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Case Reports in Anesthesiology 2018Pycnodysostosis is a rare congenital disorder with several implications, which might complicate anesthesia. Patients are more prone to fractures and have an anticipated...
Pycnodysostosis is a rare congenital disorder with several implications, which might complicate anesthesia. Patients are more prone to fractures and have an anticipated difficult airway. We report a case of a 34-year-old woman with pycnodysostosis who underwent elective caesarean delivery under epidural blockade.
PubMed: 30538866
DOI: 10.1155/2018/5675637 -
Case Reports in Dentistry 2017Pycnodysostosis (PDO) is a rare genetic disorder characterized by cathepsin K deficiency which plays an important role in bone metabolism. Among clinical features of...
Pycnodysostosis (PDO) is a rare genetic disorder characterized by cathepsin K deficiency which plays an important role in bone metabolism. Among clinical features of this disease which are mainly caused by altered bone remodeling are craniofacial abnormalities such as hypoplastic maxilla and obtuse gonial angle which consequently lead to respiratory insufficiency in forms of pharyngeal narrowing and severe snoring. In this paper, another case of this rare disorder is presented along with a review on etiology and management issues of respiratory insufficiency in these patients.
PubMed: 29318055
DOI: 10.1155/2017/4352485 -
Acta Ortopedica Mexicana 2018Pycnodysostosis is a rare disease secondary to a mutation in gen 1q21 that codifies the cathepsin K, proteolitic enzyme implicated in the metabolism of osteonectin,... (Observational Study)
Observational Study
INTRODUCTION
Pycnodysostosis is a rare disease secondary to a mutation in gen 1q21 that codifies the cathepsin K, proteolitic enzyme implicated in the metabolism of osteonectin, osteopontin and type I colagen. Its global incidence is around 1-1.7 cases per million, without genre prevalences, it is clinically caracterized by short stature, craneal deformities, «birds face» and bone fragility with pathological fractures tendency predominantly affecting long bones and occasionally vertebral pedicles. Radiologically is characterized by sclerous bones with permeable medular cannel. Despite there are numerous clinical reports on medical literature, just a litlle describe families with more than one afected member and its followship is usually short-term.
OBJECTIVE
To analize clinical evolution of these afected patients.
MATERIAL AND METHODS
A retrospective, descriptive, observational study was reelized in three patients with diagnosis of pycnodisostosis, between July 2006 and March 2016.
RESULTS
different affection forms of pycnodisostosis where observed, some of them, atipical, as for example spondilolisis and a escapule fracture in one patien.
CONCLUSIONS
The present study could be the longest longitudinal report ever registered. By knowing the presented variety of manifestations and complications, the reader could select the best treatment method for each case.
Topics: Cathepsin K; Follow-Up Studies; Fractures, Spontaneous; Humans; Pycnodysostosis; Retrospective Studies
PubMed: 30726592
DOI: No ID Found -
European Journal of Dentistry Oct 2012Pycnodysostosis is a rare genetic disorder and was first described in 1962 by Maroteaux and Lamy. The incidence of this anomaly is estimated to be 1.7 per 1 million...
Pycnodysostosis is a rare genetic disorder and was first described in 1962 by Maroteaux and Lamy. The incidence of this anomaly is estimated to be 1.7 per 1 million births. The principal characteristics of this disorder are short stature, prominent eyes with blue sclera, beaked nose, cranial dysplasia, exposed fontanelles and cranial sutures, clavicular dysplasia, total/partial dysplasia of the terminal phalanges, obtused mandibular gonial angle, and generally increased bone density. Some features of pycnodysostosis are similar to osteopetrosis and cleidocranial dysostosis. Therefore, it must be distinguished from osteopetrosis and cleidocranial dysostosis in order to diagnose it in individuals of a younger age.The aims of this case report were to show the clinical, radiographic, and diagnostic features, as well as the cephalometric characteristics of pycnodysostosis in comparison with Turkish cephalometric norms.
PubMed: 23077428
DOI: No ID Found -
Proceedings of the National Academy of... Nov 1998Cathepsin K is a recently identified lysosomal cysteine proteinase. It is abundant in osteoclasts, where it is believed to play a vital role in the resorption and...
Cathepsin K is a recently identified lysosomal cysteine proteinase. It is abundant in osteoclasts, where it is believed to play a vital role in the resorption and remodeling of bone. Pycnodysostosis is a rare inherited osteochondrodysplasia that is caused by mutations of the cathepsin-K gene, characterized by osteosclerosis, short stature, and acroosteolysis of the distal phalanges. With a view to delineating the role of cathepsin K in bone resorption, we generated mice with a targeted disruption of this proteinase. Cathepsin-K-deficient mice survive and are fertile, but display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space. Cathepsin-K-deficient osteoclasts manifested a modified ultrastructural appearance: their resorptive surface was poorly defined with a broad demineralized matrix fringe containing undigested fine collagen fibrils; their ruffled borders lacked crystal-like inclusions, and they were devoid of collagen-fibril-containing cytoplasmic vacuoles. Assaying the resorptive activity of cathepsin-K-deficient osteoclasts in vitro revealed this function to be severely impaired, which supports the contention that cathepsin K is of major importance in bone remodeling.
Topics: Animals; Bone Resorption; Cathepsin K; Cathepsins; Disease Models, Animal; Mice; Mice, Knockout; Osteoclasts; Osteopetrosis
PubMed: 9811821
DOI: 10.1073/pnas.95.23.13453 -
European Journal of Medical Research Aug 2016Pycnodysostosis 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...
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.
Topics: Brazil; Cathepsin K; Female; Founder Effect; Homozygote; Humans; Male; Mutation; Pedigree; Polymorphism, Genetic; Pycnodysostosis
PubMed: 27558267
DOI: 10.1186/s40001-016-0228-7 -
Genome Research Nov 1996Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and...
Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and fragility. Linkage analysis localized the disease gene to human chromosome 1q21, and subsequently the genetic interval was narrowed to between markers D1S2612 and D1S2345. Expressed sequence tagged markers corresponding to cathepsin K, a cysteine protease highly expressed in osteoclasts and thought to be important in bone resorption, were mapped previously in the candidate region. We have identified a cytosine to thymidine transition at nucleotide 862 (GenBank accession no. S79895) of the cathepsin K coding sequence in the DNA of an affected individual from a large, consanguinous Mexican family. This mutation results in an arginine to STOP alteration at amino acid 241, predicting premature termination of cathepsin K mRNA translation. All affected individuals in this family were homozygous for the mutation, suggesting that this alteration may lead to pycnodysostosis. Recognition of the role of cathepsin K in the etiology of pycnodysostosis should provide insights into the pathogenesis and treatment of other disorders of bone remodeling, including osteoporosis.
Topics: Blotting, Southern; Bone Diseases, Developmental; Cathepsin K; Cathepsins; Chromosome Mapping; Chromosomes, Human, Pair 1; Codon, Nonsense; Consanguinity; DNA Primers; Genetic Diseases, Inborn; Genetic Linkage; Genetic Markers; Humans; Lod Score; Mexico; Molecular Sequence Data; Mutation; Pedigree; Sequence Analysis
PubMed: 8938428
DOI: 10.1101/gr.6.11.1050 -
Journal of Bone and Mineral Research :... Jul 2008Pycnodysostosis is an extremely rare genetic osteosclerosis caused by cathepsin K deficiency. We hypothesized that teriparatide, a potent anabolic agent used in the...
Pycnodysostosis is an extremely rare genetic osteosclerosis caused by cathepsin K deficiency. We hypothesized that teriparatide, a potent anabolic agent used in the treatment of osteoporosis, might reduce skeletal fragility by activating bone turnover. We studied a typical case of pycnodysostosis in a 37-yr-old woman who exhibited short stature, skull and thorax deformities, and a history of severe fragility fractures. Cathepsin K gene sequencing was performed. Before and after 6 mo of 20 microg/d teriparatide, biochemical markers of bone turnover were measured, and 3D bone structure and microarchitecture was assessed in vivo by HR-pQCT. Qualitative and quantitative analysis of transiliac bone biopsies were performed, and the degree of mineralization was evaluated by quantitative microradiography. In vitro assessment of bone resorption was performed after separation and differentiation of CD14(+) monocytes from peripheral blood. Bone structure assessed by HR-pQCT on the radius and tibia showed augmentation of cortical and trabecular density. Transiliac bone biopsy showed highly increased bone mass (+63% versus age- and sex-matched controls), a decrease in bone remodeling without evidence of active osteoblasts, and a severe decrease in the dynamic parameters of bone formation (mineralizing surfaces, -90% and bone formation rate, -93% versus age- and sex-matched controls). This depressed bone turnover probably explained the increased degree of mineralization. The presence of a novel missense mutation leading to an A141V amino acid substitution confirmed a genetic defect of cathepsin K as the cause of the disease. The deficiency of active osteoclasts was confirmed by an in vitro study that showed a decreased concentration of CD14(+) monocytes (the precursor of osteoclasts) in blood. These osteoclasts had low resorptive activity when incubated on bone slices. After 6 mo of teriparatide, the structure, microarchitecture, and turnover of bone--assessed by HR-pQCT, histology, and bone turnover markers--remained unchanged. Our data strongly suggest that some features of the osteoclastic phenotype--that are absent in pycnodysostosis--are a prerequisite for the anabolic effect of PTH on osteoblasts.
Topics: Adult; Anabolic Agents; Bone and Bones; Cathepsin K; Cathepsins; Dysostoses; Female; Humans; Teriparatide
PubMed: 18302508
DOI: 10.1359/jbmr.080231 -
The Journal of Clinical Investigation Mar 1999Cathepsin K, a lysosomal cysteine protease critical for bone remodeling by osteoclasts, was recently identified as the deficient enzyme causing pycnodysostosis, an...
Cathepsin K, a lysosomal cysteine protease critical for bone remodeling by osteoclasts, was recently identified as the deficient enzyme causing pycnodysostosis, an autosomal recessive osteosclerotic skeletal dysplasia. To investigate the nature of molecular lesions causing this disease, mutations in the cathepsin K gene from eight families were determined, identifying seven novel mutations (K52X, G79E, Q190X, Y212C, A277E, A277V, and R312G). Expression of the first pro region missense mutation in a cysteine protease, G79E, in Pichia pastoris resulted in an unstable precursor protein, consistent with misfolding of the proenzyme. Expression of five mature region missense defects revealed that G146R, A277E, A277V, and R312G precursors were unstable, and no mature proteins or protease activity were detected. The Y212C precursor was activated to its mature form in a manner similar to that of the wild-type cathepsin K. The mature Y212C enzyme retained its dipeptide substrate specificity and gelatinolytic activity, but it had markedly decreased activity toward type I collagen and a cathepsin K-specific tripeptide substrate, indicating that it was unable to bind collagen triple helix. These studies demonstrated the molecular heterogeneity of mutations causing pycnodysostosis, indicated that pro region conformation directs proper folding of the proenzyme, and suggested that the cathepsin K active site contains a critical collagen-binding domain.
Topics: Cathepsin K; Cathepsins; Dysostoses; Female; Humans; Male; Mutation; Protein Conformation
PubMed: 10074491
DOI: 10.1172/JCI653 -
Journal of Bone and Mineral Research :... Nov 1999Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal...
Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.
Topics: Acid Phosphatase; Adolescent; Adult; Amino Acids; Biomarkers; Bone Matrix; Bone and Bones; Cathepsin K; Cathepsins; Child; Collagen; Collagen Type I; Humans; Isoenzymes; Mutagenesis; Osteocalcin; Osteosclerosis; Peptide Fragments; Peptides; Procollagen; Tartrate-Resistant Acid Phosphatase
PubMed: 10571690
DOI: 10.1359/jbmr.1999.14.11.1902