal birth characteristics (n = 62 cases); PC (dark green) —pregnancy complications (n = 31 pregnancies); O (maroon)—ocular abnormality (n = 57 cases); IN (royal blue) —infections (n = 51 patients); D (red)—DNA repair abnormality (n = 41); D in red rectangle—XPD (n = 32 cases); B in striped red rectangle—XPB (n = 2 cases); A in striped red rectangle—TTDA (n = 2); N in striped pink rectangle—TTDN1 (n = 6 cases); I in red rectangle—cellular ultraviolet (UV) hypersensitivity, gene not determined (n = 5); G—gender (n = 105 patients); blue rectangles—males (n = 54 cases); pink rectangles—females (n = 51 cases). Patients whose clinical features fulfil the criteria for PIBIDS (28%), IBIDS (20%), BIDS (16%) and those that do not (OTHER) (36%), are grouped by bold outline (decreased fertility is ignored in this grouping due to inability to assess in children.)

Figure 5

Abnormal characteristics at birth reported (n = 62) in trichothiodystrophy patients. The number in each bar indicates the number of patients reported with the indicated birth characteristic among the 62 reported patients. A patient may have more than one abnormal birth characteristic. The inset shows the proportion of the 112 cases reporting abnormal birth characteristics, pregnancy complications or both.

Figure 6

Reported course of pregnancy in mothers delivering trichothiodystrophy (TTD) patients (n = 60). The number in each bar indicates the number of TTD pregnancies reported with the indicated pregnancy complication among the 60 pregnancies detailed in the reports. The pregnancies with complications are indicated with shaded bars. A pregnancy may have more than one complication reported. The inset shows the proportion of the 112 cases reporting pregnancy complications. The bar labelled “Other” refers to bleeding (2 patients), oligohydramnios (1), placental abnormalities (1). IUGR, intrauterine growth retardation.

Figure 7

cular abnormalities reported (n = 57) in trichothiodystrophy (TTD) patients. The number in each bar indicates the number of TTD cases reported with the indicated ocular abnormality among the 57 patients detailed in the reports. “Bilat” in shaded bar—bilateral cataracts; of the 32 patients with cataracts, 20 were reported as bilateral and 8 as congenital. NOS—cataracts not otherwise specified. “Other” refers to dry eyes (1 patient) and retinal pigmentation (1). A patient may have more than one ocular abnormality reported.