Trichothiodystrophy

A spectrum of recessive disorders, autosomal and one X-linked, defined by brittle, sulfur-deficient hair with “tiger-tail” banding under polarised light, comprising photosensitive forms caused by deficiency of the transcription and repair factor TFIIH and nonphotosensitive forms caused by defects in transcription, RNA processing, and translation; there is no predisposition to skin cancer outside the XP/TTD complex.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Original clinical descriptions and the unifying concept

The history of trichothiodystrophy is that of a series of independently described syndromes that were brought together only once hair began to be analysed with chemical and optical methods. In 1968, Pollitt and colleagues described two siblings with microcephaly, intellectual and growth retardation, and trichorrhexis nodosa, with a reduced content of sulfur-rich proteins in the hair, whose cystine content was about half of normal; the same report already noted toxaemia of pregnancy, the first hint of the gestational complications recognised today [1, 34, 35]. In 1970, Brown documented alternating birefringence of the hair shaft in a 4-year-old girl of normal intelligence [1]. In 1971, Tay described three siblings born to first-cousin parents of Chinese ancestry in Singapore, with nonbullous congenital ichthyosiform erythroderma, intellectual disability, growth retardation, a progeroid appearance, and short, sparse, dull hair with pili torti and trichorrhexis nodosa, and proposed autosomal recessive inheritance; one sibling had hypogammaglobulinaemia and another died at 2 months of age from intestinal obstruction [1, 5].

In 1971 (Allen) and 1974 (Jackson and colleagues), a syndrome of short stature, intellectual disability, brittle hair, and decreased fertility was delineated in an Amish kindred, with 25 cases in a pedigree consistent with autosomal recessive inheritance and hair sulfur content about half of normal; in 1976, Baden named it BIDS and showed that the hair had normal alpha proteins but a marked deficiency of cystine-rich matrix proteins, which was also present in the nails [1, 34]. Also in 1976, siblings from Sabinas, Mexico, were described, followed in 1981 by a group of 11 patients with hair and nail abnormalities, intellectual disability, and normal stature, who gave their name to Sabinas syndrome [1]. Crovato added photosensitivity in 1983 (PIBIDS), and Chapman added skeletal abnormalities in 1988 (SIBIDS) [1].

The unifying concept is owed to Vera Price, who proposed the term “trichothiodystrophy” in 1979 and, in a 1980 article, showed that sulfur-deficient hair was the clinical marker of a neuroectodermal complex with intellectual and physical retardation and, at times, nail dystrophy, lamellar ichthyosis, ocular dysplasia, dental caries, and decreased fertility. The hair was cystine-deficient in every patient; in two new patients she observed light and dark bands under crossed polarisers, all banded samples had low sulfur content, and two-dimensional electrophoresis showed decreased synthesis of sulfur-rich matrix proteins [1, 2]. The acronyms that followed (BIDS, IBIDS, PIBIDS, SIBIDS) describe patients poorly: in the review of 112 published cases, 36% fit none of them, and the acronyms omit abnormalities at birth, ocular abnormalities, and infections [1]. In 1989, Van Neste proposed a classification by increasing neuroectodermal severity, from A (hair alone) to F, later extended to chronic neutropenia, immunoglobulin deficiency, severe intrauterine growth restriction, and basal ganglia calcifications, but not all patients follow a uniform sequence [1, 22].

1.2. Milestones of molecular discovery

In 1985, Van Neste demonstrated defective excision repair in ultraviolet (UV)-irradiated lymphocytes from a patient with TTD [1]. In 1986, Stefanini and colleagues studied four photosensitive patients from three Italian families: DNA synthesis in stimulated lymphocytes and fibroblast survival were reduced, and post-UV unscheduled DNA synthesis (UDS) was very low and was restored by fusion with normal cells and with XP-A cells but not with XP-D cells, which placed photosensitive TTD in xeroderma pigmentosum (XP) complementation group D [36]. In 1993, the TTD1BR cell line showed a repair defect that complemented all XP groups and was not corrected by the cloned repair genes, defining the TTD-A group [37, 38]. In 1994, Broughton and colleagues identified mutations in XPD (ERCC2) in four patients, all compound heterozygotes, and suggested that the location of the variants linked the protein's domains to its repair and transcription functions [39]. In 1997, Weeda and colleagues assigned two mildly affected patients to the XP-B group, with the missense variant p.Thr119Pro in a conserved region, and proposed the concept of “transcription syndromes” [40].

In 2004, Giglia-Mari and colleagues showed that in TTD-A none of the nine known TFIIH subunits was mutated, but the steady-state level of the entire complex was markedly reduced; they identified the tenth subunit, GTF2H5 (TTDA, p8), whose cDNA microinjection corrected the repair defect, and three inactivating mutations in three families [41]. In 2005, C7orf11 (TTDN1, now MPLKIP), at 7p14, became the first nonphotosensitive TTD gene: it was mutated in the Amish syndrome and in other patients with intellectual disability and decreased fertility, but not in Sabinas or Pollitt syndrome, demonstrating genetic heterogeneity [42]. By 2008, four genes had been identified (ERCC2, ERCC3, GTF2H5, MPLKIP) [1]. These were followed by RNF113A in the X-linked form (2015), GTF2E2 (2016), the aminoacyl-tRNA synthetases CARS1 and TARS1 (2019) and AARS1 and MARS1 (2021), and, in 2026, DBR1 in Sabinas syndrome [7, 43–47]. In 2014, genome sequencing of Pollitt's original siblings, in whom no MPLKIP mutation had been detected in 2005, found a homozygous 1-bp deletion in MPLKIP, previously seen in a Dutch girl and an Italian girl, consistent with a founder origin [34].

1.3. Current nomenclature and definition of entities

OMIM numbers nine types of TTD (TTD1 to TTD9) and lists separately microcephaly, developmental delay, and brittle hair syndrome (MDBH) due to CARS1 and Sabinas syndrome (%211390), the latter without a molecular basis in the entry [5, 6, 13]. Orphanet grouped all forms under ORPHA:33364 and deactivated the former subtype codes [4]. The 2025 international classification of disorders of epidermal differentiation (EDD, the new term for inherited ichthyoses) designates TTD as “sEDD-TTD” prefixed by the gene, or “unspecified-sEDD-TTD” when the gene is unknown, and places it in the group of DNA repair and transcription genes [3].

In this article, “photosensitive TTD” refers to TTD with cellular UV hypersensitivity due to biallelic variants in TFIIH subunits (ERCC2, ERCC3, GTF2H5); “nonphotosensitive TTD” refers to TTD with normal nucleotide excision repair (MPLKIP, RNF113A, GTF2E2, TARS1, AARS1, MARS1, CARS1, DBR1, and cases with no identified gene) [46, 48]. Clinical photosensitivity (abnormal sunburn) and cellular photosensitivity do not always coincide: there are patients with ERCC2 variants who do not burn and one patient with MPLKIP variants who burned after brief exposure [1, 24]. “XP/TTD”, “CS/TTD”, and “COFS/TTD” denote the complex phenotypes due to ERCC2 variants in which the hair features of TTD coexist with those of xeroderma pigmentosum, Cockayne syndrome (CS), or cerebro-oculo-facio-skeletal syndrome (COFS) [8]. Xeroderma pigmentosum and Cockayne syndrome are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. TFIIH in transcription and nucleotide excision repair

Nucleotide excision repair (NER) removes bulky DNA lesions, such as UV-induced pyrimidine dimers, by excising the DNA segment containing the damaged base [25]. It operates through two subpathways: global genome repair (GG-NER) and transcription-coupled repair (TC-NER), which is initiated by RNA polymerase II stalled at a lesion and is the pathway that is defective in Cockayne syndrome, COFS, and UV-sensitive syndrome (UVSS) [25, 49]. After lesion recognition, the XPB (ERCC3) and XPD (ERCC2) helicases of TFIIH partially unwind the DNA; the XPF-ERCC1 complex incises on the 5′ side and XPG (ERCC5) on the 3′ side, releasing about 30 nucleotides; a DNA polymerase with PCNA fills the gap, and DNA ligase I seals it [8].

TFIIH has ten subunits: a seven-subunit core (XPB, XPD, p62, p52, p44, p34, and p8/TTDA) and the CAK kinase module (CDK7, MAT1, and cyclin H) [44, 49]. It is essential for transcription initiation by RNA polymerases I and II, where it unwinds the promoter for polymerase binding, and for NER, where it verifies and opens the lesion [44, 49]. XPB is an ATP-dependent 3′→5′ translocase whose ATPase activity “wedges open” the duplex and anchors XPD; XPD is an ATP-dependent 5′→3′ helicase that, in transcription, links CAK to the core and is required for promoter opening and escape; p8 stabilises the complex and stimulates the ATPase activity of XPB [9, 49]. This dual function explains why different variants in the same gene cause XP (predominant repair defect, cancer proneness), CS or COFS (predominant TC-NER defect), or TTD (predominant transcriptional defect and complex instability) [1, 9, 49]. The authors of the 2025 review argue that NER disorders form a continuum, with XP/TTD, TTD/CS, and XP/CS overlaps, and that the same subunit can give rise to distinct phenotypes depending on the variant's effect on transcription, GG-NER, or TC-NER [8, 49].

2.2. TFIIH instability and transcriptional deficiency as a common mechanism

All TTD variants studied in TFIIH genes reduce the steady-state level of the entire complex [44]. In TTD-A, partially functional p8 forms unstable p52–p8 heterodimers; TFIIH becomes deficient in p8 and p52, unstable, and present at low levels, with impaired transcription, GG-NER, and TC-NER [30, 49]. The reduction affects repair more than transcription: NER requires higher TFIIH concentrations and occupies the complex for longer, and microinjected TFIIH is less stable in TTD-A cells [38]. The current interpretation is that terminally differentiating cells with high transcriptional demand (hair and nail keratinocytes, epidermis, oligodendrocytes) exhaust the unstable TFIIH before completing differentiation, which accounts for the brittle hair and nails, ichthyosis, and hypomyelination; TFIIH instability has been described as “a common driver of TTD” [14, 49].

Several concrete findings support the transcriptional deficiency. Eleven TTD patients with characterised XPD variants had the haematological phenotype of beta-thalassaemia trait, with reduced beta-globin synthesis and mRNA, whereas parameters were normal in three XP-D patients [1, 5]. TTD-ERCC2 fibroblasts fail to induce collagen VI (COL6A1) at confluence because mutant XPD does not displace the SREBP1 repressor from the promoter, a defect that is absent in XP-D cells and corrected by normal XPD [5]. TTD-associated XPD variants reduce the activation of hormone-dependent nuclear receptors (vitamin D receptor, thyroid hormone receptor, retinoic acid receptor, PPAR) [14, 21]. The p.Arg658Cys variant renders TFIIH thermolabile, which matches the temperature-sensitive clinical picture (hair loss and neurological worsening during fever) [1, 5]. In 2025, TTD-associated XPD variants were shown to cause partial dissociation of CAK from chromatin and from the TFIIH core and to impair the cooperation of TFIIH with DDX1, SFPQ, NONO, and RNA polymerase II in resolving DNA:RNA hybrids (R-loops) formed during elongation; R-loops accumulate, with transcriptional stress and widespread dysregulation of gene expression (cellular data) [50].

Mice carrying the XPD p.Arg722Trp variant have osteoporosis, kyphosis, osteosclerosis, premature greying, cachexia, infertility, and reduced life span; adding an Xpa defect accelerates ageing and increases sensitivity to oxidative damage [5, 14]. In 2019, the identification of variants in aminoacyl-tRNA synthetases led to TTD being redefined from a “transcription syndrome” to a “gene expression syndrome”: the cysteine-deficient hair results from premature arrest of terminal differentiation [46]. In 2021, instability of gene expression proteins was proposed as a feature common to all forms [47]; in 2026, the discovery of DBR1 led its authors to present TTD as an “RNAopathy” as well [7].

2.3. Genes, proteins, and relative frequency

The Orphanet summary for ORPHA:33364 states that, in the photosensitive form, ERCC3 is the most frequently mutated gene, followed by GTF2H5 and ERCC2 [4]. The primary sources contradict this order: in the 2008 systematic review, of the 47 photosensitive patients, 27 had XPD variants, 1 XPB, and 1 TTDA, and among the 112 patients with cellular data, reduced repair was attributed to XPD in 32, XPB in 2, and TTD-A in 2 [1]; in the NIH cohort, 23 of 37 patients had ERCC2 variants and none had ERCC3 variants [51]; and the Oxford Desk Reference gives XPD as the most common [25]. The most frequent gene in photosensitive TTD is ERCC2. Similarly, a table of causes of hypomyelination in Saudubray places MPLKIP among the photosensitive forms of TTD [55], which is incorrect: MPLKIP cells have normal UV repair, and the gene does not act on TFIIH [24, 42].

2.4. Variant spectrum and nomenclature

Complete absence of XPD is incompatible with life; all NIH patients with XP and TTD due to ERCC2 were compound heterozygotes, and some alleles are null only for certain functions [35]. In the 1998 Italian series, p.Arg112His was the most common variant (homozygous in 5 patients and compound heterozygous in 2); the title of that study sums up the correlation: the mutation site correlates with the repair defect, but gene dosage appears to determine clinical severity [5]. Null alleles combined with hypomorphic alleles are associated with more severe phenotypes [56]. TTD variants cluster in the C-terminal region of XPD (p.Arg722Trp, p.Ala725Pro, p.Ala725Thr) and in other regions, whereas the most frequent XP variant is p.Arg683Trp [35]. The following table lists the variants cited in this article, normalised with VariantValidator (GRCh38, MANE Select transcripts), together with their ClinVar classification at the time of consultation [57, 58].

The Heller 2015 table gives the Amish founder variant as “c.480A>G p.Met144Val”; on NM_138701.4, c.480A>G corresponds to p.(Ile160Met), and the correct description of p.(Met144Val) is c.430A>G, which is also the one used in the GeneReviews resource on Amish founder variants [24, 57, 59]. The CARS1 variants in Kuo 2019 use transcript NM_001751.6, which is not the MANE transcript; applying the article's numbering to NM_001014437.3 would yield a different variant (c.1138C>T would be p.Leu380Phe) [45, 57]. The remaining CARS1 variants from that study (c.1022G>A p.(Arg341His), c.1076C>T p.(Ser359Leu), c.1199T>A p.(Leu400Gln)), the TARS1 variants c.826A>G p.(Lys276Glu) and c.1912C>T p.(Arg638*), and the AARS1 (p.Ile699Thr, p.Cys901Tyr, p.Thr726Ala, p.Thr756Ile) and MARS1 (p.Val401Met) variants are kept in the nomenclature of the sources, without normalisation to MANE [11, 12, 45, 46]. Large MPLKIP deletions (11 kb to ≥150 kb) were detected only by array comparative genomic hybridisation (aCGH) and are predicted to include the adjacent gene SUGCT [24]; a contiguous 7p14 deletion removing both MPLKIP and SUGCT in the homozygous state associated TTD4 with biochemical glutaric aciduria type 3 [60].

2.5. Genotype–phenotype correlations

The most robust correlation is that between ERCC2 and systemic severity. In the NIH cohort, debilitating hip degeneration, central osteosclerosis, and pregnancy complications clustered in the ERCC2 subgroup, and median survival was 15 years with ERCC2 versus 36 years with the other genes or with no identified gene [51, 61]. Weight-for-age and weight-for-length were significantly lower in children with ERCC2 variants [62]. Severe hypogammaglobulinaemia and neutropenia were almost exclusive to ERCC2 [61]. There is also allele specificity in pregnancy: XP-associated ERCC2 variants are not associated with obstetric complications, and even among the C-terminal TTD variants, preeclampsia occurred with p.Ala725Thr and p.Glu731Argfs*14 but not with p.Arg722Trp [35]. Loss-of-function GTF2H5 variants cause the most severe form of TTD-A, including lethal neonatal cases [30, 38].

In the nonphotosensitive forms, patients presumed to be null for MPLKIP (homozygous deletion, frameshift) had more severe neurological disease than the Amish patients with the missense variant [34], but in a series of 44 patients severity did not correlate with mutation type, suggesting other modifying factors [34]. The MPLKIP phenotype is distinctive (epilepsy, delayed bone age, autistic behaviour, absence of pregnancy complications) [24]. Even within a single gene, predicting the phenotype is difficult, because each variant affects the repair and transcription pathways differently [8].

2.6. Allelic disorders and complex phenotypes

In addition to TTD1, ERCC2 causes XP complementation group D, COFS type 2, and the complex XP/TTD, CS/TTD, and COFS/TTD phenotypes [8, 63]. In XP/TTD, patients have the features of TTD together with the clinical and cellular phenotype of XP and, unlike in TTD, an increased frequency of skin cancers [8, 64]. In the consanguineous Italian families reported by Nuzzo (1986), TTD and XP-D cosegregated, with a common origin from remote inbreeding [5]. In 2001, two patients with features of both disorders were described: a 3-year-old girl with photosensitivity and developmental delay and almost undetectable repair, and a 28-year-old woman with photosensitivity, pigmentary changes, and skin cancers typical of XP, carrying p.Arg112His (a TTD variant) and p.Leu485Pro; both had “tiger-tail” banding and a sulfur content between the normal and TTD ranges [5, 64]. In addition to TTD2, ERCC3 causes XP-B and the XP/CS complex [8]. In COFS and CS/TTD due to ERCC2, the hair may be short and brittle with “tiger-tail” banding [8, 65]. The XP-J group (GTF2H4, p52) was described in 2025; in the XP-J patient, truncated p52 (p52ΔC) lacking p8 kept TFIIH stable, with no TTD or CS features [30, 49]. GTF2H2 (p44) is unlikely to be a disease gene because it is duplicated; GTF2H1 (p62) and GTF2H3 (p34) are speculative candidates [49].

2.7. Mechanisms in the nonphotosensitive forms

TFIIE (α and β subunits) enters the preinitiation complex after RNA polymerase II, recruits TFIIH, stimulates CDK7-mediated phosphorylation of the polymerase C-terminal domain, and regulates the XPB helicase; it does not take part in NER [44]. In the two children with GTF2E2 variants, NER was normal (post-UV survival, host-cell reactivation, removal of 6-4 photoproducts and cyclobutane pyrimidine dimers, UDS of 95%, and normal recovery of RNA synthesis), TFIIEα and TFIIEβ levels were markedly reduced, and TFIIEα phosphorylation was decreased; this reduction is also present in TTD-ERCC2 cells but not in XP-ERCC2 cells, indicating that TTD results from a transcriptional deficiency distinct from the repair defect of XP [44].

MPLKIP (TTDN1) is a small 179-amino-acid nuclear protein encoded by two exons that localises to the centrosome during mitosis and to the midbody during cytokinesis [9, 24]. Its function relevant to TTD is to maintain levels of the RNA lariat debranching enzyme (DBR1), which is required for correct debranching of excised introns and for ectodermal differentiation [66]; an independent study demonstrated the functional link between DBR1 and the intron-binding complex, which is defective in nonphotosensitive TTD [67]. MPLKIP fibroblasts, including those from a clinically photosensitive patient, had normal post-UVC survival [24]. In Sabinas syndrome, the DBR1 p.(Asp262Tyr) variant reduces DBR1 mRNA and protein and also TTDN1, which interacts with DBR1 [7].

RNF113A is a component of the spliceosome, including the minor spliceosome, and an E3 ubiquitin ligase that builds Lys-63-linked ubiquitin chains to recruit the ALKBH3/ASCC complex in alkylation damage repair; cells lacking RNF113A fail to form ASCC foci and are hypersensitive to alkylating agents [9, 68]. The p.(Gln301Ter) variant markedly reduced the protein in lymphoblastoid cell lines, with no NER defect [43]. In the aminoacyl-tRNA synthetases, TTD variants cause protein instability, enzyme deficiency, and slower tRNA charging; the brittle hair and nail phenotype reflects the high cysteine content of keratins, and in TTD9 the hair had undetectable methionine and low cysteine, and in TTD7 reduced cysteine and threonine [10, 12, 45–47].

2.8. Why photosensitive TTD does not predispose to cancer

TTD-ERCC2 cells have a repair defect indistinguishable from that of XP-D cells, yet TTD carries no increased risk of skin cancer [4, 9]. Unlike XP cells, TTD cells neither accumulate nor retain NER proteins at sites of unrepaired damage: TFIIH, present at low levels and unstable, does not persist at photoproducts [69]. In melanoma and melanocyte models carrying the TTD variant p.Arg722Trp, reduced proliferation, an increased MITF signature, baseline overexpression of REDD2 (an inhibitor of the mTOR/S6K/4EBP1 translation pathway), and reduced ribosomal protein synthesis after UV stress were observed; the p.Ala725Pro variant also impaired translation, unlike an XP variant, which offers a possible preclinical explanation for the absence of melanoma [70]. In the review of 112 cases, there was a single invasive squamous cell carcinoma of the nose in a TTD patient without freckles, and freckles were associated with the XP/TTD complex [1].

2.9. Heterozygotes

Parents heterozygous for variants in the autosomal genes are clinically healthy; mothers in the NIH cohorts had no hypertension, diabetes, or autoimmunity, and pregnancy complications depend on the fetal, not the maternal, genotype [21, 35]. In RNF113A carriers, X inactivation was 100% skewed; the three obligate carriers in the Australian family had short stature, and one also had delayed walking and speech, learning difficulties, and slow-growing hair, without “tiger-tail” banding [19, 43]. The mother and maternal grandmother of the boy described in 2020 had heights at the 2nd and 1st percentiles [19].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

Clinical information comes from two types of source, with different biases. The systematic review by Faghri and colleagues (2008) compiled 112 patients published in 94 articles between 1968 and 2005, included if they met at least two of four criteria (brittle hair or hair shaft abnormality, “tiger-tail” banding under polarised light, decreased hair sulfur or cystine, DNA repair abnormality); ages ranged from 12 weeks to 47 years, with a median of 6 years; underreporting of undescribed features and preferential publication of severe cases limit the frequencies [1]. The second source is the prospective cohorts of protocol 99-C-0099 of the National Cancer Institute (NCI) at the US National Institutes of Health (NIH), registered as NCT00001813, which studied the same families across several articles: pregnancy and the neonatal period (27 pregnancies, 2001–2011), the eye (32 patients, 2001–2010), growth and nutrition (25 children, 2001–2012), the MPLKIP phenotype (36 patients, 2001–2013), immunology and haematology (40 patients, 2001–2017), and the hip (37 patients, 2001–2019) [14, 21, 24, 51, 61, 62, 71]. The 2011 ophthalmology article cites the protocol as “NCT00004044”, an identifier that returns no record on ClinicalTrials.gov; the protocol's registration is NCT00001813 [14, 71]. In the 2001–2019 NIH cohort, the genes were ERCC2 in 23, MPLKIP in 5, GTF2H5 in 3, GTF2E2 in 1, and unknown in 5, with 20 male and 17 female patients and ages at last observation of 2 to 36 years (median 12) [51]. Data from both sources mainly describe natural history under supportive care, without disease-modifying therapy.

Table sources: [1, 14, 21, 51, 61, 62]. Photosensitivity is given as “about half” of patients in OMIM, Orphanet, the Oxford Desk Reference, and Weeda 1997, and as 42% in the 2008 review; the difference reflects different denominators and underreporting in published cases [1, 4, 5, 25, 40].

3.2. Hair and nails

The hair is short, dry, brittle, and sparse, with slow growth and sometimes alopecia; the eyebrows, especially the lateral third, look like short stubble, and the eyelashes may be brittle and sparse, although in most patients the upper lashes are long and thick [1, 14]. In the 2008 review, the hair was brittle in 98 patients (88%), with hair shaft abnormality in 76 (68%), “tiger-tail” banding in 82 (73%), decreased sulfur or cystine in 79 (71%), sparse hair in 54 (48%), alopecia in 44 (39%), dry hair in 24 (21%), fine hair in 16 (14%), slow growth in 8 (7%), and hair loss with fever or infection in 8 (7%) [1]. Five patients had long or normal-length hair, and two XP/TTD patients did not have brittle hair but had low sulfur, “tiger-tail” banding, and an XPD mutation [1]. In the NIH cohort, “tiger-tail” banding was present in every patient, even when the hair looked normal on casual inspection; the eyebrows were abnormal in 23/25 (92%) TTD patients and in no XP/TTD patients [14]. Intermittent hair loss during infections such as pneumonia was described in a child with PIBIDS [5].

On transmission electron microscopy after partial reduction of disulfide bonds, hair from three ERCC2 patients showed an aberrant marginal band and exocuticle, clusters of cortical cells with different staining, and much shorter keratin macrofibrils, with heterogeneity between samples and along the same shaft; in some samples the isopeptide-stabilised protein of the exocuticle was almost entirely absent [72]. The deficiency is not limited to the sulfur-rich components (keratin-associated proteins): there is a profound imbalance in protein content and organisation [72]. The nails were abnormal in 70 patients (63%): onychodystrophy in 41 (37%), brittle nails in 16 (14%), hypoplasia in 15 (13%), koilonychia in 13 (12%), onychoschizia in 8 (7%), and ridging in 7 (6%) [1].

3.3. Skin

In the 2008 review, 89 patients (79%) had skin abnormalities: ichthyosis (all forms) in 73 (65%), 27 of whom had a collodion membrane at birth, lamellar ichthyosis in 10 (9%), photosensitivity in 47 (42%), eczema in 9 (8%), freckles in 8 (7%), dry skin in 7 (6%), erythroderma in 5 (4%), and, more rarely, telangiectasias, pruritus, folliculitis, cheilitis, keratosis pilaris, hypohidrosis, haemangioma, and poikiloderma; 70% had photosensitivity and/or ichthyosis and 28% had both [1]. The ichthyosis of TTD is a generalised congenital ichthyosiform erythroderma, with a collodion membrane less often than in nonsyndromic autosomal recessive congenital ichthyoses, followed by generalised ichthyosis with scales of variable size and colour and follicular hyperkeratosis [16]. Neonatal erythroderma or collodion membrane generally persisted for one to two weeks in the NIH cohort [21]. In Tay syndrome, the flexural areas may be spared, lack of subcutaneous fat is characteristic and gives the face an aged appearance, and in women breast tissue may be absent despite normal nipples [5]. Atopic dermatitis is described in about 10% of patients [73].

Photosensitivity manifests as acute sunburn after minimal exposure; it occurred in 11 TTD patients and in all XP/TTD patients in the ophthalmology study [14]. In the NIH cohort, 13 of 23 ERCC2 patients (57%) had abnormal sunburn, 8 of the 10 with hip degeneration (80%) and 5 of the 13 without it (38%) [51]. Freckles are associated with XP rather than TTD: two of the eight patients with freckles in the 2008 review had the XP/TTD complex, one of them with skin cancer [1]. In Italian women aged 20 to 30 years with ERCC2 variants, freckles appeared in childhood without progression to malignancy [5].

3.4. Development and nervous system

Developmental delay or intellectual disability was described in 96 of 112 patients (86%): intellectual disability in 84 (75%), developmental delay in 76 (68%), and motor impairment in 41 (37%); 11 of the 16 patients without reported delay were younger than 5 years [1]. Intelligence quotient, measured in 21 patients with different tests, ranged from 25 to 89 [1]. Of the 73 patients with ichthyosis, 67 (92%) had developmental delay [1]. A sociable, outgoing personality was described in 17 patients (15%); a high-pitched or hoarse voice in 9, attention-deficit/hyperactivity in 6, and autistic-like behaviour in 3 [1]. The neurological course is generally nonprogressive, with exceptions (one progressive encephalopathy with ataxia and one regression after measles at age 4), and one patient remained stable for 30 years; by contrast, about 20% of patients with XP have progressive neurological degeneration [1]. Neurological symptoms, including nystagmus, tend to worsen during infections and return to baseline on recovery [14].

Neurological findings (n=112) included microcephaly in 50% (Table 5 of the review gives 46 patients and Table 6 gives 56, both 50%), abnormal gait or ataxia in 29 (26%), increased reflexes in 15 (13%), spasticity in 11 (10%), hypotonia in 11 (10%), intention tremor in 8 (7%), seizures in 7 (6%), paresis in 6 (5%), dysarthria in 5 (4%), pyramidal signs in 5 (4%), and peripheral neuropathy in 2 (2%); of the 25 tested, 5 had sensorineural hearing loss [1]. Neuroimaging was abnormal in 26 patients (23%), with dysmyelination in 16 (14%), cerebellar atrophy in 5, cortical atrophy in 3, enlarged ventricles in 4, calcifications in 2, and, in single patients, partial agenesis of the corpus callosum, thin corpus callosum, infarction, and heterotopia [1]. Magnetic resonance imaging (MRI) frequently shows cerebral white matter hypomyelination, without prominent cerebral atrophy or basal ganglia calcifications [14, 17]. In a boy with ERCC2 variants, MRI was normal at 8 months and showed subcortical and periventricular hypomyelination at 22 months and diffuse, progressive supratentorial hypomyelination at 4 years 2 months, with normal brain volume; in a 2024 review, five published TTD-ERCC2 patients had abnormal myelination [74]. Hypomyelination is related to deficient transcription of structural myelin components and sulfur-rich proteoglycans (neurocan, phosphacan) [74]. Clinically, hypomyelination presents with nystagmus, spasticity or a mixed movement disorder, ataxia, and intellectual disability [55].

3.5. Growth and nutrition

In the 2008 review, 81% of patients had short height and/or low weight and 61% had both [1]. In the NIH cohort of 25 children (2001–2012; 10 girls and 15 boys; 92% White; ERCC2 in 17, MPLKIP in 2, and unknown gene in 6), followed for a mean of 2.7 years, the height-for-age z-score was −2.75 ± 2.09 at the first assessment and −2.90 ± 2.45 at the last, and the weight-for-age z-score −2.60 ± 2.35 and −3.24 ± 3.29, with progressive divergence from the growth curves (annual change −0.18 ± 0.42 for height and −0.36 ± 0.51 for weight) [62]. About half (52%) maintained weight-for-length ≥25th percentile at all assessments, indicating proportionate growth delay [62]. Children with ERCC2 variants had a baseline weight-for-age of −3.53 ± 2.12 versus −0.68 ± 1.54 in the others (p=0.002), a baseline weight-for-length at the 27th ± 23 percentile versus the 79th ± 19 percentile (p<0.0001), and a mean height-for-age during follow-up of −3.35 ± 1.84 versus −1.61 ± 2.36 (p=0.03) [62]. Nutritional markers were generally normal (albumin 3.8 ± 0.3 g/dL, low in 4/25 and none <3.2 g/dL; vitamin B12, folate, and iron rarely low; normal faecal fat in the three tested), and resting energy expenditure was normal in two patients [62]. 25-Hydroxyvitamin D was 35 ± 12 ng/mL, with no values <10 ng/mL and four patients <25 ng/mL, a possible effect of photoprotection [62]. Baseline heart rate was 120 ± 19 bpm, negatively correlated with height- and weight-for-age [62]. The authors concluded that the short stature does not appear to result from malabsorption or malnutrition and hypothesised mitochondrial or energy-regulation dysfunction [62].

3.6. Eyes

In the NEI/NIH ophthalmology study (32 patients, 2001–2010: 25 with TTD, median age 9 years, and 7 with XP/TTD, median age 17 years, all in the XP-D group), 94% had some visual abnormality [14]. Developmental abnormalities included microcornea in 44% of TTD patients (diameter ≤10.0 mm in 7 and 10.5 mm in 4 of 17 measured), microphthalmia in 8% of TTD and 14% of XP/TTD patients, nystagmus in about 40% of TTD patients, and infantile cataracts in 56% of TTD (14/25) and 86% of XP/TTD (6/7) patients, almost always bilateral, many punctate, congenital, and without visual significance [14]. Of the 14 cataracts observed in the study, 6 (43%) were punctate only; they progressed in two TTD patients, one of whom underwent surgery at age 6 after lamellar opacities with functional loss; more than 60% of patients had cataracts, compared with 2.03 to 13.6 per 10,000 births in the USA [14]. Two thirds (65%) needed glasses, and best-corrected acuity was reduced in 28% of TTD and 71% of XP/TTD patients (20/30 to 20/400), worsening over time [14]. Degenerative changes included dry eye in 32% of TTD and 57% of XP/TTD patients (all patients aged ≥20 years were symptomatic), ocular surface fluorescein staining in 8 of 16 TTD patients tested, low endothelial cell density in 3 of 6 (1739–1825 cells/mm² at ages 9–13 years, versus 2500–3000 in adults), corneal neovascularisation in 4 of the 7 XP/TTD patients and in no TTD patients, and retinal or macular degeneration, with cone-rod dystrophy on electroretinography, in the two TTD-A siblings aged 26 and 29 years [14]. In the 2008 review, 32 patients had cataracts (20 bilateral, 8 congenital; median age 7.5 years) [1]. A retinal dystrophy documented by multimodal imaging and electroretinography was described in 2026 in a young Brazilian woman with genetically confirmed TTD [75].

3.7. Immunity, infections, and haematology

In the 2008 review, 51 patients (46%) had infections, 14 in the first year of life (5 neonatal) and 40 (36%) recurrent: respiratory in 29%, gastrointestinal in 13%, ear in 11%, and recurrent urinary tract infections in 5, with bacterial, fungal, and viral aetiologies [1]. Two patients had hypogammaglobulinaemia treated with intravenous immunoglobulin (IVIG), one had combined immunodeficiency on co-trimoxazole prophylaxis (defective dendritic cell maturation, reduced T-cell repertoire), and three stopped having infections in adolescence; 13 of the 20 deaths were related to infection [1]. In the NIH cohort of 40 patients (2001–2017; ERCC2 25, MPLKIP 5, GTF2H5 3, GTF2E2 1, unknown 6), IgG was below the lower limit for age in 13 patients, 12 of them with ERCC2 variants; the lowest IgG was 2.69 g/L, and the 6 patients with IgG <5.0 g/L (aged 2–17 years; 5 ERCC2) had a median survival of 3.7 years versus 36 years in the remaining 34 (p=0.002) [61]. The absolute neutrophil count (ANC) was <1.0 ×10⁹/L in 17 patients (13 ERCC2) and <0.5 ×10⁹/L in 8 (6 ERCC2), with a nonsignificant trend towards shorter survival [61]. No patient with MPLKIP, GTF2H5, or GTF2E2 variants had IgG <6.42 g/L [61].

In Vienna, three unrelated TTD1 patients with compound heterozygous ERCC2 variants and early recurrent infections had hypogammaglobulinaemia or reduced vaccine responses; their B cells accumulated γ-H2AX, had reduced proliferation and viability after UV, defective B-cell receptor activation, and few naive and transitional B lymphocytes [56]. A 1-year-old patient had IgG of 79 mg/dL and, after three vaccine doses, anti-tetanus antibodies of 0.03 IU/mL (normal ≥0.4), anti-Haemophilus antibodies of 0.56 (normal ≥1.0), and antipneumococcal antibodies of 1:20 (normal ≥1:200); another, aged 11 years, had normal total IgG but reduced vaccine responses [56]. A 2026 mini-review concluded that ERCC2-related TTD is the genotype with the most consistent evidence of immune dysfunction among the NER disorders (hypogammaglobulinaemia, deficient vaccine responses, altered B-cell differentiation, CD4 lymphopenia, restricted T-cell repertoire, defective dendritic cell maturation), that there is one adult ERCC3 case with IgG subclass deficiency and deficient vaccine responses, and that the absence of data for other genotypes does not prove immune normality [76]. NER disorders are not included in the International Union of Immunological Societies (IUIS) classifications of inborn errors of immunity [76].

The typical haematological abnormality of ERCC2-related TTD is beta-thalassaemia trait: decreased mean corpuscular volume (MCV) and mean corpuscular haemoglobin and increased HbA2 [25]. In the growth cohort, MCV was low for age in 46% (61–88 fL), HbA2 was 4.2 ± 1.2% (normal 2.2–3.2%) and was abnormal in 79% of the 19 tested, with a strong correlation between low MCV and high HbA2 (r=−0.825), and without clinically significant anaemia [62]. In the 40-patient cohort, eight had mild anaemia (lowest Hb 100 g/L), all microcytic, with low iron saturation and normal ferritin, and with no effect on survival [61]. In the 2008 review, 24 patients (21%) had haematological abnormalities: anaemia in 13, low MCV in 10, neutropenia in 10, and elevated HbA2 in 8 [1]. In the GTF2E2 patients, MCV was low (64.5 fL) and HbA2 elevated [44].

3.8. Skeleton, hip, and teeth

In the 2008 review, 43 patients (38%) had radiographic abnormalities: osteosclerosis in 16 (14%, usually axial), delayed bone age in 14 (13%), osteopenia in 10 (9%, usually distal), kyphosis in 7, and coxa valga in 4; 15 had joint abnormalities (contractures in 8) and 23 (21%) dental abnormalities, mainly caries (21; severe in 11) and enamel hypoplasia (4); all but one of the 46 patients with skeletal or dental findings had neurological abnormalities [1]. Central osteosclerosis with TTD was described in 2004 and corresponds to the former SIBIDS [77, 78].

In the NIH cohort of 37 patients, debilitating hip degeneration (pain, inability to walk, and avascular necrosis on imaging) occurred in 10 (27%), all with ERCC2 variants (10/23, 43%), and in none of the 14 with other genes [51]. Pain with walking difficulty began at age 8 years (median; 5–12), imaging became positive at 9 years (5–13), disease became bilateral in 7/10 at 9 years (6–17), and the pattern was avascular necrosis of the femoral head in 7/10; progression from pain on walking (median 9 years) to inability to walk (10.3 years) took about one year, and four of these patients died at age 11 years (median; 9–15) [51]. All patients with hip degeneration had central osteosclerosis, peripheral osteopenia, and coxa valga, and the nine who could be assessed had lower limb stiffness [51]. Central osteosclerosis occurred only in the ERCC2 subgroup (17/20 over follow-up, versus 0/12), was diagnosed from 21 months of age onwards, may appear late (imaging negative at 65 months and positive at 122), and may progress; osteopenia was present in 27/35 (77%) patients with radiographs, across all subgroups, and there was a single fracture [51]. Calcium and phosphorus were normal, and abnormalities of parathyroid hormone and vitamin D were not associated with the bone disease; there was no corticosteroid therapy or other risk factor for osteonecrosis [51].

3.9. Reproduction, endocrinology, and other organs

Sixteen patients (14%) in the 2008 review had sexual or reproductive abnormalities: hypogonadism in 13 (2 women), cryptorchidism in 9 (17% of boys), delayed puberty in 2, deficient sexual maturation in women in 2, and partial panhypopituitarism in 1 [1]. The Italian women with TTD1 had menarche at age 18 and a height of 140 cm [5]. Eight patients had heart defects (cardiomyopathy, pulmonary stenosis, ventricular septal defect), and two had multiple hepatic haemangioendotheliomas [1].

3.10. Phenotype by gene and nonphotosensitive forms

TTD2 (ERCC3). The two siblings reported in 1997, born to consanguineous parents, were collodion babies who were left with mild ichthyosis of the trunk, scalp, palms, and soles, mild photosensitivity, and coarse hair with “tiger-tail” banding and reduced cysteine, and at ages 10 and 16 years had no physical or intellectual impairment [40, 79]. In 2026, a newborn of African ancestry was described who was born as a collodion baby and developed severe atopic dermatitis, food allergies, and eosinophilic oesophagitis in the first year of life (section 10) [73].

TTD3 (GTF2H5, TTD-A). The phenotype ranges from classic photosensitive TTD (patient TTD1BR: collodion membrane, bilateral congenital cataracts, persistent ichthyosiform changes with hand contractures, IQ 70–80, photosensitivity without freckles or tumours at age 20) to severe neonatal forms: an infant born at 33 weeks after growth restriction, with congenital ichthyosis, absent hair, microphthalmia, ectropion, eclabium, natal teeth, cryptorchidism, hypertrophic pyloric stenosis, recurrent infections with multiorgan failure, neutropenia and B-cell lymphopenia, and delayed myelination, who died at 6 months [38]. In the NIH cohort, the TTD-A siblings had no pregnancy complications or collodion membrane, and a third patient was born at term with a collodion membrane and neonatal cataracts [21]; the two adult siblings developed retinal degeneration [14], and one GTF2H5 patient died at age 36 years of cardiogenic shock during pneumonia [51].

TTD4 (MPLKIP). In the NIH cohort (5 patients from 4 families, aged 1–14 years), compared with the other 31 patients, epilepsy (3/5 versus 3/31; p=0.024) and delayed bone age (4/5 versus 4/23; p=0.009) were more frequent; the patients had sulfur-deficient hair with “tiger-tail” banding (2.35–2.9%; normal 5.0%), recurrent infections (otitis media requiring ventilation tubes), intellectual disability, hypotonia, and osteopenia [24]. Pregnancy complications, low birth weight, collodion membrane, short stature, cataracts, thalassaemia-like changes, and dysmyelination were absent or underrepresented; ichthyosis was absent (xerosis, keratosis pilaris, and peeling or spoon-shaped nails were present instead) [24]. The three oldest patients had autistic behaviour, with autism spectrum disorder diagnosed at age 10 years in two, in contrast to the sociable personality typical of TTD [24]. Clinical photosensitivity occurred in 1 of 30 MPLKIP patients (the NIH patients and the 25 published patients) [24]. Other series documented hypergonadotropic hypogonadism and three Finnish patients with a novel variant [80, 81]. In the Amish kindred, growth and intellectual impairment were mild in most patients [34].

TTD5 (RNF113A, X-linked). The two Australian cousins had intrauterine growth restriction, progressive microcephaly with profound intellectual disability, absent or rudimentary testes and micropenis, severe growth failure with normal growth hormone production, partial posterior agenesis of the corpus callosum, cerebellar hypoplasia and Dandy-Walker malformation, an aged appearance, ataxic gait, sparse sulfur-deficient hair with “tiger-tail” banding, and recurrent infections; one of them had IgG1 deficiency, panhypopituitarism, retinal dystrophy, optic nerve hypoplasia, photosensitivity, and a short oesophagus with an intrathoracic stomach [19, 43]. An 11-year-old boy had refractory epilepsy with recurrent status epilepticus, hypogammaglobulinaemia, hypergonadotropic hypogonadism, and duodenal stenoses, and another boy, from Saudi Arabia, had ambiguous genitalia with severe hypospadias, microcephaly, and seizures [19, 82]. Two French fetuses with microcephaly, a short corpus callosum, and micropenis on ultrasound had absent or rudimentary testes and adrenal hypoplasia at autopsy [19, 83]. 46,XY twins had bilateral testicular regression, callosal dysgenesis, intractable epilepsy, and thyroid dysfunction [84]. Two brothers in their fourth decade, the oldest known patients, with the p.(Gly212Asp) variant, had intellectual disability, microcephaly, growth failure, severe myopia, and “tiger-tail” banding, with no endocrine, genital, infectious, or MRI abnormalities, showing that these features are not universal [52].

TTD6 (GTF2E2). A 10-year-old boy from India and a 16-year-old girl from Morocco had short stature and microcephaly below the 3rd percentile, short brittle hair with “tiger-tail” banding, ichthyosis, developmental delay (IQ 40 in one; cognitive and speech delay with attention deficit in the other) with a cheerful personality, low MCV and elevated HbA2, mild bilateral sensorineural hearing loss, long-tract signs, and cerebellar dysfunction, without photosensitivity, recurrent infections, freckles, or cancer [44, 53]. One patient had growth hormone deficiency [44]. A 2024 French series expanded the phenotype [85].

TTD7 to TTD9 and CARS1. The TARS1 patients had ichthyosis, keratosis pilaris, and a collodion membrane in one, and delayed physical development, recurrent respiratory infections, and acromandibular dysplasia in another [10]. The AARS1 patients had growth failure and microcephaly, spasticity, delayed myelination, and woolly hair; a sister with dystonia and self-injury died at age 9, and the Scottish boy described by King in 1984 as photosensitive had normal repair and profound physical and neurological degeneration at age 13 [11, 47]. The first MARS1 patient, a 32-year-old Italian woman, had intellectual disability, ataxia, decreased reflexes, ichthyosis and keratosis pilaris, congenital facial palsy, amenorrhoea after three cycles, and type 2 diabetes at age 20 [12]. The second TTD9 case, in Spain (2026), had long hair, eyebrows and eyelashes of normal density, and precocious puberty [54]. The four CARS1 patients had microcephaly (two), developmental delay with a wide-based ataxic gait, fine, sparse, brittle hair with “tiger-tail” banding, and brittle nails, hepatic steatosis in three, and type 2 diabetes in the third decade in two; MRI showed mild cerebral and cerebellar atrophy, delayed myelination, and hypoplasia of the corpus callosum [6, 45].

Sabinas syndrome (DBR1). The five adults from three unrelated Mexican families had a mild, nonphotosensitive form, with normal post-UV survival [7].

Hair-only TTD. There are cases of TTD with an isolated hair defect (Van Neste type A), such as a 10-year-old girl born to consanguineous parents, with sparse, short, brittle, light-coloured hair from 11 months of age, “tiger-tail” banding, and trichoschisis, without ichthyosis, neurological abnormalities, photosensitivity, or ocular abnormalities, in whom genetic testing was not performed because the parents declined [22]. In the 2008 review, five patients had “mild TTD” limited to hair, skin, and nails, with no identified gene [1].

3.11. Natural history and treated disease

No therapy alters the course of TTD, so the data above describe natural history under supportive care. The high mortality in childhood is concentrated in ERCC2 patients and is associated with infections and postoperative complications (section 11); patients who survive childhood may have a stable neurological course for decades, and three patients in the 2008 review stopped having infections in adolescence [1, 51].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

Pregnancy. Fetal TTD, particularly ERCC2-related, is associated with preeclampsia, HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets), preterm delivery, fetal growth restriction, and elevated human chorionic gonadotropin (hCG) on maternal serum screening with no identified fetal anomaly; these findings, especially in a family with a previous case, should raise suspicion [21, 86]. Sonographic absence of scalp hair in a fetus with severe growth restriction was the clue to a prenatal diagnosis described in a 2026 preprint [87].

Neonatal period. A newborn with ichthyosiform erythroderma or a collodion membrane, especially if small for gestational age or preterm, with congenital cataracts or cryptorchidism, should be evaluated for TTD [16, 21]. More than one third of newborns with TTD are small for gestational age [62]. The 2025 classification of syndromic EDDs recommends polarised light examination of the hair for early diagnosis of sEDD-TTD, which usually has neurological manifestations [3].

Infant and child. Short, brittle, sparse, dry hair, stubble-like eyebrows, developmental delay, microcephaly, short stature and low weight, ichthyosis, cataracts, recurrent infections, and easy sunburn make up the typical picture [1, 14]. The hair may look normal on gross examination: a child with hypotonia, microcephaly, global delay, and progressive hypomyelination was diagnosed with an autism and intellectual disability panel [74]. Recurrent infections, poor vaccine responses, or antibody deficiency may precede the syndromic diagnosis [76]. Hypomyelination with photosensitivity is a clue [55]. Beta-thalassaemia trait with additional features should prompt consideration of ERCC2 (TTD) or GATA1 [18].

Adolescent and adult. The spectrum includes the healthy adult with learning difficulties and brittle hair [1] and hair-only forms [22]. In a woman, brittle hair since childhood and an obstetric history of preeclampsia or HELLP syndrome with an affected child should prompt evaluation of the child [21].

4.2. Red flags and emergency signs

Warning signs include severe infections in infants with ERCC2-related TTD, especially if IgG is <5.0 g/L or the ANC is <0.5 ×10⁹/L, because these patients have much shorter survival [61]; hip pain or loss of ambulation in a child with ERCC2 variants between ages 5 and 12 years [51]; weight loss and divergence from the growth curves, which preceded terminal illness in the patients who died in the growth cohort [62]; and neurological worsening during fever [14]. Corneal neovascularisation in a patient with TTD should raise suspicion of the XP/TTD complex, with an increased risk of cancer [14]. Freckles, skin cancers, or early pigmented lesions likewise suggest XP/TTD [1, 8]. In the collodion newborn, transepidermal water loss can cause electrolyte imbalance, hypothermia, high metabolic expenditure, and infection [3].

4.3. Newborn screening

There is no newborn screening for TTD. The sources consulted describe no population screening programmes.

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Criteria

There are no consensus-validated diagnostic criteria. The 2008 review used, for case selection rather than clinical diagnosis, the presence of at least two of four criteria: (1) brittle hair or hair shaft abnormality; (2) “tiger-tail” banding on polarised light microscopy; (3) decreased hair sulfur or cystine; (4) DNA repair abnormality [1]. In the NIH cohort of 37 patients, the diagnosis was confirmed in all by “tiger-tail” banding and hair shaft abnormalities under polarised light and, in 33, by reduced sulfur content [51]. Orphanet lists as diagnostic findings short, unruly, brittle hair, alternating bands under polarised light, trichoschisis or trichorrhexis, an absent or defective cuticle on scanning electron microscopy, and cystine content usually reduced to less than half of normal [4].

5.2. Hair examination

Routine light microscopy shows trichoschisis (clean transverse fractures), atypical trichorrhexis nodosa–like defects, surface irregularity, and a ribbon-like appearance; polarised light shows alternating light and dark bands (“tiger-tail” banding) [1, 72]. In a controlled study using a standardised technique on a rotating stage, every hair from each of 14 TTD and 4 XP/TTD patients showed “tiger-tail” banding, and no hair from any of the 173 controls did (15 normal individuals, 13 XP patients, 11 relatives, 101 patients with other disorders of cornification, and 33 with leukodystrophies); only 5 controls had any weathering abnormality of the hair shaft [23]. In a series of 15 patients, sulfur and cystine were reduced in all samples and inversely correlated with the proportion of abnormal shafts, but that proportion did not correlate with clinical severity [88]. Cysteine content is usually about half of normal; in the NIH patients, sulfur was 2.2–2.9% (normal 4.9–5.0%) [24, 72]. Limitations include small series, nonconsecutive controls, technique dependence, and the inability to distinguish genetic subtypes [23, 88]. Trichoscopy has low specificity (wavy outline, “grains of sand” appearance) [22]. When a polarising microscope is unavailable, dermoscopy with cross-polarised light and a trichogram slide under transillumination demonstrated the bands at the bedside in a 4-year-old girl [89]. The French PNDS for inherited ichthyoses places hair analysis by light microscopy and polarised light in specialised centres and identifies “tiger-striped” hair under polarised light as the hallmark finding of TTD [28]. Polarised light microscopy of the hair is a simple, inexpensive test that establishes the diagnosis from the collodion newborn in the neonatal intensive care unit (NICU) through adulthood [1, 21].

5.3. Functional tests

The post-UV repair assay in cultured fibroblasts (UDS, post-UV survival, recovery of RNA synthesis) distinguishes the photosensitive, repair-deficient forms from those with normal repair, but does not identify the gene [9, 25]. A repair defect was documented in only 37% of the 112 patients in the review (no data in 48%), so a normal assay does not exclude TTD: hair with “tiger-tail” banding and normal repair points to the nonphotosensitive group [1, 9]. Orphanet states that UDS can help identify the photosensitive forms [4]. Cellular complementation is not available in clinical practice [8].

5.4. Genetic testing

Given the heterogeneity, the first-line molecular test is a multigene panel for DNA repair disorders, TTD, and ichthyoses, or exome or genome sequencing [8, 25]. The panel should include ERCC2, ERCC3, GTF2H5, MPLKIP, RNF113A, GTF2E2, TARS1, AARS1, MARS1, CARS1, and DBR1 [7, 72]. Large MPLKIP deletions were detected only by aCGH, not by PCR or sequencing, which makes copy-number analysis mandatory [24]. Neurodevelopmental panels may detect unsuspected TTD [74]. In series of nonphotosensitive patients without an identified gene, the new genes explained a small fraction (2 of 48 with TARS1, 3 of 34 with AARS1 or MARS1, none of 41 with GTF2E1 or GTF2E2), and in the NIH cohort the gene remained unknown in 5 of 37 patients; a negative test does not exclude TTD [10, 11, 51, 53].

The report should state the gene, the versioned transcript (e.g., NM_000400.4 for ERCC2), the HGVS description, the zygosity, and the classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [57]. In the autosomal forms, confirming that variants are in trans requires parental testing; the ERCC3 variant c.1004C>T and the ERCC2 variant c.587G>C were of uncertain significance and, in the latter case, supported by a cellular UV defect, an example of the role of functional assays in reclassifying variants of uncertain significance (VUS) [56, 73]. The DBR1 variant in Sabinas syndrome is classified in ClinVar as a VUS by a single submitter, despite the causal role proposed in 2026 [7, 58]. For ERCC2 splice variants, the historical nomenclature (c.2190+1delG, c.1479+2dupT) should be converted to c.2190+1del and c.1479+2dup [57].

5.5. Initial ancillary evaluation

The NIH evaluation included skin examination, biopsy for fibroblast culture, general chemistry and liver, lipid, mineral, and iron panels, complete blood count with differential, IgA, IgE, IgG, and IgM, haemoglobin electrophoresis, thyroid function, vitamin D and B12, hair for polarised light microscopy and amino acid analysis, and ophthalmology, audiology, neurology, and radiology assessments [24]. The 2026 immunology mini-review proposes serum immunoglobulins, IgG subclasses, lymphocyte subsets with a focus on the B-cell compartment, and specific post-vaccination antibodies, emphasising that a single normal assessment does not exclude dysfunction and that longitudinal follow-up in early childhood is more informative [76]. In TTD5, endocrine evaluation (thyroid, gonadotropins and testosterone, cortisol and adrenal reserve, growth hormone axis), IgG subclasses, MRI, and electroencephalography (EEG) are added [9, 84]. For ichthyoses in general, the 2021 French PNDS includes in the initial evaluation at a specialised centre an ophthalmological examination, an ear, nose, and throat examination with hearing assessment, 25-hydroxyvitamin D measurement, nutritional assessment if there is growth delay, psychological assessment, and a diagnostic orientation blood panel (complete blood count, total IgE, transaminases, γ-GT, bilirubin, CK, and a search for lipid droplets on the blood smear for Chanarin-Dorfman syndrome); it considers molecular testing the only route to a definitive diagnosis and indicated mainly when there are reproductive plans, but not essential for management [28]. MRI with spectroscopy may show low choline, a generic marker of hypomyelination [55].

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

Molecular prenatal diagnosis is possible only when a molecular diagnosis has been made in the index case [4]. Before the molecular era, post-UV UDS in amniocytes (17 weeks) or chorionic villi (9 weeks), the alkaline comet assay in amniocytes or villi, and, in families with normal repair, endoscopy-guided fetal eyebrow biopsy in the second trimester showing “tiger-tail” banding and low cystine were used; UDS does not distinguish between the different repair defects [1, 21, 90]. Exome sequencing of amniotic fluid enabled a prenatal diagnosis in 2026 (preprint not peer reviewed) [87]. The 2024 international guidelines on congenital ichthyosis include prenatal diagnosis and preimplantation genetic testing within their scope [91].

6. Differential Diagnosis

6.1. Comparison table

6.2. Xeroderma pigmentosum and the XP/TTD complex

The most useful comparison is the direct one between patients with ERCC2 variants: TTD-ERCC2 patients have ichthyosis, brittle hair with “tiger-tail” banding, short stature, microcephaly, a cheerful personality, recurrent infections, low MCV, and elevated HbA2, without freckles or skin cancer; XP-ERCC2 patients have acute sunburn, freckles, skin cancer, and enlarged ventricles, without hair or haematological abnormalities [44]. Cells from the two groups have similar repair defects, but only TTD cells show reduced TFIIEα phosphorylation and impaired collagen VI induction [5, 44]. The XP/TTD complex combines the TTD phenotype with the clinical and cellular phenotype of XP and includes skin cancers: in the NIH ophthalmology study, one XP/TTD patient died of metastatic melanoma at age 31 and another had a basal cell carcinoma of the face at age 27 [8, 14]. Corneal neovascularisation, present in more than half of XP/TTD patients and absent in isolated TTD, is a clinical sign of this overlap [14]. The extreme photoprotection and cancer surveillance of XP apply to XP/TTD, not to isolated TTD [8, 9].

6.3. Cockayne syndrome and COFS

It shares with TTD photosensitivity, short stature, developmental delay, intrauterine growth restriction, dysmyelination, a sociable and outgoing personality, congenital cataracts, and an aged, “bird-like” appearance [1]. The major criteria for CS are postnatal growth failure (height and weight <5th percentile by age 2 years) and progressive microcephaly with neurological dysfunction, with dysmyelination, cerebral and cerebellar atrophy, and, in some patients, basal ganglia calcifications; minor criteria include photosensitivity, demyelinating neuropathy, pigmentary retinopathy or cataracts, sensorineural hearing loss, dental anomalies, and cachexia with sunken eyes [15]. Types I (classic), II (severe and congenital, overlapping with COFS, with death usually by age 5 years), and III (mild and late-onset) and COFS (fetal) are distinguished [15]. In CS, post-UV UDS is normal and recovery of RNA synthesis is delayed (TC-NER defect) [15, 25]. CS does not feature brittle hair; retinal degeneration is characteristic of CS but occurred in two adults with TTD-A [14, 74]. In TTD, MRI shows hypomyelination without prominent atrophy or calcifications, and the neurological course is generally nonprogressive, unlike classic CS [1, 17]. The GeneReviews entry on CS states that recurrent infections (other than otitis or respiratory infections) and anaemia suggest an alternative diagnosis, which, in a patient with photosensitivity and delay, points to TTD [15]. The minimum incidence of CS in Western Europe is 2.7 per million births [20].

6.4. Other causes of brittle hair and congenital ichthyosis

Trichorrhexis nodosa with brittle hair is almost pathognomonic of argininosuccinate lyase deficiency; it results from arginine deficiency and responds to arginine supplementation, making it a treatable differential that is excluded with plasma amino acids [92, 93]. Other metabolic causes of abnormal hair include Menkes disease, congenital disorders of glycosylation, mitochondrial disorders, homocystinuria, sialic acid storage disease, and Vici syndrome [55]. Among the congenital ichthyoses, Netherton syndrome (congenital erythroderma, hair shaft abnormality, atopy, elevated IgE), Chanarin-Dorfman syndrome, Sjögren-Larsson syndrome, and sphingosine-1-phosphate lyase insufficiency are part of the syndromic differential [16, 74, 94]. Orphanet includes TTD in the differential diagnosis of congenital alopecias [4]. Tricho-dento-osseous dysplasia and TTD with osteosclerosis share increased bone density [78].

6.5. Differential diagnosis of hip degeneration

In Legg-Calvé-Perthes disease (ages 2–14 years, peak at 5), bilateral involvement occurs in 10–15% and is usually not simultaneous, and the deformity stabilises; in multiple epiphyseal dysplasia (autosomal dominant), several joints are affected; in ERCC2-related TTD, degeneration is confined to the hips, rapidly becomes bilateral, and does not reossify [51].

7. Treatment and Risk Management Strategies

7.1. Principles and evidence base

There is no specific treatment or disease-modifying therapy, and no drug is approved for TTD [4, 9]. Nor is there an international guideline or consensus dedicated to TTD, or a GeneReviews chapter [9]. Management rests on three sources: the authors' recommendations from the NIH cohorts (immunology and haematology, eye, growth, hip), identified as such throughout the chapter; the Orphanet summary, reviewed in 2022 by an ERN-Skin expert, which recommends regular follow-up for early detection of neurological, cutaneous, growth, malformative, and immunological abnormalities, early intervention by a multidisciplinary team (paediatrics, neurology, physiotherapy, psychology), nonspecific treatment of ichthyosis with ointments and keratolytics, and mandatory photoprotection in the photosensitive forms; and the 2024 international guidelines on congenital ichthyosis, which cover the syndromic ichthyoses [4, 14, 51, 61, 62, 91, 95]. The Orphanet page for ORPHA:33364 also links three French documents to the disease, bearing the label of the rare dermatological diseases network [4]. The first is the national diagnostic and care protocol (PNDS) for inherited ichthyoses, from September 2021, developed by the reference centres for rare skin and mucosal diseases of paediatric onset following the methodology of the Haute Autorité de Santé (HAS), which did not validate it; it includes TTD (ERCC2, ERCC3, GTF2H5, MPLKIP, RNF113A, GTF2E2) among the syndromic ichthyoses and gives recommendations and intervals for the complications of ichthyosis, almost all common to the group and based on expert consensus, with follow-up at least annually coordinated by a dermatologist at a reference or competence centre [28]. The second is the English version of that protocol, published in 2024 in Annales de Dermatologie et de Vénéréologie, of which only the abstract was read [96]. The third is the PNDS for chronic neutropenias, from May 2024, from the reference centre for chronic neutropenias; the text does not mention TTD, and its recommendations apply by extension to patients with TTD and neutropenia [29]. None of these documents addresses photoprotection, humoral immunodeficiency, the hip, anaesthesia, or pregnancy in TTD, and the NIH cohort recommendations remain the only source in those areas. The 2008 review lists the specialties involved: obstetrics, neonatology, paediatrics, ophthalmology, neurology, orthopaedics, internal medicine, rehabilitation, immunology, infectious diseases, haematology, genetics, radiology, and dermatology [1].

7.2. Photoprotection

Photoprotection (sun avoidance, protective clothing, broad-spectrum sunscreen) is indicated in the photosensitive forms to prevent sunburn [4, 9, 97]. It should not be prescribed on the basis of the TTD label alone: it is not indicated in forms with normal UV repair, such as GTF2E2- or MPLKIP-related TTD, unless clinical photosensitivity has been demonstrated [9, 24, 44]. The intensive skin cancer surveillance regimen of xeroderma pigmentosum (ambient UV measurement, UV-blocking window films, skin examination every 3–12 months, retinoid chemoprevention) is not indicated in isolated TTD on current evidence and is reserved for the XP/TTD complex [8, 9]. Photoprotection can lower 25-hydroxyvitamin D: in the growth cohort, 4 of 25 children had values <25 ng/mL [62].

7.3. Skin: neonatal period, ichthyosis, and atopic dermatitis

In the collodion newborn, the barrier defect causes transepidermal water loss with electrolyte imbalance, high metabolic expenditure and poor weight gain without supplementation, hypothermia, and risk of infection, and dermatological management is carried out together with the neonatal team [3]. In the NIH cohort, erythroderma or collodion membrane persisted for one to two weeks and was treated with humidified air and emollients; 70% of newborns were admitted to the NICU, 26% for more than a month [21]. Ichthyosis is treated with emollients and topical keratolytics, and the hair with gentle care, avoiding chemical and thermal trauma [4, 9]. The 2024 congenital ichthyosis guidelines cover topical and systemic therapies (oral retinoids, biologics, Janus kinase inhibitors), psychosocial management, telemedicine, communication of the diagnosis, and complications (eye, ear, pruritus, pain, skin infections, vaccination, growth and nutritional deficiencies, hair and nails, heat and cold intolerance, physical limitations, neonatal period); only the abstracts were read, so the specific recommendations are not reproduced [91, 95]. No data on the use of oral retinoids in TTD were found in the sources.

For scalp scaling, the French PNDS for inherited ichthyoses recommends applying an emollient or a fluid keratolytic for a few hours or overnight, for example every night during the initial phase and then twice weekly, removing it with shampoo and a comb, and taking care with brittle hair, particularly in TTD; it also mentions compounded shampoos with a keratolytic in a neutral base [28]. Keratolytics are used with caution in children because of the risk of percutaneous absorption, which is increased on the scalp [28]. For alopecia in ichthyosis, the protocol calls for a search for aggravating factors (iron deficiency, thyroid dysfunction, drugs, including oral retinoids) and provides for prescription of a hairpiece in moderate to severe alopecia [28]. First-line systemic treatment of ichthyoses with moderate to severe scaling, when topical treatment is insufficient, is acitretin (Neotigason®; Soriatane® in France), prescribed by an experienced dermatologist: in adults, 10–25 mg once daily, usually ≤0.5 mg/kg/day, up to 1 mg/kg/day in very severe forms (maximum authorised dose 75 mg/day); in children, with no minimum age, reserved for severe forms with functional impact, as compounded capsules protected from light, ideally close to 0.5 mg/kg/day and always <1 mg/kg/day [28]. This is the reference dose; by comparison, the Portuguese SmPC for Neotigason® specifies 25–30 mg/day for 2–4 weeks in adults and, in keratinisation disorders, the lowest possible maintenance dose, not exceeding 50 mg/day; in children, about 0.5 mg/kg/day, up to 1 mg/kg/day for limited periods and a maximum of 35 mg/day; PNDS doses above these limits (up to 75 mg/day in adults) are, for information, outside the labelled conditions [98]. The protocol requires pretreatment evaluation (transaminases, γ-GT, alkaline phosphatase, bilirubin, complete blood count with platelets, electrolytes, fasting glucose, creatinine, CK, cholesterol, and triglycerides), liver monitoring every 2–4 weeks for the first two months, then quarterly in the first year, every six months in the second year, and annually thereafter, discontinuation if transaminases exceed 3 times normal or triglycerides exceed 10 mmol/L, and, with prolonged treatment, baseline radiographs (cervicothoracic spine, hips, ankles) and densitometry, in children at age 5 years and at the end of adolescence [28]. Hair loss is a short-term adverse effect of acitretin, which weighs on the decision in a patient whose hair is already sparse and brittle; neither the protocol nor the cohorts describe the use of acitretin in TTD [28]. Isotretinoin (0.25–0.3 mg/kg/day, up to 0.5–1 mg/kg/day) and alitretinoin (10 mg/day in children, 10–30 mg/day in adults, with thyroid monitoring) are alternatives with a short half-life [28].

Severe concomitant atopic dermatitis has been treated with dupilumab (Dupixent®), an interleukin-4 receptor alpha antagonist, in three case reports. In a child with ERCC3-related TTD and atopic dermatitis refractory to emollients and topical corticosteroids, dupilumab 300 mg every 4 weeks, started at 18 months of age under compassionate use, improved the skin at 4 weeks, left it almost clear at 3 months, and maintained the effect at 6 months, with resolution of eosinophilic oesophagitis symptoms and no adverse effects [73]. Two earlier reports in ERCC2-related TTD described major improvement at 3 months and near-clearance at 1 year, and improvement at 8 months, with no adverse effects [73]. The approved indication is atopic dermatitis, not TTD, and the evidence is limited to these reports [73, 99].

7.4. Infections and immunity

Infections are the leading cause of early death, and the sources recommend active surveillance and prompt treatment of infections and attention to immune status [1, 9]. The NIH cohort authors propose monitoring for recurrent infections, hypogammaglobulinaemia, and neutropenia and considering haematological evaluation to manage hypogammaglobulinaemia with immunoglobulin replacement and neutropenia with granulocyte colony-stimulating factor (G-CSF); this is a cohort-based proposal, without doses or intervals [61]. The 2026 mini-review adds that early immunological evaluation can guide closer follow-up, tailored vaccination strategies, and, in selected cases, immunoglobulin replacement [76]. In published patients, monthly intravenous immunoglobulin in TTD5 raised IgG without normalising it [9, 82]; in a TTD-ERCC2 child with recurrent otitis media, a short course of immunoglobulin was associated with improvement [74]; two published TTD1 patients received immunoglobulin replacement, and in one of them discontinuation was followed by death from severe infection [56]. In the Vienna cohort, the 1-year-old patient started immunoglobulin replacement, and on this therapy seven doses of tick-borne encephalitis vaccine produced specific IgG of 274 IU/mL, versus 2174–11,214 IU/mL in controls [56]. The TTD sources give no doses for immunoglobulin or G-CSF; the immunoglobulin dose follows the immunology service's protocols, and the G-CSF dose the regimen of the PNDS for chronic neutropenias described below. One child with combined immunodeficiency was on co-trimoxazole prophylaxis [1].

The PNDS for chronic neutropenias, which does not address TTD, provides the framework for patients with neutropenia [29]. It defines neutropenia as neutrophils <1.5 G/L (1.5 ×10⁹/L), profound below 0.5 G/L, and severe when it causes infections or oral lesions (aphthae, periodontal disease); urgency depends not on depth but on association with bacterial infection, anaemia, or thrombocytopenia, and chronicity requires persistence for more than 3 months [29]. Antibacterial prophylaxis with co-trimoxazole (Bactrim®) is given to patients at highest infectious risk, particularly those with genetic neutropenias, at 10–30 mg/kg/day of sulfamethoxazole in 1 or 2 doses in children or one 800-mg tablet daily in adults (grade C, expert opinion) [29]. G-CSF (filgrastim or lenograstim, with no documented difference in efficacy; pegfilgrastim is not recommended) is started at 5 µg/kg once daily for 14 days, adjusted in steps of 3–5 µg/kg assessed after 2–3 weeks, and spaced out, for example to alternate days, when there are no infections or aphthae; the target is clinical status, not a neutrophil count; once the appropriate dose is reached and there are no infections, a complete blood count is performed every 6 months and the patient is reassessed at an annual visit [29]. A patient is a nonresponder if neutrophils do not reach 1 G/L with >50 µg/kg/day, and prolonged exposure to >10 µg/kg/day increases leukaemic risk and prompts discussion of bone marrow transplantation [29]. Most febrile episodes in these patients are viral, and antibiotic therapy is guided by the clinical picture; in the presence of signs of severity or an infectious focus (cellulitis, pneumonia, colitis), the patient is admitted for empiric broad-spectrum intravenous antibiotics covering S. aureus, streptococci, and Pseudomonas aeruginosa (cefepime or piperacillin/tazobactam), G-CSF at the patient's usual dose or at 5 µg/kg/day, and contact with haematology; protective isolation is of no benefit (grade B for the clinical approach) [29]. The same protocol requires prevention and treatment of oral and dental infections, with regular dental follow-up, because co-trimoxazole does not prevent them [29]. In ichthyoses, the 2021 PNDS describes skin infections with Staphylococcus aureus (sometimes methicillin-resistant) and group A streptococcus, dermatophytoses, and scabies that is difficult to diagnose; worsening pruritus or skin should prompt microbiological sampling, and treatment is standard, with a lower threshold for systemic therapy and attention to percutaneous absorption of topical agents in children [28].

7.5. Growth and nutrition

In the growth cohort, four children had a gastrostomy; in the two in whom it was placed during the study, the weight z-score rose by 0.66 and 0.61 and the height z-score by 0.84 (one patient) [62]. The authors suggest increasing caloric density with oils and oral nutritional supplements and consider that gastrostomy may benefit some patients, with no data to justify routine use [62]. Two deaths in the NIH cohort were due to respiratory failure after gastrostomy, one after laparoscopic gastrostomy with fundoplication, which makes the decision to operate a high-risk one [51]. Growth hormone was used in one ERCC2 patient for 15 months (from age 4 to 5 years), whose height and weight remained <3rd percentile; the GH/IGF-1 axis has not been systematically evaluated in TTD [62]. In a GTF2E2 patient with documented growth hormone deficiency, treatment produced a “good response”, with no dose reported [44]. In TTD5, short stature occurred with normal growth hormone production [19]. In patients with dysphagia, gastrostomy with continuous tube feeding was necessary [74]. The PNDS for inherited ichthyoses recommends monitoring weight and height at a frequency inversely proportional to age, every 3–6 months in children depending on the complications, seeking paediatric gastroenterology or paediatric endocrinology input in the presence of growth delay, looking for deficiencies of selenium, iron, vitamin D, calcium, and zinc and, in adolescence, for signs of pubertal delay; malnutrition affected 32% of children with ichthyosis in a series cited by the protocol, which is not specific to TTD [28]. For vitamin D, the same protocol proposes measuring 25-hydroxyvitamin D at the initial evaluation and then 1–2 times a year in severe forms or when there are risk factors (dark phototype, winter and spring; in photosensitive TTD, photoprotection adds to these), preferably in the same laboratory, with a target of >30 ng/mL (75 nmol/L), deficiency defined as <20 ng/mL (50 nmol/L) and severe deficiency as <10 ng/mL (25 nmol/L); in severe deficiency, PTH, calcium, and phosphorus are measured and treatment continues until the target is reached, with a check after supplementation [28]. Prophylactic supplementation follows the general rules: 400–800 IU daily from ages 0 to 18 years (400 IU without risk factors, 800 IU in risk groups), daily until age 2 years and then daily or as doses every 3 or 6 months, using medicinal vitamin D rather than food supplements [28]. Bone densitometry is performed when demineralisation is present and at least once during the course of the disease [28]. General recommendations for DNA repair disorders (avoiding acetaldehyde from alcohol, aflatoxins, and polycyclic aromatic hydrocarbons from smoke) and the data on caloric restriction derive from animal models of TC-NER deficiency, not from patients with TTD [49].

7.6. Eye

The authors of the ophthalmology study recommend regular refraction and amblyopia treatment, monitoring of cataracts, best-corrected acuity, and motility with updating of lenses, examination of the retina and macula, possibly early monitoring of endothelial cell density, and screening for and treatment of dry eye and ocular surface disease even in children, with early artificial tears and lubricating ointments and careful use of contact lenses, to prevent corneal ulcers [14]. Visually significant cataracts are extracted: one TTD-ERCC2 child underwent surgery at 6 weeks and was fitted with contact lenses, and one patient in the NIH cohort underwent surgery at age 6 after progression of lamellar opacities [14, 72]. The PNDS for inherited ichthyoses recommends regular ophthalmological follow-up with refraction, visual acuity, and slit-lamp examination of the ocular surface and eyelids, at intervals ranging from monthly to 1–2 times a year depending on severity [28]. In lagophthalmos, continuous lubrication with preservative-free eye drops (carboxymethylcellulose 0.5–1%, carmellose sodium, or hyaluronic acid) is essential, with vitamin A eye ointment at bedtime if the lagophthalmos is nocturnal; in meibomian gland dysfunction, lipid-based eye drops are used, from 1–2 times a day up to every 30 minutes in severe cases [28]. Ectropion is managed stepwise: lubrication and eyelid massage; oral retinoids, which worsen dry eye; and eyelid surgery only for symptomatic corneal exposure or epiphora, before permanent keratinisation of the conjunctiva, with frequent recurrences [28]. These recommendations apply to ichthyosis in general; the TTD cohorts do not describe ectropion as a dominant complication, and dry eye and cataracts are managed according to the NEI recommendations [14]. In XP/TTD, surveillance must distinguish degenerative and inflammatory lesions (early pterygium at age 5) from conjunctival squamous cell carcinoma [14].

7.7. Development, epilepsy, and hearing

Early intervention, educational support, and rehabilitation are the foundation of developmental care [4, 9]. Epilepsy is more frequent in TTD4 and may be refractory in TTD5; in TTD5, several antiseizure medications and a vagus nerve stimulator were used, with no doses described [9, 24, 82]. Mild conductive hearing loss with recurrent otitis media was treated with ventilation tubes, and obstructive sleep apnea has been documented [24, 74]. In ichthyoses, hearing loss is mainly conductive, due to accumulation of scale in the external auditory canal, and the 2021 PNDS recommends hearing assessment every 6 months before age 6 years, daily ear drops (docusate sodium) or oils if the tympanic membrane is intact, mechanical removal of scale by an otolaryngologist 1–4 times a year (1–3 times in the complications table of the same document), referral for pruritus, pain, otorrhoea, a blocked ear, or hearing loss, and, for otitis externa, canal cleaning and ciprofloxacin drops with or without a corticosteroid [28]. The same protocol includes in management the disclosure of the diagnosis at a multidisciplinary visit with a psychologist, quality-of-life assessment with validated questionnaires, therapeutic education, social support, and an individualised school accommodation plan; for heat intolerance due to hypohidrosis, it recommends avoiding extreme temperatures and outdoor activities during the hottest hours and cooling the skin with water sprays, showers, or cold compresses [28].

7.8. Hip, contractures, and rehabilitation

In the NIH cohort, seven of the ten patients with debilitating hip degeneration underwent surgery: only one regained lasting pain-free ambulation (hip resurfacing or hip replacement), three died 0.6 to 2.2 years after surgery, two of the four surviving operated patients did not regain ambulation, and one regained it and lost it again [51]. One patient without degeneration who underwent bilateral femoral derotational osteotomies at ages 8 and 9 walked again and had not developed the disease by age 9 [51]. Contractures were treated with physiotherapy, casting and splinting, botulinum toxin, or surgery [51]. Unlike in Legg-Calvé-Perthes disease, the surgical response is poor [51]. In children with ERCC2-related TTD, the authors recommend close monitoring of hip geometry and motor function (history, physical examination, imaging, and rehabilitation medicine), early identification of pain, promotion of developmentally appropriate weight bearing and mobility, prevention of contractures, and a coordinated team of paediatric rehabilitation medicine, occupational and physiotherapy, orthopaedics, genetics, neurology, a child life specialist, psychology, and social work [51].

7.9. Endocrinology and reproduction

In TTD5, endocrine evaluation includes thyroid function, gonadotropins and testosterone, cortisol with adrenal reserve, and the growth hormone axis; thyroid dysfunction was treated with levothyroxine, with no dose described [9, 84]. Hypergonadotropic hypogonadism occurs in TTD4 and TTD5, and gonadotropins are assessed when fertility is at issue [9, 80]. The sources describe no TTD-specific pubertal induction regimens.

7.10. Dosing of drugs with documented use in TTD

7.11. Comparative regulatory status

7.12. Clinical and interventional studies

There are no registered interventional trials for TTD: a ClinicalTrials.gov search for the condition on 17 October 2026, returned two studies, both observational [114]. A negative search does not prove that no research is under way. The available therapeutic data are case reports and cohort observations without a comparison group; they do not allow effects to be estimated or interventions to be compared and are subject to publication bias towards favourable results; the EASI (Eczema Area and Severity Index) and IDQoL (Infants' Dermatitis Quality of Life Index) scores in the Irish case have no confidence interval because they refer to a single patient [73].

7.13. Developments in the past 12 months and level of evidence

There were no regulatory communications, opinions, or authorisations concerning TTD in this period [26, 27].

7.14. Agents and circumstances to avoid, anaesthesia, and surgery

Anaesthesia and surgery are poorly tolerated by frail, underweight patients with infections; in the NIH cohort, five of the ten deaths followed surgery or procedures (hip tenotomy, hip surgery, two gastrostomies, one of them with fundoplication, and dental surgery) and one followed a dose of methadone, and in the growth cohort a 12-year-old child had cardiorespiratory arrest after receiving an opioid for severe chronic pain [51, 62]. In one patient, a multidisciplinary preoperative conference, epidural rather than general anaesthesia, and planned admission to paediatric intensive care with fluid management to avoid pulmonary oedema proceeded without serious complications; the authors suggest preoperative assessment and careful postoperative monitoring in frail patients (case series) [51]. OrphanAnesthesia has no recommendation for TTD, only for XP [115]. In Cockayne syndrome, metronidazole causes severe hepatitis, opioids and sedatives require monitoring, and growth hormone is not recommended [15]; the sources describe no metronidazole hepatotoxicity in TTD, but the opioid data above justify the same caution. Sun avoidance should not be imposed on the nonphotosensitive forms [9]. The two French PNDS consulted contain no anaesthetic recommendations; the ichthyosis PNDS merely notes that an Orphanet Urgences emergency sheet for inherited ichthyoses exists [28].

7.15. Pregnancy, lactation, and transition

In adult women with TTD, the sources describe no pregnancies and no lactation data. The high-risk pregnancy that matters is that of a heterozygous mother carrying an affected fetus: these pregnancies should be managed as high risk, with surveillance for preeclampsia, HELLP syndrome, growth restriction, and preterm delivery, and with delivery planned at a centre with a NICU (section 8) [21, 86]. Transition to adult care is relevant because there are patients up to 47 years of age and brothers with TTD5 in their fourth decade, and because dry eye, retinal degeneration, and loss of acuity appear or progress with age [1, 14, 52]; the sources consulted describe no transition models. If a woman with TTD and severe ichthyosis receives acitretin, the ichthyosis PNDS mandates the pregnancy prevention programme: informed consent, contraception started 1 month before and continued until 3 years after discontinuation, a pregnancy test before the first prescription and monthly during treatment (renewal only with a negative test less than 3 days old), tests every 1–3 months during the following 3 years, no breastfeeding or blood donation during treatment and for the following 3 years, and no alcohol until 2 months after discontinuation; isotretinoin or alitretinoin, which are prohibited until 1 month after discontinuation, are preferred if pregnancy is planned in the short or medium term, and topical retinoids are contraindicated in pregnancy [28].

7.16. Available recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All forms of TTD are autosomal recessive except TTD5 due to RNF113A, which is X-linked [4, 16]. In the autosomal forms, when both parents are heterozygous, each sibling of a patient has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier [15]. In the 2008 review, consanguinity was reported in 17% of families, and 37 patients had an affected sibling (18 families) [1]. In the NIH genetic epidemiology study, the ratio of affected to unaffected live births was 4:3, versus an expected 1:3, partly because 6 of the 15 families stopped having children after the first affected child [86].

In TTD5, a mother who carries an RNF113A variant transmits it to 50% of her sons, who will be affected, and to 50% of her daughters, who will be carriers; the carriers studied had 100% skewed X inactivation, frequent short stature, and, in one case, learning difficulties [19, 43, 82]. An apparently de novo variant does not eliminate the risk: in the French family, the mother was heterozygous and the variant was absent in the grandparents (de novo occurrence in the mother), and in the 2026 family the variant shared by the two brothers was absent from the maternal tissues tested, indicating low-level germline or somatic mosaicism; the authors recommend counselling about recurrence risk and offering reproductive testing to the parents and sisters [19, 52]. The sources describe no cases of germline mosaicism in the autosomal forms.

8.2. Carrier and cascade testing

Once the familial variants are identified, at-risk siblings can be tested, allowing early diagnosis and surveillance for complications, and relatives can undergo carrier testing [4, 8]. In the Lancaster Amish communities, the carrier frequency of the MPLKIP c.430A>G variant was estimated at 1 in 300 from the allele frequency in exomes from 301 controls [59]. The TTD sources consulted do not address carrier testing in minors; diagnostic testing of symptomatic or at-risk siblings has a direct clinical benefit, because it allows earlier surveillance of infections, the eyes, and the hips [8, 51].

8.3. Pregnancy with an affected fetus

Obstetric complications depend on the fetal genotype. In the 2001–2011 NIH study, 27 pregnancies with TTD fetuses (23 healthy mothers without hypertension, diabetes, or autoimmunity; maternal age 19–37 years) had complications in 22 (81%): preterm delivery <37 weeks in 15 (56%; reference 10.9%), preeclampsia in 8 (30%; reference 6.5%), placental abnormalities in 5 (19%: three adherent placentas requiring manual removal, one circumvallate placenta, one velamentous cord insertion), HELLP syndrome in 3 (11%; reference 0.35%), and documented growth restriction in 2 (8%); 12 (44%) had two or more complications, and only 5 (19%) reached term without complications [21]. One mother had three pregnancies, all affected, with elevated hCG and delivery at 34 weeks [21]. On maternal serum screening in 10 pregnancies, hCG was elevated (>2.50 MoM or >95th percentile) in 8, alpha-fetoprotein (AFP) was also elevated in 3, and unconjugated oestriol was low in 2; 7 of 8 XP-D pregnancies had abnormal screening, and the MPLKIP pregnancy had normal values [21].

Table source: 2001–2006 NIH genetic epidemiology study, with 15 obligate heterozygous mothers and 49 pregnancies; the affected fetuses included 4 with XP/TTD and 1 with COFS/TTD [86]. In the internal comparison with unaffected siblings, relative risks were 5.2 (95% CI 0.4–61.3) for preeclampsia, 2.9 (1.0–8.8) for preterm delivery, 3.5 (1.1–11.0) for low birth weight, and 9.3 (1.4–60.5) for small for gestational age <10th percentile; the wide intervals reflect the small number of pregnancies, and the data were self-reported and confirmed by records in more than two thirds [86]. Of the placentas examined, 4 of 5 had velamentous cord insertion and 4 had infarcts [86]. The four XP/TTD pregnancies in one family had no complications [86]. In a comparison of 17 TTD-ERCC2 pregnancies with 17 XP-ERCC2 pregnancies, complications occurred in 16/17 versus 0/17 (p<0.0001), and NICU admission in 15 versus 2 [35]. The authors attribute the complications to insufficient transcription of essential genes in the placenta, which has the fetal genotype, and note the parallel with other fetal disorders that cause preeclampsia or HELLP syndrome (fatty acid oxidation defects, argininosuccinic aciduria, triploidy, Beckwith-Wiedemann syndrome) [21]. In the 2008 review, 5 pregnancies of mothers with a child with TTD ended in pregnancy loss (one fetal death at 19 weeks and four spontaneous miscarriages), and the median parental age (25 years maternal, 27 paternal) ruled out advanced age as an explanation [1].

These data support managing pregnancy as obstetrically high risk in a couple with known TTD variants, especially ERCC2 variants; allele specificity (XP-associated ERCC2 variants are not associated with complications) should be included in counselling [35].

8.4. Prenatal and preimplantation diagnosis

Once the variants in the index case are known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible; the 2024 congenital ichthyosis guidelines include both [4, 91]. In the 2008 review, five fetuses from families with a child with TTD were diagnosed prenatally by repair studies or fetal hair studies, and no affected pregnancy went to term [1]. Functional methods (UDS, comet assay) apply only to forms with a repair defect [1, 90]. Early neonatal diagnosis is useful for anticipating comorbidities and for counselling about future pregnancies [21]. The French PNDS for inherited ichthyoses, which covers TTD, allows prenatal and preimplantation diagnosis when the variants have been identified and criteria of severity and incurability are met, after a genetics consultation and presentation to a multidisciplinary prenatal diagnosis centre, with psychological support [28]. Chorionic villus sampling is performed from 12 weeks of amenorrhoea and amniocentesis from 15 weeks, with a miscarriage risk <0.5%; noninvasive prenatal diagnosis on maternal blood, from 10 weeks, was available in France for autosomal dominant disorders of paternal origin and, in recessive disorders with compound heterozygosity, can only exclude fetuses that lack the paternal variant, sparing them the invasive procedure; there were five preimplantation diagnosis centres in France; fetal ultrasound and MRI are late and do not provide a definitive diagnosis [28]. The same document recommends confirming the heterozygosity of each parent in the autosomal recessive forms (25% risk per pregnancy), offering testing for the familial variant in the setting of consanguinity, and not performing systematic carrier screening in the general population; counselling is provided jointly with a psychologist and includes the legal obligation to inform relatives [28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Incidence and prevalence

The only population-based estimate is European. Kleijer and colleagues combined data from the DNA repair diagnostic centres of France, (West) Germany, Italy, the Netherlands, and the United Kingdom, where TTD had been diagnosed in the laboratory since the mid-1980s, and estimated an incidence of 1.2 per million live births in Western Europe (1.1 in the native population), similar to that of XP in the native population (XP 2.3 overall and 0.9 native; CS 2.7 and 1.8), with immigrant populations overrepresented [20]. Because ascertainment was through repair laboratories, the study underestimates the nonphotosensitive forms with normal repair [9]. Orphanet adopts this figure (birth prevalence 1/830,000 in Europe; <1/1,000,000 class) and counts 201 published cases or families [4]. The figure of “1.2 per 10 million” in the GeneGuidance curation for GTF2H5 is a conversion error from 0.12 per 100,000 [9]. For comparison, XP has a prevalence of about 1 per million in the USA and Europe and 1 in 22,000 in Japan [8]. The sources consulted provide no estimates for the USA; the NIH cohorts (92% White in the growth cohort) are not population samples [62].

9.2. Geographic distribution of published cases

In the 2008 review, the 112 patients came from 20 countries on all continents, mainly Italy (27; 23%), the USA (19; 16%), the United Kingdom (18; 16%), and France (12; 11%), followed by Canada, Morocco, Turkey, and Switzerland (4 each) and Germany (3); the distribution reflects the centres that publish rather than prevalence [1]. In the Italian ERCC2 cohort, p.Arg112His was the most frequent variant [5].

9.3. Founder populations

Among the Amish of northern Indiana, the MPLKIP variant c.430A>G p.(Met144Val) accounts for all pathogenic variants in the gene described in the community, with 20 published homozygous patients; the carrier frequency estimated from exomes of Lancaster Amish controls is 1 in 300 [24, 59]. The variant was not found in 148 controls, 48 of them unrelated Amish individuals [34]. The 1-bp MPLKIP deletion in Pollitt's British siblings and in two girls, one Dutch and one Italian, suggests a European founder origin [34]. The MPLKIP c.277del variant arose in three unrelated families, which may indicate a mutational hotspot [24]. In Sabinas syndrome, the DBR1 p.(Asp262Tyr) variant has an ancient origin in Mexican families [7]. Consanguineous families from Morocco carry MPLKIP and GTF2E2 variants [34, 44].

9.4. Portugal and Brazil

The sources consulted provide no epidemiological data for Portugal or Brazil. The Brazilian textbook of genetic syndromes describes TTD and distinguishes it from XP by the higher frequency of pregnancy complications and neonatal anomalies [116]. In 2026, the case of a young Brazilian woman with genetically confirmed TTD and retinal dystrophy was published [75].

9.5. Special populations

Adult women with TTD often have impaired puberty and fertility (menarche at age 18 in the Italian women with TTD1; amenorrhoea after three cycles in the MARS1 patient) [5, 12]. In boys, cryptorchidism and hypogonadism are frequent, and in TTD5 genital anomalies may be the first prenatal manifestation [1, 83]. Adult patients are few, which limits information on ageing [1].

9.6. European reference networks and patient organisations

The relevant European reference network is ERN-Skin, for rare skin diseases, which includes the ichthyoses and syndromic genodermatoses; the Orphanet review of TTD was carried out by an expert from this network [4, 31]. The Orphanet page links TTD to specialised centres, networks, diagnostic tests, registries and biobanks, and patient organisations [4]. The dedicated organisations are Amy and Friends, in the United Kingdom, and the Share & Care Cockayne Syndrome and Trichothiodystrophy Network, in the USA [32, 33]. In France, the PNDS for inherited ichthyoses organises follow-up within the FIMARAD network, with a “South” reference centre (Bordeaux, coordinator, Toulouse, and Nice) and a “North” centre (Paris-Necker, coordinator, and five other sites), and refers to the Ichtyose France association, founded in 1991 by parents; for neutropenia, the reference centre for chronic neutropenias maintains a national registry and a multidisciplinary consultation meeting and refers to the IRIS association [28, 29].

10. Illustrative Clinical Case

10.1. ERCC2-related TTD with hip degeneration (NIH patient TTD354BE)

The patient, followed under NIH protocol 99-C-0099, is described in detail in the hip degeneration study and is also included in the pregnancy, eye, and growth series [14, 21, 51, 62]. The pregnancy proceeded with normal maternal serum screening, and delivery was at 37 weeks, with a birth weight of 2210 g (8th percentile) [21]. She was evaluated at the NIH at age 3: she had microcephaly, height and weight below the 3rd percentile, global developmental delay, photosensitivity, recurrent infections (otitis media and pneumonia), mild ichthyosis, dental caries, and hair with “tiger-tail” banding [51]. The lens opacities, punctate at age 3, became lamellar and were extracted at ages 6 and 7 [14, 51]. She walked with a walker until age 6. At age 7, hip pain and walking difficulty appeared; a radiograph at 7 years 5 months showed widening of the right joint due to effusion and bilateral coxa valga, and MRI three months later showed osteonecrosis of the right femoral epiphysis, effusion, and mild subluxation [51]. By 7 years 11 months she could no longer walk; she underwent bilateral adductor tenotomies and hip reduction, with deterioration two and a half months later. At age 9, there was osteonecrosis and subluxation on the left as well, kyphosis, W-sitting, hamstring weakness and tightness, and she moved about by scooting on her bottom [51]. She died at 9 years 3 months of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, with low IgG [51]. The 2011 ophthalmology article describes the death of a female TTD patient from MRSA at age 10, and the 2014 growth article has an internal discrepancy regarding the identification of the patient who died at age 9; the age used here is that given in the 2022 article, the most detailed one [14, 51, 62].

Figure 1 of the 2022 article shows the patient at 8 years 11 months, thin and short, with short brittle hair and contractures, and the hair with “tiger-tail” banding and trichoschisis under polarised light (https://pmc.ncbi.nlm.nih.gov/articles/PMC9669218/figure/F1/); Figure 3 shows the radiographic progression of hip osteonecrosis over two years (https://pmc.ncbi.nlm.nih.gov/articles/PMC9669218/figure/F3/) [51].

The case brings together the features that define the prognosis of ERCC2-related TTD: photosensitivity, progressive cataracts, infections with hypogammaglobulinaemia, and rapidly bilateral hip degeneration between ages 7 and 9, with a poor surgical response. The surgeries described are those of the report and are not routine; no guideline defines the surgical indication, and the authors emphasise that, in the cohort, only one of the seven operated patients regained lasting pain-free ambulation [51].

10.2. ERCC3-related TTD in a collodion baby with atopic dermatitis

A newborn of African ancestry was born with a collodion membrane, tight, shiny skin, and ectropion; an autosomal recessive congenital ichthyosis panel identified, in compound heterozygosity, ERCC3 c.1841C>A p.(Ser614Ter), of paternal origin and classified as pathogenic, and c.1004C>T p.(Ser335Leu), of maternal origin and of uncertain significance [73]. In the first year of life, the child developed severe atopic dermatitis refractory to emollients and topical corticosteroids, multiple food allergies, dysphagia consistent with eosinophilic oesophagitis, and recurrent wheezing; the hair was relatively resilient with hair care using vitamin E, panthenol, shea butter, and coconut oil [73]. At 18 months, dupilumab 300 mg every 4 weeks was started, with an EASI of 24.6 and an IDQoL of 27/30 at baseline, improvement at 4 weeks, almost clear skin at 3 months, and maintenance at 6 months, with resolution of the oesophagitis and no adverse effects [73]. Figure 1 of the report shows the skin before treatment and at 3 and 6 months (https://pmc.ncbi.nlm.nih.gov/articles/PMC13052132/figure/ccr372473-fig-0001/) [73]. Dupilumab was used under compassionate use and off-label for TTD; this is a single report, and no guideline recommends it in TTD [73].

11. Prognosis and Long-Term Follow-Up

11.1. Mortality and causes of death

In the review of 112 published cases, there were 20 deaths, between 12 weeks and 47 years of age, all but one before age 10 (median 3 years); 13 were due to pneumonia or other infection, mainly sepsis, and the rest to drowning, cachexia and dehydration, respiratory failure, and sudden death [1]. On Kaplan-Meier analysis, the reported probability of death was 10.7% at 3 years and 21.3% at 9 years, about 20 times the mortality of the general US population; these figures derive from published cases, which are biased towards severe cases [1].

In the NIH cohort of 37 patients, 10 (27%) died, at a median age of 9 years (2–36), mainly from respiratory failure or infection: 8 with ERCC2 variants (8/23, 35%; median 8 years, 2–15), 1 with GTF2H5 (36 years, cardiogenic shock during pneumonia), 1 with an unknown gene (9 years, cardiac arrest during intubation), and none with MPLKIP [51]. In the 40-patient immunology cohort, median survival was 15 years with ERCC2 (25 patients, 8 deaths) versus 36 years in the others (15 patients, 2 deaths; p=0.04); infection or sepsis caused 7 of the 10 deaths, and 5 of the 6 ERCC2 patients who died of infection had hospitalisations lasting several months with multiorgan failure [61]. IgG <5.0 g/L was associated with a median survival of 3.7 years [61]. In the growth cohort, the 5 patients who died (all ERCC2) had, before the terminal illness, a height-for-age of −4.54 ± 2.35, a weight-for-age of −6.18 ± 4.05, a weight-for-length <3rd percentile, and a higher heart rate than survivors [62]. In the pregnancy cohort, 4 of 27 children (15%) died of infection, at ages 0.7, 7, 9, and 15 years [21]. The prognosis of the nonphotosensitive forms is better in the NIH series, but the series are small [51, 61].

11.2. Long-term course

The neurological course is generally stable, and there are adult patients with moderate impairment and no infections after childhood [1, 5]. The oldest patient in the 2008 review, aged 47, had been a collodion baby and had congenital hip subluxation and psychomotor delay, and died with generalised oedema and urinary retention that progressed to coma [1]. The ocular changes have a degenerative component (dry eye, ocular surface disease, loss of acuity, retinal degeneration in TTD-A adults) [14]. In the XP/TTD complex, the prognosis includes the skin cancers of XP [14].

11.3. Surveillance

There are no surveillance intervals validated in patients with TTD. The authors' recommendations from the NIH cohorts and the immunology mini-review state what to monitor but not how often, and Orphanet recommends regular follow-up by a multidisciplinary team [4, 14, 51, 61, 62, 76]. The published intervals come from two French expert-consensus protocols: the 2021 PNDS for inherited ichthyoses, which includes TTD among the syndromic ichthyoses and sets follow-up at least annually, and the 2024 PNDS for chronic neutropenias, which does not mention TTD and applies by extension [28, 29]. The table brings together the recommended examinations; where no source gives a frequency, this is stated explicitly.

12. Summary and Concluding Remarks

Trichothiodystrophy is a spectrum of rare disorders, with an estimated incidence of 1.2 per million live births in Western Europe, unified by a single marker: short, brittle hair deficient in sulfur and cystine, with alternating “tiger-tail” bands under polarised light that are present in every hair of affected patients and absent in controls. Hair examination is inexpensive, rapid, and feasible from the collodion newborn onwards, and should be requested in the presence of any combination of collodion membrane or ichthyosis, developmental delay, short stature, cataracts, recurrent infections, beta-thalassaemia trait, or a pregnancy with preeclampsia, HELLP syndrome, and elevated hCG.

About half of patients have photosensitivity due to TFIIH deficiency, almost always from biallelic ERCC2 variants and rarely from ERCC3 or GTF2H5 variants; the other half have normal repair and variants in genes involved in transcription, RNA processing, and translation (MPLKIP, X-linked RNF113A, GTF2E2, TARS1, AARS1, MARS1, CARS1, DBR1). The proposed common mechanism is instability of gene expression proteins, which exhausts the transcriptional capacity of terminally differentiating cells. Despite the repair defect, TTD does not predispose to skin cancer, and the cancer surveillance of xeroderma pigmentosum is reserved for the XP/TTD complex.

Prognosis depends on the gene. In ERCC2-related TTD, median survival was 15 years in the NIH series, with deaths from infection associated with hypogammaglobulinaemia and neutropenia, from postoperative complications, and in the setting of rapidly bilateral hip degeneration at school age; in the other forms, survival was longer. Pregnancy with a fetus with ERCC2-related TTD has complications in more than 80% of cases, with implications for counselling and obstetric surveillance.

There is no specific treatment, interventional trial, orphan designation, or dedicated guideline. Management is supportive and multidisciplinary: photoprotection only in the photosensitive forms, ichthyosis care, early immunological evaluation with immunoglobulin replacement when indicated, nutrition, ophthalmology, hip surveillance in ERCC2 patients, rehabilitation, and careful planning of anaesthesia and surgery, with no surveillance intervals validated in patients with TTD; the available intervals come from the French protocols for inherited ichthyoses and chronic neutropenias. The only targeted approach described, antisense oligonucleotides that generate p52ΔC and stabilise TFIIH in TTD-A, is at the preclinical stage.

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