-
Ear, Nose, & Throat Journal Dec 2019
Review
Topics: Adult; Humans; Male; Maxillofacial Abnormalities; Medical Illustration; Pycnodysostosis; Radiography
PubMed: 31847556
DOI: 10.1177/0145561319825738 -
Journal of Orthopaedics 2019Pycnodysostosis is an autosomal recessive disease caused by a gene mutation leading cathepsin K deficiency. Pathological fractures of the long bones are common, but...
Pycnodysostosis is an autosomal recessive disease caused by a gene mutation leading cathepsin K deficiency. Pathological fractures of the long bones are common, but guidelines on fracture treatment in these patients are still lacking. We have treated 5 fractures in 2 pediatric pycnodysostosis patients. We hypothesize that pycnodysostosis patients have an incomplete remodeling process in fracture healing because of cathepsin K deficiency. Therefore, to minimize the role of endochondral bone formation (indirect) after a fracture, it seems prudent to strive for direct bone healing (intramembranous) instead of indirect bone healing. Open reduction with internal fixation should be the goal.
PubMed: 31048950
DOI: 10.1016/j.jor.2019.03.022 -
The Pan African Medical Journal 2018Pycnodysostosis is a very rare genetic disease of the bone characterized by osteocondensation associated with dysmorphic syndrome and growth retardation. This study aims...
Pycnodysostosis is a very rare genetic disease of the bone characterized by osteocondensation associated with dysmorphic syndrome and growth retardation. This study aims to highlight the phenotypic abnormalities, the radiological signs, the therapeutic and evolutionary features of pycnodysostosis in a 11-year old child. The child was referred by his dentist for clinical evaluation. He was born to first-degree consanguineous parents and had recurrent spontaneous fractures since the age of 3 years. Clinical examination showed dysmorphic syndrome characterized by frontal hump, persistent anterior fontanelle, micrognathia, finger deformities, dental malposition, curved nails, asymmetric chest, lumbar spine scoliosis with severe growth retardation (-4DS). Skeletal X-rays showed bony densification of the skull base, persistent anterior fontanelle, dental malposition, diaphysometaphyseal densification of the long bones mainly at the level of the lower limbs with malunions and tapered phalanges of the hands. Bone densitometry was normal. The diagnosis of pycnodysostosis was retained based on the clinical and radiological signs. Genetic counselling was proposed to the family as well as dental and orthopaedic treatment. Pycnodysostosis is a rare disorder; diagnosis is sometimes difficult and delayed posing diagnostic problem due to its resemblance with osteoporosis. Treatment is essentially based on fractures and dental caries prevention.
Topics: Abnormalities, Multiple; Child; Fractures, Spontaneous; Humans; Male; Pycnodysostosis
PubMed: 31011394
DOI: 10.11604/pamj.2018.31.93.8388 -
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 -
Theranostics 2019Human encodes voltage-gated chloride channel 7 (ClC-7); mutations of lead to osteopetrosis which is characterized by increased bone mass and impaired osteoclast...
Human encodes voltage-gated chloride channel 7 (ClC-7); mutations of lead to osteopetrosis which is characterized by increased bone mass and impaired osteoclast function. In our previous clinical practice, we noticed that osteopetrosis patients with mutations had some special deformities in craniofacial morphology and tooth dysplasia. It is unclear whether these phenotypes are the typical features of involved osteopetrosis and whether ClC-7 could regulate the development of craniofacial bone and tooth in some signaling pathways. : First, we collected 80 osteopetrosis cases from the literature and compared their craniofacial and dental phenotypes. Second, four osteopetrosis pedigrees with mutations were recruited from our clinic for gene testing and clinical analysis of their craniofacial and dental phenotypes. Third, we used a zebrafish model with morpholino treatment to detect the effects of ClC-7 deficiency on the development of craniofacial and dental phenotypes. General observation, whole mount alcian blue and alizarin red staining, whole mount hybridization, scanning electron microscope observation, lysoSensor staining, Q-PCR and western blotting were performed to observe the characteristics of craniofacial bone and tooth changes. Fourth, mouse marrow stromal cells were further primarily cultured to detect ClC-7 related mRNA and protein changes using siRNA, Q-PCR and western blotting. Over 84% of osteopetrosis patients in the literature had some typical craniofacial and tooth phenotypes, including macrocephaly, frontal bossing, and changes in shape and proportions of facial skeleton, and these unique features are more severe and frequent in autosomal recessive osteopetrosis than in autosomal dominant osteopetrosis patients. Our four pedigrees with mutations confirmed the aforementioned clinical features. knockdown in zebrafish reproduced the craniofacial cartilage defects and various dental malformations combined the decreased levels of , , , , and . Loss of function resulted in lysosomal storage in the brain and jaw as well as downregulated cathepsin K (CTSK). The craniofacial phenotype severity also presented a dose-dependent relationship with the levels of ClC-7 and CTSK. ClC-7/CTSK further altered the balance of TGF-β/BMP signaling pathway, causing elevated TGF-β-like Smad2 signals and reduced BMP-like Smad1/5/8 signals in morphants. SB431542 inhibitor of TGF-β pathway partially rescued the aforementioned craniofacial bone and tooth defects of morphants. The ClC-7 involved CTSK/BMP and SMAD changes were also confirmed in mouse bone marrow stromal cells. These findings highlighted the vital role of in zebrafish craniofacial bone and tooth development and mineralization, revealing novel insights for the causation of osteopetrosis with mutations. The mechanism chain of ClC-7/CTSK/ TGF-β/BMP/SMAD might explain the typical craniofacial bone and tooth changes in osteopetrosis as well as pycnodysostosis patients.
Topics: Animals; Chloride Channels; Disease Models, Animal; Facial Bones; Humans; Mice; Models, Theoretical; Mutant Proteins; Osteopetrosis; Skull; Tooth; Zebrafish
PubMed: 30867839
DOI: 10.7150/thno.29761 -
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 -
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 -
JBMR Plus Jan 2018Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long-term antiresorptive therapy, including bisphosphonates. Although the... (Review)
Review
Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long-term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate-naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand-searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (): osteogenesis imperfecta (), pycnodysostosis (), hypophosphatasia (), X-linked osteoporosis (), osteopetrosis, X-linked hypophosphatemia (), and osteoporosis pseudoglioma syndrome (). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate-naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X-linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole-exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted gene sequencing, an heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in . Targeted sequencing of , , , and genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well-phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition.
PubMed: 30283886
DOI: 10.1002/jbm4.10024 -
The FEBS Journal Nov 2018Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of...
Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder called pycnodysostosis. Although a number of pycnodysostotic missense mutations have been reported, underlying mechanism of the disease is not clear. In this study, we investigated in vitro six recombinant pycnodysostosis-related mutants of human CTSK (G79E, I249T, G243E, G303E, G319C and Q187P). While all the mutants, like wild-type, show similar high levels of expression in Escherichia coli, four of them (G79E, G303E, G319C and Q187P) are inactive, unstable and spontaneously degrade during purification process. In contrast, proteolytic/collagenolytic activity, zymogen activation kinetics and stability of G243E and I249T mutants are nominally affected. Crystal structure of I249T at 1.92 Å resolution shows that the mutation in R-domain causes conformational changes of a surface loop in the L-domain although the catalytic cleft remains unaltered. Molecular simulation, normal mode analysis and fluorescence lifetime measurement eliminated the possibility that the change in L-domain surface loop orientation is a crystallization artefact. CD-based thermal melting profile indicates that stability of I249T is significantly higher than wild-type. Our studies first time reports that pycnodysostosis-related mutations do not always lead to complete loss of general proteolytic activity or specific collagenolytic activity of CTSK. The first crystal structure of a pycnodysostotic mutant (I249T) provides critical information that may pave new avenues towards understanding the disease at molecular level. DATABASE: The atomic co-ordinates and structure factors for I249T mutant of human CTSK (codes 5Z5O) have been deposited in the Protein Data Bank (http://wwpdb.org/).
Topics: Amino Acid Sequence; Catalysis; Cathepsin K; Crystallography, X-Ray; DNA Mutational Analysis; Humans; Models, Molecular; Mutation; Protein Conformation; Pycnodysostosis; Sequence Homology
PubMed: 30199612
DOI: 10.1111/febs.14655 -
Journal of Pediatric Genetics Mar 2018Pycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K ( ) gene. We report seven patients from four unrelated...
Pycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K ( ) gene. We report seven patients from four unrelated families with this condition in whom we have identified three novel pathogenic variants, c.120 + 1G > T in intron 2, c.399 + 1G > A in intron 4, and c.148T > G (p.W50G) in exon 2, and a known variant, c.568C > T (p.Q190*) in exon 5 of . We present the clinical, radiographic, and molecular findings of all individuals with molecularly proven pycnodysostosis from the present cohort. We also report the occurrence of giant cell tumor in the skull of a patient with this condition.
PubMed: 29441215
DOI: 10.1055/s-0037-1604100