Subject(s)
Alopecia/diagnosis , Bone and Bones/abnormalities , Ectodermal Dysplasia/diagnosis , Hydrocortisone/blood , Hyperpigmentation/diagnosis , Lymphedema/diagnosis , Nail Diseases/diagnosis , Noonan Syndrome/diagnosis , Rothmund-Thomson Syndrome/diagnosis , Skin Neoplasms/diagnosis , Alopecia/blood , Ectodermal Dysplasia/blood , Female , Humans , Hyperpigmentation/blood , Lymphedema/blood , Nail Diseases/blood , Noonan Syndrome/blood , Rothmund-Thomson Syndrome/blood , Skin Neoplasms/blood , Young AdultABSTRACT
Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia, gingivitis, nail dystrophy, palmoplantar keratoderma and pachyonychia of the great toenails. Previously undetected and silent neutropenia was evidenced after C16orf57 molecular analysis. Neutropenia was absent in the C16orf57-negative patients. This report confirms that neutrophil count should be performed in all patients with poikiloderma to target the C16orf57 gene sequencing analysis, prior to RECQL4 analysis.
Subject(s)
Genetic Testing , Neutropenia/diagnosis , RecQ Helicases/genetics , Rothmund-Thomson Syndrome/diagnosis , Abnormalities, Multiple/blood , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Child, Preschool , Codon, Nonsense , Diagnosis, Differential , Erythrocyte Count , Female , Heterozygote , Humans , Neutropenia/blood , Neutropenia/genetics , Neutropenia/pathology , Pedigree , RecQ Helicases/metabolism , Retrospective Studies , Rothmund-Thomson Syndrome/blood , Rothmund-Thomson Syndrome/genetics , Rothmund-Thomson Syndrome/pathologyABSTRACT
We report on a patient with Rothmund-Thomson syndrome (RTS) whose cytogenetic evaluation showed a normal karyotype with no evidence of trisomy mosaicism or chromosomal rearrangements. Cultured lymphocytes from the patient, her mother, and a control exposed to mitomycin C and diepoxybutane did not show increased sensitivity to the dialkylating agents. Unlike some previous reports, we found no evidence of a deficiency in nucleotide excision repair, as measured with the functional unscheduled DNA synthesis assay. Glycophorin A analysis of red blood cells for somatic mutation revealed suspiciously high frequencies of both allele loss and loss-and-duplication variants in the blood of the patient, a pattern consistent with observations in other RecQ-related human diseases, and evidence for clonal expansion of a mutant clone in the mother. Discrepant results in the literature may reflect true heterogeneity in the disease or the fact that a consistent set of tests has not been applied to RTS patients.
Subject(s)
Chromosome Fragility/genetics , Rothmund-Thomson Syndrome/genetics , Adult , Blood Group Antigens/genetics , Child , Child, Preschool , DNA Damage/drug effects , DNA Repair/genetics , Epoxy Compounds/pharmacology , Erythrocytes/metabolism , Erythrocytes/pathology , Female , Flow Cytometry , Glycophorins/genetics , Humans , Infant , Infant, Newborn , Karyotyping , Loss of Heterozygosity/genetics , Lymphocytes/cytology , Lymphocytes/drug effects , Lymphocytes/metabolism , Lymphocytes/pathology , Male , Mitomycin/pharmacology , Mutation/genetics , Rothmund-Thomson Syndrome/blood , Rothmund-Thomson Syndrome/pathologyABSTRACT
An 11-year-old boy had dyskeratosis congenita, elevated fetal hemoglobin level, X-linked ocular albinism, and juvenile-onset diabetes mellitus. A review of the international literature revealed that elevated fetal hemoglobin has been noted in 15 reported cases of dyskeratosis congenita. It is a previously unrecognized, commonly associated finding in dyskeratosis congenita that may provide insight into the location and function of the gene for dyskeratosis congenita.
