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Clinical Oral Investigations Oct 2023Skeletal dysplasia (SD) comprises more than 450 separate disorders. We hypothesized that their dental features would be distinctive and investigated the tooth...
OBJECTIVE
Skeletal dysplasia (SD) comprises more than 450 separate disorders. We hypothesized that their dental features would be distinctive and investigated the tooth characteristics of four patients with different SDs.
MATERIAL AND METHODS
Four SD patients with molecularly confirmed diagnoses, Pt-1 acromicric dysplasia, Pt-2 hypophosphatasia and hypochondroplasia, Pt-3 cleidocranial dysplasia, and Pt-4 achondroplasia, were recruited. A tooth from each patient was evaluated for mineral density (micro-computerized tomography), surface roughness (surface profilometer), microhardness, mineral contents (energy-dispersive X-ray), and ultrastructure (scanning electron microscopy and histology), and compared with three tooth-type matched controls.
RESULTS
Pt-1 and Pt-3 had several unerupted teeth. Pt-2 had an intact-root-exfoliated tooth at 2 years old. The lingual surfaces of the patients' teeth were significantly smoother, while their buccal surfaces were rougher, than controls, except for Pt-1's buccal surface. The patients' teeth exhibited deep grooves around the enamel prisms and rough intertubular dentin. Pt-3 demonstrated a flat dentinoenamel junction and Pt-2 had an enlarged pulp, barely detectable cementum layer, and ill-defined cemento-dentinal junction. Reduced microhardnesses in enamel, dentin, and both layers were observed in Pt-3, Pt-4, and Pt-1, respectively. Pt-1 showed reduced Ca/P ratio in dentin, while both enamel and dentin of Pt-2 and Pt-3 showed reduced Ca/P ratio.
CONCLUSION
Each SD has distinctive dental characteristics with changes in surface roughness, ultrastructure, and mineral composition of dental hard tissues.
CLINICAL RELEVANCE
In this era of precision dentistry, identifying the specific potential dental problems for each patient with SD would help personalize dental management guidelines.
PubMed: 37548766
DOI: 10.1007/s00784-023-05194-w -
Bone Oct 2023Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter...
Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification.
Topics: Animals; Anion Transport Proteins; Sulfate Transporters; Achondroplasia; Glycosaminoglycans; Biomarkers; Collagen; Sulfates
PubMed: 37454964
DOI: 10.1016/j.bone.2023.116838 -
European Journal of Medical Genetics Nov 2023The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical,...
The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia.
Topics: Adolescent; Humans; Child; Adult; Quality of Life; Chronic Pain; Achondroplasia
PubMed: 37758167
DOI: 10.1016/j.ejmg.2023.104850 -
Annals of Neurology Dec 2023Rare variants of CCNK (cyclin K) give rise to a syndrome with intellectual disability. The purpose of this study was to describe the genotype-phenotype spectrum of...
OBJECTIVE
Rare variants of CCNK (cyclin K) give rise to a syndrome with intellectual disability. The purpose of this study was to describe the genotype-phenotype spectrum of CCNK-related syndrome and the underlying molecular mechanisms of pathogenesis.
METHODS
We identified a number of de novo CCNK variants in unrelated patients. We generated patient-induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) as disease models. In addition, we constructed NPC-specific Ccnk knockout (KO) mice and performed molecular and morphological analyses.
RESULTS
We identified 2 new patients harboring CCNK missense variants and followed-up 3 previous reported patients, which constitute the largest patient population analysis of the disease. We demonstrate that both the patient-derived NPC models and the Ccnk KO mouse displayed deficient NPC proliferation and enhanced apoptotic cell death. RNA sequencing analyses of these NPC models uncovered transcriptomic signatures unique to CCNK-related syndrome, revealing significant changes in genes, including WNT5A, critical for progenitor proliferation and cell death. Further, to confirm WNT5A's role, we conducted rescue experiments using NPC and mouse models. We found that a Wnt5a inhibitor significantly increased proliferation and reduced apoptosis in NPCs derived from patients with CCNK-related syndrome and NPCs in the developing cortex of Ccnk KO mice.
INTERPRETATION
We discussed the genotype-phenotype relationship of CCNK-related syndrome. Importantly, we demonstrated that CCNK plays critical roles in NPC proliferation and NPC apoptosis in vivo and in vitro. Together, our study highlights that Wnt5a may serve as a promising therapeutic target for the disease intervention. ANN NEUROL 2023;94:1136-1154.
Topics: Mice; Animals; Humans; Neural Stem Cells; Signal Transduction; Cyclins; Intellectual Disability; Apoptosis
PubMed: 37597256
DOI: 10.1002/ana.26766 -
Journal of Neurosurgery. Pediatrics Dec 2023The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal...
OBJECTIVE
The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal dysplasia centers.
METHODS
The Achondroplasia Natural History Study (CLARITY) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the US from 1957 to 2017. Data were entered and stored in a REDCap database and included surgeries with indications and complications, medical diagnoses, and radiographic information.
RESULTS
A total of 1374 patients with achondroplasia were included in this study. Of these, 123 (9%) patients underwent treatment of hydrocephalus at a median age of 14.4 months. There was considerable variation in the percentage of patients treated for hydrocephalus by center and decade of birth, ranging from 0% to 28%, although in the most recent decade, all centers treated less than 6% of their patients, with an average of 2.9% across all centers. Undergoing a cervicomedullary decompression (CMD) was a strong predictor for treatment of hydrocephalus (OR 5.8, 95% CI 3.9-8.4), although that association has disappeared in those born since 2010 (OR 1.1, 95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with endoscopic third ventriculostomy (ETV) has become more common; it was used as the first line of treatment in 38% of patients in the most recent decade. Kaplan-Meier analysis suggests that a single ETV will treat hydrocephalus in roughly half of these patients.
CONCLUSIONS
While many children with achondroplasia have features of hydrocephalus with enlarged intracranial CSF spaces and relative macrocephaly, treatment of hydrocephalus in achondroplasia patients has become relatively uncommon in the last 20 years. Historically, there was a significant association between symptomatic foramen magnum stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor with the recognition that CMD alone will treat hydrocephalus in some patients. Despite good experimental data demonstrating that hydrocephalus in achondroplasia is best understood as communicating in nature, ETV appears to be reasonably successful in certain patients and should be considered an option in selected patients.
Topics: Child; Humans; Infant; Treatment Outcome; Hydrocephalus; Achondroplasia; Ventriculostomy; Third Ventricle; Neuroendoscopy; Retrospective Studies
PubMed: 37877951
DOI: 10.3171/2023.7.PEDS2354 -
Brain & Spine 2023Lumbar spinal stenosis (LSS) is the main problem for adult achondroplasia (Ach). Sagittal imbalance of the spine may play a role in LSS causing neurogenic claudication...
INTRODUCTION
Lumbar spinal stenosis (LSS) is the main problem for adult achondroplasia (Ach). Sagittal imbalance of the spine may play a role in LSS causing neurogenic claudication in Ach patients.
RESEARCH QUESTION
The purpose of this study is to describe the sagittal balance parameters in Ach patients.
METHODS
A single-centre retrospective study of Ach patients that visited the Neurosurgery outpatient clinic of the Leiden University Medical Centre (LUMC) between 2019 and 2022 was performed. We defined sagittal imbalance by a C7 sagittal vertical axis (SVA) of more than 10 mm.
RESULTS
There were 13 patients with a spinal sagittal imbalance and 15 patients with a balanced spine. In both groups, the sacral slope (SS) was comparable (45.0° and 49.0°, p = 0.305), but exceeding the mean SS in non achondroplasts (38.0°). Lumbar lordosis (LL) was more pronounced in the balanced group (55.5° versus 41.7°, p = 0.019), and positively correlated to SS in contrast to the absence of a correlation in the imbalanced group. Thoracolumbar kyphosis (TLK) was increased comparably in both groups (19.6° and 24.6°), and far exceeding the TLK in non achondroplasts (circa 0°), and in both groups negatively correlated with the LL, although not enough to compensate for the smaller LL in the imbalanced group.
CONCLUSION
Only if the LL compensates for both a larger SS and TLK, the Ach spine can maintain sagittal balance. An explanation for the current data can be the failure of the lumbar spine to give sufficient lordosis due to degenerative processes.
PubMed: 38021024
DOI: 10.1016/j.bas.2023.102670 -
Deutsches Arzteblatt International Feb 20243% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. (Review)
Review
BACKGROUND
3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders.
METHODS
This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience.
RESULTS
Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management.
CONCLUSION
There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.
Topics: Child; Adult; Humans; Adolescent; Insulin-Like Growth Factor I; Human Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Physicians
PubMed: 38051162
DOI: 10.3238/arztebl.m2023.0247 -
Psychiatric Genetics Dec 2023Achondroplasia and autism spectrum disorder (ASD) are two genetically based disorders. The coexistence of autism with chromosomal abnormalities such as Down syndrome,... (Review)
Review
Achondroplasia and autism spectrum disorder (ASD) are two genetically based disorders. The coexistence of autism with chromosomal abnormalities such as Down syndrome, monogenic syndromes such as tuberous sclerosis, Fragile X, and Rett syndrome, and microdeletion syndromes such as Phelan-McDermid syndrome helps to shed light on the genetic basis of autism spectrum disorder. The association between ASD and achondroplasia has been reported twice in the literature. In this article, we report Turkish patients who were born as identical twins from IVF pregnancy of 34 and 36-year-old parents, clinically and molecularly diagnosed with achondroplasia, and diagnosed with ASD at the age of 39 months. Our case is the first twin patient with the coexistence of achondroplasia and autism. We discuss environmental and genetic factors contributing to the development of ASD.
Topics: Child, Preschool; Humans; Autism Spectrum Disorder; Chromosome Deletion; Chromosome Disorders; Syndrome; Diseases in Twins
PubMed: 37706508
DOI: 10.1097/YPG.0000000000000350 -
Spine Deformity Nov 2023Thoracolumbar kyphosis (TLK) is common in children with achondroplasia and resolves in 90% by 10 years of age. Our purpose was to describe the natural progression of...
PURPOSE
Thoracolumbar kyphosis (TLK) is common in children with achondroplasia and resolves in 90% by 10 years of age. Our purpose was to describe the natural progression of TLK in a cohort of pre-walking children with achondroplasia.
METHODS
A single-center, retrospective review identified 62 children (32 male, 30 female) with achondroplasia. Clinical information and sagittal spinopelvic parameters were collected. The children were divided into positive pelvic tilt (PT) and negative PT. All parents were routinely counseled about unsupported sitting.
RESULTS
Spontaneous resolution rate was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% at 10 years of age. None of the children required posterior spinal decompression and fusion for progressive deformity or symptomatic spinal stenosis. At 1-year post-walking, the negative PT group had a higher sacral slope (p = 0.006), higher lumbar lordosis (p < 0.001), and lower pelvic incidence (p < 0.001). This relationship remained constant up to 10 years of age, and there was no association with TLK.
CONCLUSION
In this largest series to date, spontaneous resolution of TLK in children with achondroplasia was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% in children followed to 10 years of age. With early identification and regular follow-up with patient education, no patient in this series required treatment or developed symptomatic spinal stenosis. While not predictive of resolution of TLK, the dichotomous presentation of PT in young children with achondroplasia persists at 5 and 10 years of age and reliably predicts the spinopelvic parameters.
LEVEL OF EVIDENCE
III-retrospective comparative study.
PubMed: 37493935
DOI: 10.1007/s43390-023-00733-7 -
Results and complications of bilateral limb lengthening in achondroplasia: a retrospective analysis.Frontiers in Pediatrics 2023Achondroplasia is one of the main causes of disharmonic dwarfism. Patients with achondroplasia might have physical and psychological limitations due to their...
BACKGROUND
Achondroplasia is one of the main causes of disharmonic dwarfism. Patients with achondroplasia might have physical and psychological limitations due to their disproportionate stature. Surgical limb lengthening is the only practical option available to achieve a stature comparable to normal population range. The purpose of this study is to analyze results and complications of our lengthening protocol.
METHODS
A retrospective analysis was performed on 33 patients with achondroplasia (21 females and 12 males) undergoing simultaneous bilateral tibia or femur lengthening in four surgical stages from 2017 to 2021 (46 lengthening procedures, with a total of 56 tibias and 36 femurs). For each patient, patients' characteristics and antero-posterior and lateral radiographs were obtained. The following parameters were analyzed: duration of lengthening with external fixator, amount of lengthening, complications or events that influenced outcomes and the healing index (HI).
RESULTS
The average tibial and femoral gain was 7.9 cm and 6.9 cm, respectively. The tibiae achieved better results than the femurs ( = 0.005). Nineteen complications were reported for 92 segments (20.7%), and the variables influencing complications were: step ( = 0.002) and fixation duration ( = 0.061).
CONCLUSIONS
Bilateral parallel lower limb lengthening in four surgical steps may be a viable technique in patients with achondroplasia.
PubMed: 38027309
DOI: 10.3389/fped.2023.1281099