RESUMO
BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia, the prevalence of which is estimated to be low (1 per million). Nevertheless, in recent years we have found 27 affected individuals from 22 families in Ceará State, a region of the Brazilian Northeast, giving a local prevalence of 3 per million. This local prevalence associated with a high parental consanguinity, suggesting a possible founder effect, prompted us to perform a molecular investigation of these families to test this hypothesis. METHODS: The CTSK gene was sequenced by the Sanger method in the patients and their parents. In addition to 18 families from Ceará, this study also included 15 families from other Brazilian regions. We also investigated the origin of each family from the birthplace of the parents and/or grandparents. RESULTS: We have studied 39 patients, including 33 probands and 6 sibs, from 33 families with pycnodysostosis and identified six mutations, five previously described (c.436G>C, c.580G>A, c.721C>T, c.830C>T and c.953G>A) and one novel frameshift (c.83dupT). This frameshift variant seems to have a single origin in Ceará State, since the haplotype study using the polymorphic markers D1S2344, D1S442, D1S498 and D1S2715 suggested a common origin. Most of the mutations were found in homozygosity in the patients from Ceará (83.3 %) while in other states the mutations were found in homozygosity in half of patients. We have also shown that most of the families currently living outside of Ceará have northeastern ancestors, suggesting a dispersion of these mutations from the Brazilian Northeast. CONCLUSIONS: The high frequency of pycnodysostosis in Ceará State is the consequence of the high inbreeding in that region. Several mutations, probably introduced a long time ago in Ceará, must have spread due to consanguineous marriages and internal population migration. However, the novel mutation seems to have a single origin in Ceará, suggestive of a founder effect.
Assuntos
Catepsina K/genética , Mutação , Linhagem , Polimorfismo Genético , Picnodisostose/genética , Brasil , Feminino , Efeito Fundador , Homozigoto , Humanos , MasculinoRESUMO
Pycnodysostosis (OMIM 265800) is an uncommon hereditary disorder characterized by osteosclerosis of the skeleton, short stature, and bone fragility. The syndrome was first described by Maroteaux and Lamy (1962). Facial dysmorphology, hypoplasia of the mandible,dysplasia of the skull, bones with delayed closure of the cranial sutures, clavicular dysplasia, acroosteolysis or partial aplasia of the terminal phalanges, and abnormal tooth eruption have also been reported (Gelb et al., 1995). An autosomal recessive mode of inheritance has been also suggested and the locus of the disease was initially mapped to human chromosome 1q21 by genetic linkage (Bernard et al., 1980). Since then, several mutations on unrelated patients and consanguineous families have been identified in the cathepsin K gene (CTSK), affecting osteoclast function.Only two previous reports have demonstrated the presence of craniosynostosis in patients with pycnodysostosis(Fleming et al., 2007; Osimani et al., 2010). The purpose of this case report is to describe the craniofacial and dental features of a 12-year-old boy with pycnodysostosisand an uncommon association with craniosynosotosis.
Assuntos
Disostose Craniofacial/genética , Craniossinostoses/genética , Picnodisostose/genética , Criança , Craniossinostoses/patologia , Ossos Faciais/anormalidades , Genes Recessivos , Humanos , Masculino , Picnodisostose/patologia , Crânio/anormalidadesAssuntos
Cromossomos Humanos Par 1/genética , Impressão Genômica/genética , Obesidade/genética , Picnodisostose/genética , Dissomia Uniparental/genética , Índice de Massa Corporal , Catepsina K/genética , Criança , Feminino , Genótipo , Humanos , Repetições de Microssatélites/genética , Obesidade/patologia , LinhagemRESUMO
BACKGROUND: Pycnodysostosis, an autosomal recessive skeletal dysplasia, is characterized by short stature, osteosclerosis, delayed cranial suture closure, hypoplastic mandible, acro-osteolysis, hypoplastic clavicle, and dental anomalies. The disorder is caused by CTSK gene defects, a gene localized on 1q21. PURPOSE: To describe the clinical, radiological, and molecular findings in a family with pycnodysostosis. METHODS: The CTSK gene was analyzed from genomic DNA in a nonconsanguinity Mexican family with 3 affected members with pycnodysostosis and 100 healthy controls. RESULTS AND INTERPRETATION: We identified the novel homozygous mutation c.908G>A within exon 8 of the CTSK gene. This missense mutation leads to the substitution of the amino acid glycine at position 303 by glutamic acid (G303E) in cathepsin K protease. No genotype/phenotype correlation was present in affected members of the family with pycnodysostosis.