-
Case Reports in Orthopedics 2015The authors describe the case of a 51-year-old woman with an osteonecrosis of her right femoral head after treatment of an atypical subtrochanteric fracture caused by...
The authors describe the case of a 51-year-old woman with an osteonecrosis of her right femoral head after treatment of an atypical subtrochanteric fracture caused by pycnodysostosis. She had this fracture after a low-trauma fall. She was of short stature with typical facial features, short stubby hands, and radiological features including open cranial sutures, obtuse mandible, and generalized skeletal sclerosis. The majority of cases of atypical subtrochanteric fractures are associated with long-term use of bisphosphonates; some occur in bisphosphonate-free patients. We report a rare case of total hip arthroplasty (THA) in a patient with pycnodysostosis who developed an osteonecrosis of the femoral head after treatment of an atypical subtrochanteric femoral fracture. We performed cementless THA in combination with a plate and cables. Cementless THA is a potential intervention in a patient with pycnodysostosis; although the bone quality may have been sclerotic, healing is not a problem in this condition.
PubMed: 26448892
DOI: 10.1155/2015/731910 -
Blood Feb 2020
Topics: Heinz Bodies; Humans; Infant, Newborn; Pycnodysostosis
PubMed: 32106309
DOI: 10.1182/blood.2019004019 -
BMJ Case Reports Sep 2013Pycnodysostosis is a rare genetic disease. Impaired osteoclastic function is the basis for typical phenotypic features and bone fragility. The main differential...
Pycnodysostosis is a rare genetic disease. Impaired osteoclastic function is the basis for typical phenotypic features and bone fragility. The main differential diagnosis is osteopetrosis, also associated with altered bone remodelling, but with a more severe prognosis. We describe the case of an 8-year-old boy who presented life-threatening obstructive sleep apnoea successfully managed with non-invasive ventilation. Haematological overlap phenotype included anaemia and altered bone marrow, more common in osteopetrosis. Molecular analysis of the CTSK gene revealed a mutation not previously described in the literature.
Topics: Cathepsin K; Child; Glucosephosphate Dehydrogenase Deficiency; Humans; Male; Mutation; Noninvasive Ventilation; Pycnodysostosis; Severity of Illness Index; Sleep Apnea, Obstructive
PubMed: 24057333
DOI: 10.1136/bcr-2013-200590 -
BMC Medical Genetics Aug 2009Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures and skull...
BACKGROUND
Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures and skull deformities. Mutations in the gene encoding cathepsin K (CTSK), a lysosomal cysteine protease, have been found to be responsible for this disease.
OBJECTIVES
To identify pathogenic mutation in a consanguineous Pakistani family with 3 affected individuals demonstrating autosomal recessive pycnodysostosis.
METHODS
Genotyping of 10 members of the family, including three affected and seven unaffected individuals was carried out by using polymorphic markers D1S442, D1S498, and D1S305, which are closely linked to the CTSK gene on chromosome 1q21. To screen for mutations in the CTSK gene, all of its exons and splice junctions were PCR amplified from genomic DNA and sequenced directly in an ABI Prism 310 automated sequencer.
RESULTS
Genotyping results showed linkage of the pycnodysostosis Pakistani family to the CTSK locus. Sequence analysis of the CTSK gene revealed homozygosity for a missense mutation (A277V) in the affected individuals.
CONCLUSION
We describe a missense mutation in the CTSK gene in a Pakistani family affected with autosomal recessive pycnodysostosis. Our study strengthens the role of this particular mutation in the pathogenesis of pycnodysostosis and suggests its prevalence in Pakistani patients.
Topics: Bone Diseases, Developmental; Cathepsin K; Cathepsins; Consanguinity; DNA Mutational Analysis; Exons; Female; Genes, Recessive; Genotype; Humans; Male; Mutation, Missense; Pakistan; Pedigree; Polymerase Chain Reaction
PubMed: 19674475
DOI: 10.1186/1471-2350-10-76 -
Journal of Bone and Mineral Research :... Oct 2001Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well...
Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis.
Topics: Animals; Biomarkers; Bone Resorption; Cathepsin K; Cathepsins; Collagen; Collagen Type I; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Female; Humans; Macaca fascicularis; Molecular Structure; Osteoclasts; Ovariectomy; Peptides; Primates; Rats
PubMed: 11585335
DOI: 10.1359/jbmr.2001.16.10.1739 -
The Journal of International Medical... 2009This study investigated the relationship between a cathepsin K (CTSK) gene mutation and the pathogenesis of pycnodysostosis in a Chinese patient. A typical...
This study investigated the relationship between a cathepsin K (CTSK) gene mutation and the pathogenesis of pycnodysostosis in a Chinese patient. A typical pycnodysostosis case and 30 healthy controls were enrolled into the study. Genomic DNA was extracted from blood samples taken from the patient and controls, and the encoding exons of CTSK were amplified and sequenced. Sequencing of the CTSK gene revealed homozygosity for a novel missense mutation in the pycnodysostosis patient, predicting the amino acid exchange from glutamine to proline at position 187 (Q187P). This point mutation in exon 5 of the CTSK gene results in the typical clinical features found in Chinese patients with pycnodysostosis. No similar changes in the CTSK gene sequences were found in the healthy controls.
Topics: Asian People; Base Sequence; Bone Diseases; Case-Control Studies; Cathepsin K; Cathepsins; Child; Health; Humans; Male; Mutation; Radiography
PubMed: 19215700
DOI: 10.1177/147323000903700133 -
Archives of Disease in Childhood Sep 1996Short stature is a characteristic feature of pycnodysostosis. We report defective growth hormone secretion in response to provocation and low insulin-like growth...
Short stature is a characteristic feature of pycnodysostosis. We report defective growth hormone secretion in response to provocation and low insulin-like growth factor-I (IGF-I) concentration in five out of six patients with pycnodysostosis. Physiological replacement with growth hormone increased IGF-I concentration and improved linear growth in these children.
Topics: Adult; Bone Diseases, Developmental; Child, Preschool; Female; Growth; Growth Disorders; Growth Hormone; Humans; Infant; Infant, Newborn; Insulin-Like Growth Factor I; Male
PubMed: 8976667
DOI: 10.1136/adc.75.3.242 -
Clinical Medicine Insights. Case Reports 2019Pycnodysostosis is a rare genetic disorder with a prevalence of 1.7 per million births; it usually presents with short stature, osteosclerosis, increased bone fragility,...
Pycnodysostosis is a rare genetic disorder with a prevalence of 1.7 per million births; it usually presents with short stature, osteosclerosis, increased bone fragility, and acro-osteolysis of distal phalanges. There are less than 200 cases reported worldwide and very few from South-East Asia. We present a case of pycnodysostosis who presented with short stature, acro-osteolysis of distal phalanges, and on genetic testing revealing a variant c.847T>C, p.Y283H, in exon 7 of the in homozygous state: not reported till date to the best of our knowledge.
PubMed: 30967749
DOI: 10.1177/1179547619837234 -
Journal of Bone and Mineral Research :... Oct 1999Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important... (Comparative Study)
Comparative Study
Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.
Topics: Animals; Bone Density; Bone Matrix; Cathepsin K; Cathepsins; Growth Plate; Mice; Mice, Knockout; Osteopetrosis; Splenomegaly
PubMed: 10491212
DOI: 10.1359/jbmr.1999.14.10.1654 -
Journal of Natural Science, Biology,... 2015Pycnodysostosis is a rare sclerosing bone disorder characterized by short stature, brachycephaly, short/stubby fingers, open cranial sutures/fontanelle, and diffuse...
Pycnodysostosis is a rare sclerosing bone disorder characterized by short stature, brachycephaly, short/stubby fingers, open cranial sutures/fontanelle, and diffuse osteosclerosis, where multiple fractures of long bones and osteomyelitis of the jaw are common complications. We present a rare case of pycnodysostosis with chronic suppurative osteomyelitis of the mandible in a 36-year-old woman; which was nonsurgically managed by a conservative approach involving a novel protocol referred to as intra-lesional antibiotic therapy.
PubMed: 26283855
DOI: 10.4103/0976-9668.160043