RESUMO
Trichothiodystrophy is a group of multisystem neuroectodermal disorders with dysplastic hair as the cardinal symptom. We describe three patients from two Finnish families in whom whole-exome sequencing revealed a novel homozygous variant, c.26del, p.(Pro9Glnfs*144) in the MPLKIP-gene, confirming the diagnosis of non-photosensitive trichothiodystrophy type 4 (TTD4). The variant was confirmed by Sanger sequencing and inherited from unaffected carrier parents. This report adds to the literature by expanding the genetic and phenotypic spectra of MPLKIP-related trichothiodystrophy. We describe dysmorphic features in the patients and provide a comparison of clinical characteristics in patients with TTD4 reported to date.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Síndromes de Tricotiodistrofia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Finlândia/epidemiologia , Homozigoto , Humanos , Lactente , Masculino , Mutação/genética , Linhagem , Fenótipo , Síndromes de Tricotiodistrofia/epidemiologia , Síndromes de Tricotiodistrofia/patologia , Adulto JovemRESUMO
Photodermatoses associated with defective DNA repair are a group of photosensitive hereditary skin disorders. In this review, we focus on diseases and syndromes with defective nucleotide excision repair that are not accompanied by an increased risk of cutaneous malignancies despite having photosensitivity. Specifically, the gene mutations and transcription defects, epidemiology, and clinical features of Cockayne syndrome, cerebro-oculo-facial-skeletal syndrome, ultraviolet-sensitive syndrome, and trichothiodystrophy will be discussed. These conditions may also have other extracutaneous involvement affecting the neurologic system and growth and development. Rigorous photoprotection remains an important component of the management of these inherited DNA repair-deficiency photodermatoses.
Assuntos
Distúrbios no Reparo do DNA/genética , Transtornos de Fotossensibilidade/genética , Síndrome de Cockayne/epidemiologia , Síndrome de Cockayne/genética , Síndrome de Cockayne/terapia , Adutos de DNA , Distúrbios no Reparo do DNA/epidemiologia , Gerenciamento Clínico , Predisposição Genética para Doença , Humanos , Mutagênese , Fenótipo , RNA Polimerase II/metabolismo , Tolerância a Radiação/genética , Transcrição Gênica , Síndromes de Tricotiodistrofia/epidemiologia , Síndromes de Tricotiodistrofia/genética , Síndromes de Tricotiodistrofia/terapia , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/genéticaRESUMO
Two of DNA's worst enemies, ultraviolet light and chemical carcinogens, can cause damage to the molecule by mutating individual nucleotides or changing its physical structure. In most cases, genomic integrity is restored by specialized suites of proteins dedicated to repairing specific types of injuries. One restoration mechanism, called nucleotide excision repair (NER), recruits and coordinates the services of 20-30 proteins to recognize and remove structure-impairing lesions, including those induced by ultraviolet (UV) light. Mutations in a gene that encodes a protein from the NER machinery might cause a wide variety of rare inherited human disorders. Sun sensitivity, cancer, developmental retardation, neurodegeneration and premature aging characterize these syndromes. Identification of the causative genes and proteins in affected families in Israel allowed us to establish accurate molecular diagnosis of couples at risk, and provide them with better genetic counseling.
Assuntos
Síndrome de Cockayne/genética , Reparo do DNA , Síndromes de Tricotiodistrofia/genética , Xeroderma Pigmentoso/genética , Adulto , Senilidade Prematura/genética , Senilidade Prematura/metabolismo , Criança , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/epidemiologia , Síndrome de Cockayne/metabolismo , Humanos , Lactente , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/metabolismo , Transtornos de Fotossensibilidade/diagnóstico , Transtornos de Fotossensibilidade/epidemiologia , Transtornos de Fotossensibilidade/genética , Transtornos de Fotossensibilidade/metabolismo , Síndromes de Tricotiodistrofia/diagnóstico , Síndromes de Tricotiodistrofia/epidemiologia , Síndromes de Tricotiodistrofia/metabolismo , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/diagnóstico , Xeroderma Pigmentoso/epidemiologia , Xeroderma Pigmentoso/metabolismoRESUMO
Laboratory diagnosis for DNA repair diseases has been performed in western Europe from the early seventies for xeroderma pigmentosum (XP) and from the mid-eighties for Cockayne syndrome (CS) and trichothiodystrophy (TTD). The combined data from the DNA repair diagnostic centres in France, (West) Germany, Italy, the Netherlands and the United Kingdom have been investigated for three groups of diseases: XP (including XP-variant), CS (including XP/CS complex) and TTD. Incidences in western Europe were for the first time established at 2.3 per million livebirths for XP, 2.7 per million for CS and 1.2 per million for TTD. As immigrant populations were disproportionately represented in the patients' groups, incidences were also established for the autochthonic western European population at: 0.9 per million for XP, 1.8 per million for CS and 1.1 per million for TTD. Perhaps contrary to general conceptions, compared to XP the incidence of CS appears to be somewhat higher and the incidence of TTD to be quite similar in the native West-European population.
