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International Journal of Molecular... Nov 2022Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among... (Review)
Review
Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among people over 50 years old. We perform a systematic review of molecular and genetic mechanisms that cause SS. The five main mechanisms of SS were found to be ossification of the posterior longitudinal ligament (OPLL), hypertrophy and ossification of the ligamentum flavum (HLF/OLF), facet joint (FJ) osteoarthritis, herniation of the intervertebral disc (IVD), and achondroplasia. FJ osteoarthritis, OPLL, and HLF/OLFLF/OLF have all been associated with an over-abundance of transforming growth factor beta and genes related to this phenomenon. OPLL has also been associated with increased bone morphogenetic protein 2. FJ osteoarthritis is additionally associated with Wnt/β-catenin signaling and genes. IVD herniation is associated with collagen type I alpha 1 and 2 gene mutations and subsequent protein dysregulation. Finally, achondroplasia is associated with fibroblast growth factor receptor 3 gene mutations and fibroblast growth factor signaling. Although most publications lack data on a direct relationship between the mutation and SS formation, it is clear that genetics has a direct impact on the formation of any pathology, including SS. Further studies are necessary to understand the genetic and molecular changes associated with SS.
Topics: Humans; Middle Aged; Spinal Stenosis; Ossification of Posterior Longitudinal Ligament; Ligamentum Flavum; Achondroplasia; Osteoarthritis
PubMed: 36362274
DOI: 10.3390/ijms232113479 -
Hormone Research in Paediatrics 2023The link between the effects of recombinant human growth hormone (rhGH) therapy in patients with growth hormone deficiency (GHD) and Chiari malformation type I (CM-1) is...
BACKGROUND
The link between the effects of recombinant human growth hormone (rhGH) therapy in patients with growth hormone deficiency (GHD) and Chiari malformation type I (CM-1) is controversial.
SUMMARY
We report the case of a patient with an unusual association of GHD due to ectopic posterior pituitary and CM-1. Our patient developed a headache and worsening of CM-1 after the initiation of rhGH therapy. Following an atlo-occipital decompression surgery, the patient was able to resume therapy with a marked growth improvement. Based on this observation, we provide a systematic review of the current literature about these two pathologies.
KEY MESSAGES
A careful follow-up of all patients with CM-1 treated with GH is mandatory, paying particular attention to the appearance of any neurological signs and symptoms.
Topics: Humans; Arnold-Chiari Malformation; Human Growth Hormone; Dwarfism, Pituitary; Recombinant Proteins
PubMed: 36001954
DOI: 10.1159/000526617 -
Frontiers in Endocrinology 2022Pediatric patients with growth hormone deficiency (GHD) are currently treated with daily injections of recombinant human growth hormone (rhGH) to promote linear growth...
Treatment Adherence to Injectable Treatments in Pediatric Growth Hormone Deficiency Compared With Injectable Treatments in Other Chronic Pediatric Conditions: A Systematic Literature Review.
BACKGROUND
Pediatric patients with growth hormone deficiency (GHD) are currently treated with daily injections of recombinant human growth hormone (rhGH) to promote linear growth and enable attainment of normal adult height. One of the main reasons for suboptimal growth during rhGH therapy is non-adherence to treatment. The objective of this systematic literature review was to examine the recent literature on pediatric adherence to injectable treatments for chronic conditions (focusing on rhGH) to characterize levels of adherence and identify the factors/barriers associated with adherence.
METHODS
The Embase and MEDLINE databases (January 2015-October 2020) were searched to identify publications describing studies of pediatric patients (aged ≤17 years) with GHD and other chronic conditions requiring daily or weekly injectable treatments; a similar targeted search of Chinese literature was also performed. Adherence data were extracted from the included studies and summarized. Risk of bias was determined using the Cochrane Risk of Bias tool 2 or the Newcastle-Ottawa Scale.
RESULTS
A total of 23 publications were included, with all publications except for one (multiple sclerosis) focused on pediatric GHD studies: there were two clinical trials, 18 observational studies and three survey studies. Study sample sizes ranged from 30 to 13,553 patients (median: 95 patients). The definition of adherence varied between studies and included mean adherence rate, median adherence rate, and the percentage of patients within pre-specified adherence categories. Of the publications assessing adherence to daily rhGH, 11 studies reported 12-month mean adherence rate (range: 73.3%- 95.3%) and eight studies reported median adherence (range: 91%- 99.2%). The barriers to treatment adherence identified included self-administration, increased administration frequency, age (adolescence), longer treatment duration, device design, and insufficient family education, awareness, and/or engagement. Recommendations for increasing adherence included using adherence reminder tools, increasing patient engagement/education, and improving injection device design and drug product.
CONCLUSIONS
Adherence to rhGH treatment was high (>80%) for many studies, though comparability between studies was limited given the substantial heterogeneity in the way adherence was defined, measured, and reported. To address this heterogeneity, we recommend standardizing how adherence is defined and reported and encourage the use of standardized study designs and outcome measures.
Topics: Adolescent; Adult; Child; Dwarfism, Pituitary; Human Growth Hormone; Humans; Recombinant Proteins; Surveys and Questionnaires; Treatment Adherence and Compliance
PubMed: 35299969
DOI: 10.3389/fendo.2022.795224 -
Orphanet Journal of Rare Diseases Jan 2022Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene. Recent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene. Recent advances in drug therapy for ACH have highlighted the importance of elucidating the natural history and socioeconomic burden of this condition. Recognition that there are many potential issues for the patient with ACH is the first step in planning cost-effective interventions in Latin America (LATAM), a vast geographic territory comprising countries with multicultural characteristics and wide socioeconomic differences. We conducted a systematic literature review to characterize the impact of ACH on affected individuals and on healthcare resources in LATAM countries.
METHODS
Searches of the global medical literature as well as regional and local medical literature up to August 2020. Observational studies on patients with ACH from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias.
RESULTS
Fifty-three unique studies (28 case series and cross-sectional studies and 25 case reports) including data on 1604 patients were eligible. Of these studies, 11 had data available for meta-analysis. Both premature mortality and all-cause mortality in the pooled studies was 15% [95% Confidence Interval (CI) 1.0E-3 to 0.47; I = 82.9%, p = 0.0029; three studies, n = 99 patients]. Frequency of cardio-respiratory-metabolic disorders was 17% [95% CI 0.04-0.37; I = 90.3%, p < 0.0001; four studies, n = 230 patients]; nervous system disorders was 18% [95% CI 0.07-0.33; I = 84.6%, p < 0.0001; six studies, n = 262 patients]; ear, nose, throat and speech disorders was 32% [95% CI 0.18-0.48; I = 73.4%, p = 0.0046; five studies, n = 183 patients]; and spinal issues including stenosis, compression and associated pain was 24% [95% CI 0.07-0.47; I = 91.3%, p < 0.0001; five studies, n = 235 patients].
CONCLUSIONS
There is currently evidence of high clinical burden in ACH patients in LATAM countries. Establishing the impact of ACH provides the necessary foundation for planning tailored and effective public health interventions.
Topics: Achondroplasia; Cross-Sectional Studies; Humans; Latin America
PubMed: 34983594
DOI: 10.1186/s13023-021-02142-3 -
Inquiry : a Journal of Medical Care... 2021Primary congenital hypothyroidism (CH) is a common endocrine and metabolic disease. Various genetic factors, including the thyroid hormone receptor (TSHR), play an...
BACKGROUND
Primary congenital hypothyroidism (CH) is a common endocrine and metabolic disease. Various genetic factors, including the thyroid hormone receptor (TSHR), play an important role in CH.
AIM
To explore the occurrence of pathogenic variants in CH.
METHODS
We searched published articles in PubMed, Web of Science, and Cochrane Library databases, from the establishment of the database to September 26, 2021. Studies with sequencing partial or full exons of in CH patients were included. Gene polymorphism was excluded.
RESULTS
A total of 66 articles (44 case-control studies and 22 case reports) were selected from the database. Though case-control studies, we found the incidence of pathogenic variants were not rare (range from 0% to 30.6%) and varied greatly in different countries and race. The pathogenic genotypes varied in different regions. All the variants were "loss-of-function" mutations, in which the p.(Arg450His) variant was the most common variant. In addition, we analyzed the case reports and found that CH patients with a family genetic background expressed homozygous genotypes. Homozygotes had more obvious symptoms of hypothyroidism and higher risk of comorbidities than heterozygotes.
CONCLUSION
Pathogenic variants are not uncommon cause of the CH, especially in the Arabs. The role of gene detection in the treatment of children with CH needs to be further studied.
Topics: Child; Congenital Hypothyroidism; Humans; Mutation; Receptors, Thyroid Hormone; Receptors, Thyrotropin
PubMed: 34919466
DOI: 10.1177/00469580211067943 -
Child's Nervous System : ChNS :... Dec 2021To systematically review reported cases of Seckel syndrome (SS) and point out cases associated with central nervous system (CNS) vasculopathy and provide a summary of...
PURPOSE
To systematically review reported cases of Seckel syndrome (SS) and point out cases associated with central nervous system (CNS) vasculopathy and provide a summary of their clinical presentation, management, and outcomes including our illustrative case.
METHODS
We conducted a search on the MEDLINE, PubMed, Google Scholar, and Cochrane databases using the keywords "Seckel + syndrome." We identified 127 related articles reporting 252 cases of SS apart from our case. Moreover, we searched for SS cases with CNS vasculopathies from the same databases. We identified 7 related articles reporting 7 cases of CNS vasculopathies in SS patients.
RESULTS
The overall rate of CNS vasculopathy in SS patients is 3.16% (n = 8/253), where moyamoya disease (MMD) accounted for 1.97%. The mean age is 13.5 years (6-19 years), with equal gender distribution (M:F, 1:1). The most common presenting symptoms were headache and seizure followed by weakness or coma. Aneurysms were mostly located in the basilar artery, middle cerebral artery, and internal carotid artery, respectively. Regardless of the management approach, 50% of the cases sustained mild-moderate neurological deficit, 37.5% have died, and 12.5% sustained no deficit.
CONCLUSION
A high index of suspicion should be maintained in (SS) patients, and MMD should be part of the differential diagnosis. Prevalence of CNS vasculopathy in SS is 3.16% with a much higher prevalence of MMD compared to the general population. Screening for cerebral vasculopathy in SS is justifiable especially in centers that have good resources. Further data are still needed to identify the most appropriate management plan in these cases.
Topics: Adolescent; Central Nervous System; Cerebrovascular Disorders; Dwarfism; Humans; Microcephaly; Moyamoya Disease
PubMed: 34345934
DOI: 10.1007/s00381-021-05284-8 -
Annals of Global Health Jun 2021Blood transfusion is a traditional treatment for β-thalassemia (β-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Blood transfusion is a traditional treatment for β-thalassemia (β-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in parenchymal tissue organs and endocrine glands that cause their dysfunctions as the iron regulatory system can't excrete excess iron from the bloodstream.
OBJECTIVE
To evaluate the prevalence of iron-related complications (short stature, growth retardation, and growth hormone deficiency) in β-thalassemia major (TM) patients.
METHODS
We performed an electronic search in PubMed, Scopus, and Web of Sciences to evaluate the prevalence of growth hormone impairment in β-thalassemia major (TM) patients worldwide. Qualities of eligible studies were assessed by the Joanna Briggs Institute checklist for the prevalence study. We used Comprehensive Meta-Analysis (Version 2) to calculate the event rate with 95% CIs, using a random-effects model for all analyses.
FINDINGS
Seventy-four studies were included from five continents between 1978 and 2019; 70.27% (Asia), 16.21% (Europe), 6.75% (Africa), 2.70% (America), 1.35% (Oceania), and 2.70% (Multicenter). The overall mean age of the participants was about 14 years. The pooled prevalence of short stature (ST) was 48.9% (95% CI 35.3-62.6) and in male was higher than female (61.9%, 95% CI 53.4-69.7 vs. 50.9%, CI 41.8-59.9). The pooled prevalence of growth retardation (GR) was 41.1% and in male was higher than in female (51.6%, 95% CI 17.8-84 vs. 33.1%, CI 9.4-70.2). The pooled prevalence of growth hormone deficiency (GHD) was 26.6% (95% CI 16-40.8).
CONCLUSION
Our study revealed that near half of thalassemia patients suffer from growth impairments. However, regular evaluation of serum ferritin levels, close monitoring in a proper institute, suitable and acceptable treatment methods besides regular chelation therapy could significantly reduce the patients' complications.
Topics: Adolescent; Blood Transfusion; Body Height; Dwarfism; Endocrine System Diseases; Female; Humans; Iron Overload; Male; beta-Thalassemia
PubMed: 34164261
DOI: 10.5334/aogh.3184 -
Growth Hormone & IGF Research :... 2021We sought to obtain a better understanding of the burden of short stature using a systematic literature review.
OBJECTIVE
We sought to obtain a better understanding of the burden of short stature using a systematic literature review.
METHODS
Studies of the burden of short stature, of any cause in adults and children, were searched using Embase, MEDLINE and Cochrane databases in April 2020, capturing publications from 2008 onwards. Case series and populations with adult-onset growth hormone deficiency (GHD) were excluded.
RESULTS
Of 1684 publications identified, 41 studies (33 in children, 8 in adults) were included. All studies assessed human burden. Most study populations in children included short stature due to GHD, idiopathic short stature (ISS) and short stature after being born small for gestational age (SGA). In these populations, four studies showed that quality of life (QoL) in children with short stature was significantly worse than in children with normal stature. A significant association between QoL and short stature was observed in children with chronic kidney disease (CKD) (3 studies), achondroplasia (1 study) and transfusion-dependent β-thalassaemia (1 study), and in samples with mixed causes of short stature (3 studies). Three studies (one in GHD/ISS/SGA and two in CKD) found no significant association between short stature and QoL, and several studies did not report statistical significance. Approximately half of adult studies showed that QoL was reduced with short stature, and the other half showed no association. Two studies, one in adults with Prader-Willi syndrome and one in children with GHD, suggested a potential association between short stature and poorer cognitive outcomes. Three studies demonstrated an increased caregiver burden in parents of children with short stature.
CONCLUSIONS
Evidence suggests that, compared with those with normal stature, children and adults with short stature of any cause may experience poorer QoL. Further research could extend our understanding of the human burden in this field.
Topics: Achondroplasia; Adult; Body Height; Caregiver Burden; Child; Cost of Illness; Growth Disorders; Human Growth Hormone; Humans; Infant, Small for Gestational Age; Parents; Quality of Life; Renal Insufficiency, Chronic; beta-Thalassemia
PubMed: 33975197
DOI: 10.1016/j.ghir.2021.101392 -
Genetics Research 2021Aarskog-Scott syndrome is a genetically and clinically heterogeneous rare condition caused by a pathogenic variant in the FGD1 gene. A systematic review was carried out... (Review)
Review
Aarskog-Scott syndrome is a genetically and clinically heterogeneous rare condition caused by a pathogenic variant in the FGD1 gene. A systematic review was carried out to analyse the prevalence of clinical manifestations found in patients, as well as to evaluate the genotype-phenotype correlation. The results obtained show that clinical findings of the craniofacial, orthopaedic, and genitourinary tract correspond to the highest scores of prevalence. The authors reclassified the primary, secondary, and additional criteria based on their prevalence. Furthermore, it was possible to observe, in accordance with previous reports, that the reported phenotypes do not present a direct relation to the underlying genotypes.
Topics: Dwarfism; Face; Genetic Association Studies; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Male; Mutation; Prevalence
PubMed: 33762894
DOI: 10.1155/2021/6652957 -
American Journal of Medical Genetics.... Oct 2020Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This... (Meta-Analysis)
Meta-Analysis
Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This systematic literature review and meta-analysis was conducted to better estimate worldwide achondroplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched, complemented by manual searching, for peer-reviewed articles published between 1950 and 2019. Eligible articles were identified by two independent researchers using predefined selection criteria. Birth prevalence estimates were extracted for analysis, and the quality of evidence was assessed. A meta-analysis using a quality effects approach based on the inverse variance fixed effect model was conducted. The search identified 955 unique articles, of which 52 were eligible and included. Based on the meta-analysis, the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000. Substantial regional variation was observed with a considerably higher birth prevalence reported in North Africa and the Middle East compared to other regions, particularly Europe and the Americas. Higher birth prevalence was also reported in specialized care settings. Significant heterogeneity (Higgins I of 84.3) was present and some indication of publication bias was detected, based on visual asymmetry of the Doi plot with a Furuya-Kanamori index of 2.73. Analysis of pooled data from the current literature yields a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with considerable regional variation. Careful interpretation of these findings is advised as included studies are of broadly varying methodological quality.
Topics: Achondroplasia; Europe; Female; Humans; Male; Middle East
PubMed: 32803853
DOI: 10.1002/ajmg.a.61787