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

Faghri, Salma; Tamura, Deborah; Kraemer, Kenneth H.; DiGiovanna, John J.

doi:10.1136/jmg.2008.058743

Cited by 230 publications

(254 citation statements)

References 94 publications

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“…Accordingly, reduced amounts of normal COL1 because of a mutated COL1A1 or COL1A2 allele, are typically found in the mildest form of osteogenesis imperfecta (OI type I), which is characterized by fragile bones and reduced bone density often associated with slight spinal curvature, loose joints, muscle weakness, lax ligaments, easy bruising, blue sclerae, and early loss of hearing (32). Notably, skeletal abnormalities, including kyphosis, osteopenia and osteosclerosis, abnormalities in joints, muscle tone and deep tendon reflex, and sensorineural hearing loss are reported in several TTD patients just as are bone fragility, kyphosis and reduced mineral density of vertebrae in the TTD mouse model (30,33,34).…”

Section: Discussionmentioning

confidence: 99%

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Arseni

Lanzafame

Compe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancerprone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.T he extracellular matrix (ECM) is a complex structural network that surrounds and supports cells within connective tissues. It generally includes three major types of macromolecules: fibrous proteins (collagens and elastic fibers), glycoproteins (such as fibronectins and laminins), and glycosaminoglycans/ proteoglycans. The type, amount and composition of the ECM give tissues their unique physical and biological properties (1). Notably, the ECM is not only a structural scaffold but also exhibits important functional roles in controlling key cellular events (e.g., adhesion, migration, proliferation, differentiation, and survival) involved in tissue homeostasis, development, inflammation, and tissue repair (2, 3). Thus, inherited or acquired structural alterations as well as metabolic disturbances of the ECM may cause cellular and tissue changes leading to the onset and progression of specific disorders, such as those affecting the connective tissues (osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan's syndrome) or demanding ECM degradation (tumor invasion and metastasis) (4, 5). Recently, a reduced synthesis of the ECM component collagen type VI (COL6) was shown in confluent fibroblast cultures from patients with trichothiodystrophy [TTD; Online Mendelian Inheritance in Man (OMIM) #601675] (6), an autosomal recessive disorder characterized by symptoms affecting several tissues and organs (7). The most relevant features of TTD are hair abnormalities, ichthyotic skin, physical and mental retardation, neurodegeneration, and sign...

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Section: Discussionmentioning

confidence: 99%

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Arseni

Lanzafame

Compe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…89 Many advances in the heterogeneous field of the TTDs (Fig 5, A) have been made. 92,93 Recent studies on genotype-phenotype correlation distinguish the TTD syndromes associated with ichthyosis of delayed onset or accompanied with collodion membrane from other forms of TTD. 94 Diseases relatively new in the list of ichthyoses are loricrin keratoderma, also referred to as Camisa variant of Vohwinkel keratoderma (Fig 4, C ), [95][96][97] the cerebral dysgenesiseneuropathyeichthyosisePPK syndrome, 98 the arthrogryposiserenal dysfunctionecholestasis syndrome, 99-101 the mental retardationeenteropathye deafnesseneuropathyeichthyosisekeratodermia syndrome, 102 the ichthyosisehypotrichosisesclerosing cholangitis syndrome (also known as neonatal ichthyosis sclerosing cholangitis syndrome), 103-105 the ichthyosis hypotrichosis syndrome (Fig 5, I ) 106 and its allelic variant congenital ichthyosisefollicular atrophodermaehypotrichosisehypohidrosis syndrome, 107,108 and keratosis lineariseichthyosisecongenital sclerosing keratoderma (Fig 4, F ).…”

Section: Other Diseases Considered In the Classification Of Inheritedmentioning

confidence: 99%

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Oji

Tadini

Akiyama

et al. 2010

Journal of the American Academy of Dermatology

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704

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“…7,13 Our review of all English-language-published case reports of TTD patients found 112 TTD patients, of whom 55% had abnormal characteristics at birth and 28% had maternal pregnancy complications. 14 We then conducted two molecular epidemiological studies of pregnancy and neonatal abnormalities in mothers of TTD patients in our clinic. 15,16 We found that 81% of these pregnancies had complications, including 56% with preterm delivery, 30% with preeclampsia and 11% with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome.…”

Section: Introductionmentioning

confidence: 99%

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

et al. 2012

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The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (Po0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development. European Journal of Human Genetics (2012Genetics ( ) 20, 1308Genetics ( -1310 doi:10.1038/ejhg.2012; published online 23 May 2012Keywords: DNA repair; pre-eclampsia; transcription factor IIH INTRODUCTIONPatients with different mutations in the DNA repair/transcription helicase, XPD(ERCC2), may have markedly disparate autosomal recessive phenotypes, including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). 1-11 TTD patients have brittle hair, short stature, developmental delay and multisystem involvement without increased skin cancer risk. 12 In contrast, XP patients have sun sensitivity, freckle-like skin pigmentation, a 10 000-fold increase in skin cancer, and 25% have progressive neurologic degeneration. 12,13 At the National Institutes of Health (NIH), we have examined XP patients since 1971 and TTD patients since 2001 as part of a natural history protocol. 7,13 Our review of all English-language-published case reports of TTD patients found 112 TTD patients, of whom 55% had abnormal characteristics at birth and 28% had maternal pregnancy complications. 14 We then conducted two molecular epidemiological studies of pregnancy and neonatal abnormalities in mothers of TTD patients in our clinic. 15,16 We found that 81% of these pregnancies had complications, including 56% with preterm delivery, 30% with preeclampsia and 11% with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. 16 The TTD patients had mutations in TTD-A(GTF2H5) or TTDN1(C7orf11) in addition to XPD and unknown genes. In contrast, our 1987 review of all Englishlanguage-published case reports of XP patients did not identify a large number of pregnancy abnormalities in 830 XP case reports. 17 These patients had mutations in at least 8 different genes involved in nucleotide excision repair and polymerase function. 7 In order to determine the influence of the XPD gene, we now have conducted a molecular epidemiological s...

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

Cited by 230 publications

References 94 publications

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

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