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Anales de Pediatria Dec 2022Achondroplasia requieres multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life of people who suffer from it... (Review)
Review
Achondroplasia requieres multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life of people who suffer from it and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021). However, and despite these recommendations, there is currently a great worldwide variability in the management of people with achondroplasia, with medical, functional and psychosocial consequences in patients and their families. Therefore, it is essential to integrate these recommendations into daily clinical practice, taking into account the particular situation of each health system.
Topics: Child; Humans; United States; Quality of Life; Achondroplasia
PubMed: 36347803
DOI: 10.1016/j.anpede.2022.10.004 -
Hormone Research in Paediatrics 2020Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky... (Review)
Review
Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
Topics: Adult; Child; Diabetes Mellitus, Type 2; Dwarfism, Pituitary; Humans; Hypothyroidism; Practice Guidelines as Topic; Pseudohypoparathyroidism; Transition to Adult Care
PubMed: 32756064
DOI: 10.1159/000508985 -
Frontiers in Endocrinology 2022Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate... (Review)
Review
Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate thyroid hormones secretion as well as the impaired regulation of hypothalamus-pituitary-thyroid axis may lead to hypothyroxinemia. Two first weeks after birth are pivotal for brain neurons development, synaptogenesis and gliogenesis. The decreased level of thyroxine regardless of cause may lead to delayed mental development. Congenital hypothyroidism (CH) is a disorder highly prevalent in premature neonates and it originates from maternal factors, perinatal and labor complications, genetic abnormalities, thyroid malformations as well as side effects of medications and therapeutic actions. Because of that, the prevention is not fully attainable. CH manifests clinically in a few distinctive forms: primary, permanent or transient, and secondary. Their etiologies and implications bear little resemblance. Therefore, the exact diagnosis and differentiation between the subtypes of CH are crucial in order to plan an effective treatment. Hypothyroxinemia of prematurity indicates dynamic changes in thyroid hormone levels dependent on neonatal postmenstrual age, which directly affects patient's maintenance and wellbeing. The basis of a successful treatment relies on an early and accurate diagnosis. Neonatal screening is a recommended method of detecting CH in preterm newborns. The preferred approach involves testing serum TSH and fT4 concentrations and assessing their levels according to the cut-off values. The possible benefits also include the evaluation of CH subtype. Nevertheless, the reference range of thyroid hormones varies all around the world and impedes the introduction of universal testing recommendations. Unification of the methodology in neonatal screening would be advantageous for prevention and management of CH. Current guidelines recommend levothyroxine treatment of CH in preterm infants only when the diagnose is confirmed. Moreover, they underline the importance of the re-evaluation among preterm born infants due to the frequency of transient forms of hypothyroidism. However, results from multiple clinical trials are mixed and depend on the newborn's gestational age at birth. Some benefits of treatment are seen especially in the preterm infants born <29 weeks' gestation. The discrepancies among trials and guidelines create an urgent need to conduct more large sample size studies that could provide further analyses and consensus. This review summarizes the current state of knowledge on congenital hypothyroidism in preterm infants. We discuss screening and treatment options and demonstrate present challenges and controversies.
Topics: Congenital Hypothyroidism; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Neonatal Screening; Pregnancy; Thyroid Dysgenesis; Thyroxine
PubMed: 35370986
DOI: 10.3389/fendo.2022.860862 -
Bone Dec 2020Achondroplasia is the most common form of human dwarfism. The molecular basis of achondroplasia was elucidated in 1994 with the identification of the fibroblast growth... (Review)
Review
Achondroplasia is the most common form of human dwarfism. The molecular basis of achondroplasia was elucidated in 1994 with the identification of the fibroblast growth factor receptor 3 (FGFR3) as the causative gene. Missense mutations causing achondroplasia result in activation of FGFR3 and its downstream signaling pathways, disturbing chondrogenesis, osteogenesis, and long bone elongation. A more accurate understanding of the clinical and molecular aspects of achondroplasia has allowed new therapeutic approaches to be developed. These are based on: clear understanding of the natural history of the disease; proof-of-concept preclinical studies in mouse models; and the current state of knowledge regarding FGFR3 and related growth plate homeostatic pathways. This review provides a brief overview of the preclinical mouse models of achondroplasia that have led to new, non-surgical therapeutic strategies being assessed and applied to children with achondroplasia through pioneering clinical trials.
Topics: Achondroplasia; Animals; Chondrogenesis; Growth Plate; Mice; Mutation; Osteogenesis; Receptors, Fibroblast Growth Factor; Signal Transduction
PubMed: 32795681
DOI: 10.1016/j.bone.2020.115579 -
Nature Reviews. Endocrinology Mar 2022Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition... (Review)
Review
Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.
Topics: Achondroplasia; Consensus; Humans; Mutation; Osteogenesis; Quality of Life; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 34837063
DOI: 10.1038/s41574-021-00595-x -
Frontiers in Endocrinology 2022In standard 52-week phase III clinical trials, once weekly lonapegsomatropin, somatrogon and somapacitan have been found to yield non-inferior height velocities and... (Review)
Review
In standard 52-week phase III clinical trials, once weekly lonapegsomatropin, somatrogon and somapacitan have been found to yield non-inferior height velocities and similar safety profiles to daily GH (DGH) in children with pediatric growth hormone deficiency (PGHD). Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration (FDA) in August 2021 for the treatment of PGHD and has also been approved in other regions of the world. Somatrogon was approved for the treatment of PGHD beginning in some regions beginning in late 2021. Somapacitan was approved by the FDA for the treatment of Adult GHD in August 2020. The phase III clinical trial of somapacitan for the treatment of PGHD has been completed and demonstrated non-inferiority of somapacitan to DGH. New LAGH products may improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations and to understand how the non-physiological pharmacokinetic and pharmacodynamic profiles following administration of each LAGH product relate to short- and long-term safety and efficacy of LAGH therapy.
Topics: Adult; Child; Dwarfism, Pituitary; Growth Hormone; Histidine; Human Growth Hormone; Humans; Mannitol; Phenol; Quality of Life; United States
PubMed: 36072938
DOI: 10.3389/fendo.2022.980979 -
Current Opinion in Pediatrics Aug 2021Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening... (Review)
Review
PURPOSE OF REVIEW
Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening approach. The purpose of this review is to describe the optimal genetic approach for evaluating short stature, challenges of genetic testing, and recent advances in genetic testing for short stature.
RECENT FINDINGS
Genetic testing, such as karyotype, chromosomal microarray, targeted gene sequencing, or exome sequencing, has served to identify the underlying genetic causes of short stature. When determining which short stature patient would benefit from genetic evaluation, it is important to consider whether the patient would have a single identifiable genetic cause. Specific diagnoses permit clinicians to predict responses to growth hormone treatment, to understand the phenotypic spectrum, and to understand any associated co-morbidities.
SUMMARY
The continued progress in the field of genetics and enhanced capabilities provided by genetic testing methods expands the ability of physicians to evaluate children with short stature for underlying genetic defects. Continued effort is needed to elaborate new genetic causes of linear growth disorders, therefore, we expand the list of known genes for short stature, which will subsequently increase the rate of genetic diagnosis for children with short stature.
Topics: Body Height; Child; Dwarfism; Genetic Testing; Growth Disorders; Humans; Exome Sequencing
PubMed: 34101704
DOI: 10.1097/MOP.0000000000001033 -
The Journal of Clinical Endocrinology... Nov 2022Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD). (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD).
OBJECTIVE
To demonstrate efficacy and safety of somapacitan vs daily GH.
METHODS
REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535).
SETTING
Eighty-six sites across 20 countries.
PATIENTS
200 treatment-naïve patients were randomized and exposed.
INTERVENTIONS
Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously.
MAIN OUTCOME MEASURES
The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures.
RESULTS
Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar between treatment groups. At week 52, mean IGF-I SDS values were similar between treatment groups and within normal range (-2 to +2). Safety of somapacitan was consistent with the well-known daily GH profile. Low proportions of injection-site reactions were reported for somapacitan (5.3%) and daily GH (5.9%). Both treatments similarly reduced disease burden from baseline to week 52, whereas a greater treatment burden reduction was observed for somapacitan.
CONCLUSIONS
Similar efficacy for somapacitan compared to daily GH was demonstrated over 52 weeks of treatment with comparable safety and mean IGF-I SDS levels in treatment-naïve children with GHD.
Topics: Child; Humans; Insulin-Like Growth Factor I; Dwarfism, Pituitary; Human Growth Hormone; Growth Hormone
PubMed: 36062966
DOI: 10.1210/clinem/dgac513 -
International Journal of Molecular... May 2021Achondroplasia (ACH) is a disease caused by a missense mutation in the (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in... (Review)
Review
Achondroplasia (ACH) is a disease caused by a missense mutation in the (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in humans. The treatment of ACH is necessary and urgent because untreated achondroplasia has many complications, both orthopedic and neurological, which ultimately lead to disability. This review presents the current and potential pharmacological treatments for achondroplasia, highlighting the advantages and disadvantages of all the drugs that have been demonstrated in human and animal studies in different stages of clinical trials. The article includes the potential impacts of drugs on achondroplasia symptoms other than short stature, including their effects on spinal canal stenosis, the narrowing of the foramen magnum and the proportionality of body structure. Addressing these effects could significantly improve the quality of life of patients, possibly reducing the frequency and necessity of hospitalization and painful surgical procedures, which are currently the only therapeutic options used. The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.
Topics: Achondroplasia; Animals; Human Growth Hormone; Humans; Mutation, Missense; Natriuretic Peptide, C-Type; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 34070375
DOI: 10.3390/ijms22115573 -
Science (New York, N.Y.) Sep 2023CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies...
CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates. Using AlphaFold to screen for protein-protein interactions followed by experimental validation, we show that DONSON scaffolds a vertebrate pre-LC containing GINS, TOPBP1, and DNA pol ε. Our evidence suggests that DONSON docks the pre-LC onto MCM2-7, delivering GINS to its binding site in CMG. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. These results unify our understanding of eukaryotic replication initiation, implicate defective CMG assembly in microcephalic dwarfism, and illustrate how in silico protein-protein interaction screening accelerates mechanistic discovery.
Topics: Animals; Humans; Mice; Cell Cycle Proteins; DNA Replication; DNA-Binding Proteins; Minichromosome Maintenance Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Protein Interaction Mapping; Computer Simulation; Nuclear Proteins; Dwarfism; Microcephaly; Xenopus laevis
PubMed: 37590370
DOI: 10.1126/science.adi3448