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International Journal of Molecular... Feb 2021Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of... (Clinical Trial)
Clinical Trial
Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients.
Topics: Adult; Bone Resorption; Cathepsin K; Cathepsin L; Cathepsins; Female; Humans; Lactation; Osteoclasts; Pycnodysostosis
PubMed: 33670411
DOI: 10.3390/ijms22041810 -
Genes Sep 2021Pycnodysostosis is a rare autosomal recessive disorder with characteristic diagnostic manifestations. This study aims to phenotype and provide molecular characterization...
Pycnodysostosis is a rare autosomal recessive disorder with characteristic diagnostic manifestations. This study aims to phenotype and provide molecular characterization of Egyptian patients, with emphasis on identifying unusual phenotypes and raising awareness about pycnodysostosis with different presentations to avoid a mis- or under-diagnosis and consequent mismanagement. We report on 22 Egyptian pycnodysostosis patients, including 9 new participants, all descending from consanguineous families and their ages ranging from 6 to 15 years. In addition, prenatal diagnosis was performed in one family with affected siblings. They all presented with short stature, except for one patient who presented with pancytopenia as her primary complaint. Moreover, 41.2% of patients had sleep apnea, 14% presented with craniosynostosis, and 44.4% had failure of tooth development. Molecular analysis via direct exome sequencing of the cathepsin K gene revealed three novel mutations ((NM_000396.3) c.761_763delCCT, c.864_865delAA, and c.509G>T) as well as two previously reported mutations among nine new cases. The following is our conclusion: This study expands the molecular spectrum of pycnodysostosis by identifying three novel mutations and adds to the clinical and orodental aspects of the disease. The link between the gene mutations and the failure of tooth development has not been established, and further studies could help to improve our understanding of the molecular pathology.
Topics: Adolescent; Cathepsin K; Cells, Cultured; Child; Female; Humans; Male; Mutation; Phenotype; Protein Conformation; Pycnodysostosis; Tooth
PubMed: 34680947
DOI: 10.3390/genes12101552 -
Frontiers in Oral Health 2023Pycnodysostosis is a skeletal dysplasia characterized by short stature, generalized osteosclerosis, acro-osteolysis, and recognizable facial features. Oral...
Pycnodysostosis is a skeletal dysplasia characterized by short stature, generalized osteosclerosis, acro-osteolysis, and recognizable facial features. Oral manifestations are commonly described and include a high-arched palate with dental crowding and malocclusion, hypoplastic enamel, and retained deciduous teeth with impacted permanent teeth, and there is an increased risk of developing osteomyelitis of the jaw. We report here the history of a 9-year-old male with the typical facial and skeletal phenotype of pycnodysostosis but novel oral features. He presented with bilateral progressive facial swelling, which caused functional impairment with chewing and contributed to his severe obstructive sleep apnea (OSA). The severity of his OSA required surgical intervention, and the lesions were resected. Extensive bone remodeling and replacement by fibrous tissue were noted on submucosal dissection, and bilateral subtotal maxillectomies were required. The histopathology of the biopsied lesion was consistent with a giant cell-rich lesion. Genetic testing identified a pathogenic homozygous variant in the gene, c.953G > A, p. (Cys318Tyr). The proband had a good postsurgical response with sustained improvement in his sleep OSA. We present here the history and clinical characteristics of a patient with typical features of pycnodysostosis and an unusual presentation and histopathology of gnathic bone lesions. This report adds to the body of literature on this rare condition and also highlights the finding of giant cell-rich lesions of the gnathic bones. Giant cell-rich lesions in pycnodysostosis have previously been reported in two cases in the literature. While there is not enough evidence to support a certain association with pycnodysostosis, it is prudent to consider regular oral dental reviews in affected individuals to identify pathology early and avoid such life-threatening complications.
PubMed: 37288425
DOI: 10.3389/froh.2023.1188443 -
Bone Dec 2023Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to...
BACKGROUND
Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to investigate the molecular spectrum and natural history of the clinical and radiological features of these disorders.
METHODS
28 patients from 20 families were enrolled in the study; 20 of them were followed for a period of 1-16 years. Targeted gene analysis and whole-exome sequencing (WES) were performed.
RESULTS
Biallelic mutations in CLCN7 and TCIRG1 were detected in three families each, in TNFRSF11A and CA2 in two families each, and in SNX10 in one family in the osteopetrosis group. A heterozygous variant in CLCN7 was also found in one family. In the osteopetrosis and related osteoclast disorders group, three different variants in CTSK were detected in five families with pycnodysostosis and a SLC29A3 variant causing dysosteosclerosis was detected in one family. In autosomal recessive osteopetrosis (ARO), a malignant infantile form, four patients died during follow-up, two of whom had undergone hematopoietic stem cell transplantation. Interestingly, all patients had osteopetrorickets of the long bone metaphyses in infancy, typical skeletal features such as Erlenmeyer flask deformity and bone-in-bone appearance that developed toward the end of early childhood. Two siblings with a biallelic missense mutation in CLCN7 and one patient with the compound heterozygous novel splicing variants in intron 15 and 17 in TCIRG1 corresponded to the intermediate form of ARO (IARO); there was intrafamilial clinical heterogeneity in the family with the CLCN7 variant. One of two patients with IARO and distal tubular acidosis was found to have a large deletion in CA2. In one family, two siblings with a heterozygous mutation in CLCN7 were affected, whereas the father with the same mutation was asymptomatic. In WES analysis of three brothers from a family without mutations in osteopetrosis genes, a hemizygous missense variant in CCDC120, a novel gene, was found to be associated with high bone mass.
CONCLUSION
This study extended the natural history of the different types of osteopetrosis and also introduced a candidate gene, CCDC120, potentially causing osteopetrosis.
PubMed: 37704070
DOI: 10.1016/j.bone.2023.116897 -
Orthodontics & Craniofacial Research Mar 2024To describe the clinical and radiographic oro-dental characteristics of patients with pycnodysostosis (PDO).
OBJECTIVES
To describe the clinical and radiographic oro-dental characteristics of patients with pycnodysostosis (PDO).
MATERIALS & METHODS
A short interview and clinical examination of seven patients with PDO were performed as well as assessment of the temporomandibular joints and masticatory muscles using the diagnostic criteria for temporomandibular disorders, DC-TMD form. A full set of records were taken including photos and intraoral scan. Finally, existing cone beam computed tomography (CBCT) images and radiographs were also studied.
RESULTS
All patients presented with bimaxillary micrognathia, five had a convex profile, and two had a straight profile. In addition, posterior open bite, Angle Class III molar relation with accompanying anterior crossbite and a grooved median palate were common findings. No patient showed symptoms of temporomandibular disorder (TMD) apart from some clicking. Finally, the main radiographic findings were the obtuse mandibular angle, the frontal bossing, the elongation of the coronoid/condylar process and the presence of hypercementosis with obliterated pulp chambers.
CONCLUSION
The examined patients with PDO were characterized by dental crowding, malocclusion (anterior crossbite, posterior open bite), hypercementosis, obliterated pulp chambers and deviations in mandibular morphology. In conclusion, patients with PDO have a specific need for dental and orthodontic monitoring with focus on crowding and posterior open bite. The patients will benefit from a long-term orthodontic plan including extractions.
PubMed: 38532649
DOI: 10.1111/ocr.12782 -
Journal of Ayub Medical College,... 2022Pycnodysostosis is a rare disease with very few reported cased all over the world. It was first described in 1963 by Maroteaux and Lamy. It is also known as...
Pycnodysostosis is a rare disease with very few reported cased all over the world. It was first described in 1963 by Maroteaux and Lamy. It is also known as Toulouse-Lautrec syndrome, after a French artist, Henri de Toulouse Lautrec. The affected gene, CTSK, was first isolated in 1996. It is an autosomal recessive osteochondrodysplasia, characterized by disrupted function of osteoclasts. Incidence of this disease is 1.7 per 1 million births with a male to female ratio of 1:1 30% cases arise from consanguineous marriages.
Topics: Consanguinity; Female; Humans; Male; Pycnodysostosis; Rare Diseases
PubMed: 35466658
DOI: 10.55519/JAMC-01-10336 -
Orthodontics & Craniofacial Research Nov 2021To perform a 3D cephalometric analysis of the craniofacial characteristics of patients with pycnodysostosis and compare this with a matched control group.
OBJECTIVE
To perform a 3D cephalometric analysis of the craniofacial characteristics of patients with pycnodysostosis and compare this with a matched control group.
SETTING AND SAMPLE POPULATION
This cross-sectional descriptive study assessed eight CBCTs obtained in patients with pycnodysostosis (4 males, 4 females, mean age: 31.8 years).
MATERIALS AND METHODS
Eight Danish patients with pycnodysostosis were seen at the University's Orthodontic Clinic. All CBCTs were analysed using the Mimics 21.0 software (Materialise®, Belgium) and compared with a control group (6 males, 8 females, mean age: 33.6 years).
RESULTS
Interclass correlation coefficient showed excellent intra-rater reliability (> 0.93). All measurements in the 3D cephalometric analysis revealed statistical significance (P < .05) when compared with controls. Patients with pycnodysostosis generally had significantly smaller maxilla in the transverse (P < .001), sagittal (P < .002) and vertical (P < .001) dimensions. Their mandibles were also smaller vertically (P < .001) and in length (P < .001). Gonial angle was significantly larger than controls (P < .001), while mandibular volumes were considerably smaller (P < .001).
CONCLUSION
Patients with pycnodysostosis have significantly smaller jaws in the vertical, sagittal and transverse dimensions compared with controls. Furthermore, the gonial angle was significantly larger, while the volume of the mandible was significantly smaller.
Topics: Adult; Cephalometry; Cross-Sectional Studies; Female; Humans; Male; Mandible; Maxilla; Pycnodysostosis; Reproducibility of Results
PubMed: 33608959
DOI: 10.1111/ocr.12479 -
European Journal of Medical Genetics Feb 2021Pycnodysostosis is a rare autosomal recessive osteosclerotic skeletal dysplasia caused by variants in the cathepsin K gene (CTSK). Clinical features include short...
BACKGROUND
Pycnodysostosis is a rare autosomal recessive osteosclerotic skeletal dysplasia caused by variants in the cathepsin K gene (CTSK). Clinical features include short stature, bone fragility, characteristic facial features and acro-osteolysis of the distal phalanges. Usually, patients suffer from multiple bone fractures. The purpose of this study was to describe the Danish population of pycnodysostosis patients with respect to genotype, phenotype and the prevalence of complications. We collected medical history, performed clinical examination, collected blood- and urine samples, performed dual-energy x-ray absorptiometry scan (DXA) and high-resolution peripheral quantitative computed tomography scan (HRpQCT) and obtained clinical photos. Information about complications, bone mineral density and bone markers in the blood were collected and analysed.
RESULTS
Ten patients with a median age of 32 years ranging from five to 51 years participated. The pycnodysostosis phenotype varied with respect to the number of bone fractures and degree of complications. DXA and HRpQCT showed high bone mineral density. A tendency of growth hormone treatment escalating growth and increasing final height was seen. A marker of bone resorption measured in blood was within normal range in nine patients and elevated in one patient. A novel pathogenic variant in CSTK causing pycnodysostosis was detected in two related patients. Moreover information about the patients' own health perception was reported. An example being they rated their mental health to be good despite multiple bone fractures.
CONCLUSION
This study provides information about genotypes and phenotypes in a Danish pycnodysostosis population. It reports new data about the complications such as bone fractures and it elucidates the levels of bone turnover markers as well as the density of the bones in one of the biggest cohort of pycnodysostosis patients ever published. An individualised approach to treatment in this patient group is necessary as the phenotype including complications varies between patients. Additional studies are needed to further understand genotype-phenotype correlations.
Topics: Adult; Bone Density; Cathepsin K; Child; Female; Growth Hormone; Humans; Male; Middle Aged; Mutation; Phenotype; Pycnodysostosis; Quality of Life
PubMed: 33429075
DOI: 10.1016/j.ejmg.2021.104135 -
Imaging Science in Dentistry Mar 2024Pycnodysostosis (PYCD), an autosomal recessive syndrome, is characterized by an imbalance in bone remodeling that produces various clinical and radiographic craniofacial... (Review)
Review
PURPOSE
Pycnodysostosis (PYCD), an autosomal recessive syndrome, is characterized by an imbalance in bone remodeling that produces various clinical and radiographic craniofacial manifestations. This review represents a systematic examination of these manifestations, as well as oral features associated with PYCD.
MATERIALS AND METHODS
A systematic review was conducted across 8 databases from February to March 2023. The search strategy focused on studies reporting cases of PYCD that examined the clinical and radiographic craniofacial and oral characteristics associated with this syndrome.
RESULTS
The review included 84 studies, encompassing a total of 179 cases of PYCD. More than half of the patients were female (55.3%), and the mean age was 14.7 years. Parental consanguinity was reported in 51.4% of the cases. The most common craniofacial clinical manifestation was a prominent nose, observed in 57.5% of cases. Radiographically, the most frequently reported craniofacial characteristics included the presence of an obtuse mandibular angle (84.3%) and frontal cranial bosses (82.1%). Clinical and radiographic examinations revealed oral alterations, with micrognathia present in 62.6% of patients and malocclusion in 59.2%. Among dental anomalies, tooth agenesis was the most commonly reported, affecting 15.6% of patients.
CONCLUSION
Understanding the clinical and radiographic craniofacial features of PYCD is crucial for dental professionals. This knowledge enables these clinicians to devise effective treatment plans and improve patient quality of life.
PubMed: 38571780
DOI: 10.5624/isd.20230191 -
Journal of Clinical Rheumatology :... Dec 2021
Topics: Fractures, Spontaneous; Humans; Pycnodysostosis
PubMed: 32976200
DOI: 10.1097/RHU.0000000000001554