Materiały źródłowe

• #1 Restricted growth (dwarfism)

  https://www.nhs.uk/conditions/restricted-growth/

  Restricted growth is usually genetic, meaning it is caused by the genes passed on from your parents. […] Restricted growth can also be caused by hormone deficiencies or poor diet (malnutrition). […] Causes of restricted growth include a lack of the hormone that controls growth (growth hormone deficiency), rare genetic conditions such as Turner syndrome, Noonan syndrome and Prader-Willi syndrome, and problems affecting bone development (skeletal dysplasias), such as achondroplasia. […] Growth hormone is used to increase height in children with restricted growth, or children who are not growing as expected for their age. […] It can treat many different types of restricted growth, but it is not normally used to treat a problem with bone development (such as achondroplasia and other skeletal dysplasias). […] How well treatment works depends on what’s causing the restricted growth.

• #2 What Is Dwarfism? – Klarity Health Library

  https://my.klarity.health/what-is-dwarfism/

  Dwarfism is a condition characterised by restricted growth, which results in unusually short stature. […] Achondroplasia is caused by an autosomal dominant genetic mutation in the fibroblast growth factor receptor 3 (fgfr3) gene which is responsible for regulating bone growth. […] Restricted growth resulting in dwarfism can be caused by various medical conditions that may lead to either proportional or disproportional dwarfism.

• #3 Molecular Defects and Cellular Dysfunctions in Restricted Growth Conditions | IntechOpen

  https://www.intechopen.com/chapters/51770

  Restricted growth (RG) or dwarfism is a varied phenotype ascribable to many different causes, most of which are genetic. […] Conditions associated with disproportionate short stature (DSS) are usually caused by de novo dominant mutations in genes coding for proteins involved in cartilage/bone development. […] Causative mutations, consequent to cellular dysfunctions, genotype-to-phenotype correlations in RG conditions such as achondroplasia, hypochondroplasia, thanatophoric dysplasia, severe achondroplasia with delay in development and acanthosis nigricans, pseudoachondroplasia, multiple epiphyseal dysplasia, diastrophic dysplasia, achondrogenesis, and osteogenesis imperfecta, are discussed in this chapter. […] Dysfunctions in any of the multiple players in this complex process may cause genetic growth disorders.

• #4 Molecular Defects and Cellular Dysfunctions in Restricted Growth Conditions | IntechOpen

  https://www.intechopen.com/chapters/51770?jwsource=cl

  Restricted growth (RG) or dwarfism is a varied phenotype ascribable to many different causes, most of which are genetic. […] Conditions associated with disproportionate short stature (DSS) are usually caused by de novo dominant mutations in genes coding for proteins involved in cartilage/bone development. […] Causative mutations, consequent to cellular dysfunctions, genotype-to-phenotype correlations in RG conditions such as achondroplasia, hypochondroplasia, thanatophoric dysplasia, severe achondroplasia with delay in development and acanthosis nigricans, pseudoachondroplasia, multiple epiphyseal dysplasia, diastrophic dysplasia, achondrogenesis, and osteogenesis imperfecta, are discussed in this chapter. […] Dysfunctions in any of the multiple players in this complex process may cause genetic growth disorders.

• #5 Achondroplasia: a comprehensive clinical review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0972-6

  Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). […] The mutation that results in achondroplasia is a gain of function mutation rather than an inactivating mutation. It most likely results in ligand independent activation of FGFR3. […] Virtually all of the clinical features and medical problems of achondroplasia arise because of the consequent abnormalities of cartilaginous bone growth either directly, or because of disproportionate growth of cartilaginous bone compared with nearby structures derived from other tissues. […] The likely molecular explanation for this increased risk is discussed below. […] The full cup, then, results in a net slow down signal inside relevant cells. […] This specific mutation is at least 500- or 1000-fold more frequent than expected.

• #6 Molecular Defects and Cellular Dysfunctions in Restricted Growth Conditions | IntechOpen

  https://www.intechopen.com/chapters/51770?jwsource=cl

  Several signaling effectors fine-tune the transition from resting to hypertrophic chondrocytes, among which are FGFs. […] Dwarfism-associated chondrodysplasias are all characterized by gain-of-function mutations that render FGFR3 constitutively active, but with graded levels of signaling potential. […] Achondroplasia (ACH, OMIM #100800) is the most common among human chondrodysplasias and occurs with an incidence of 1:1030,000 live births. […] This form of dwarfism is caused by point mutations in FGFR3 characterized by autosomal dominant inheritance, as first discovered in the 1990s when heterozygous mutations were mapped to FGFR3 locus on chromosome 4. […] The Gly380Arg mutation falls in the transmembrane region causing a gain in receptor function, which reduces growth plate activity.

• #7 Achondroplasia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/achondroplasia/

  Achondroplasia is the most common form of short-limbed dwarfism. […] Variants (also called mutations) in the FGFR3 gene cause achondroplasia. The FGFR3 gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. […] These variants cause the FGFR3 protein to be overly active, which interferes with skeletal development and leads to the disturbances in bone growth seen with this disorder. […] Individuals who inherit two altered copies of the FGFR3 gene typically have a severe form of achondroplasia that causes extreme shortening of the bones and an underdeveloped rib cage.

• #8 Achondroplasia – Wikipedia

  https://en.wikipedia.org/wiki/Achondroplasia

  Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive. Achondroplasia results in impaired endochondral bone growth (bone growth within cartilage). The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. […] When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height. […] In normal development, FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active, and this leads to severely shortened bones. This is an example of a gain of function mutation. The effect is genetically dominant, with one variant of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or shortly after birth. This occurs due to respiratory failure from an underdeveloped ribcage.

• #9 Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

  https://www.mdpi.com/1422-0067/22/11/5573

  The process of discovering new facts about achondroplasia has not followed the sequence of chapters in medical textbooks. Scientists were first able to recognize and name this disease and learned about additional symptoms, but only with the development of genetic engineering were they then able to identify its main cause. In 1994, there was a breakthrough. First, Le Merrer et al., Velinov et al. and Francomano et al. determined that the achondroplasia gene was located on 4p16.3, and then, two research groups, those of Shiang et al. and Rousseau, identified mutations in the FGFR3 gene, which are responsible for the majority of achondroplasia cases. In 99% of cases, the mutation is at position 1138 and is a single substitution from G to A (guanine to adenine) or G to C (guanine to cytosine), both of which change arginine to glycine at position G380R in the transmembrane part of the receptor. The result of this mutation is the excessive activation of FGFR3, which, in turn, inhibits the development of cartilage cells while also disrupting the bone growth plate. Proper bone development is preserved due to the harmony between the multiplication and maturation of cells and their apoptosis.

• #10 Achondroplasia-Dwarfism—About

  https://www.beineinu.org/medical-information/conditions-and-syndromes/52-achondroplasia/151-achondroplasia-dwarfism-about

  Achondroplasia dwarfism is a type of autosomal dominant genetic disorder that is a common cause of dwarfism. Dwarfism is a result of autosomal dominant mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation. FGFR3 normally has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. […] New gene mutations leading to achondroplasia are associated with increasing paternal age. Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during spermatogenesis; it is theorized oogenesis has some regulatory mechanism that hinders the mutation from originally occurring in females. […] More than 99% of achondroplasia is caused by two different mutations in the fibroblast growth factor receptor 3 (FGFR3). In about 98% of cases, a G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine substitution.

• #11

  https://www.orthobullets.com/pediatrics/4094/achondroplasia

  Achondroplasia is a common congenital skeletal dysplasia caused by a sporadic or autosomal dominant gain-of-function mutation in FGFR3 gene. […] Abnormal function of FGFR3 dimers stabilized by mutation in transmembrane domain prevents ubiquitin degradation. […] Persistent activation leads to continuous inhibition of chondrocyte proliferation. […] FGF induces dimerization of FGFR3 receptor monomers, activating cascade. […] Activated FGFR3 targeted by ubiquitin to be degraded to terminate signal shortly after activation. […] The mutation is a point mutation FGFR3 (Gly1138 to Arg substitution) which results in gain of function activating FGFR3. […] This increases inhibition of chondrocyte proliferation in the proliferative zone of the physis. […] The defect in endochondral bone formation leads to a quantitative cartilage defect.

• #12 Molecular Defects and Cellular Dysfunctions in Restricted Growth Conditions | IntechOpen

  https://www.intechopen.com/chapters/51770?jwsource=cl

  Gene mutations affecting various stages of the bone formation process, e.g. osteoblast differentiation, bone extracellular matrix deposition and mineralization, may as well result in substantial growth deficiency, a hallmark feature of osteogenesis imperfecta, a molecularly heterogeneous group of connective tissue disorders. […] Dwarf-associated chondrodysplasias are caused by genetic alterations in the Fibroblast Growth Factor (FGF) Receptor 3 (FGFR3) gene and include achondroplasia (ACH), hypochondroplasia (HCH), thanatophoric dysplasia types I and II (TDI and TDII), and SADDAN. […] FGFR3 is a tyrosine kinase highly expressed in the resting and proliferating chondrocyte zones, where it plays key roles in controlling chondrocyte proliferation and/or subsequent cell cycle exit leading to differentiation into prehypertrophic chondrocytes.

• #13 Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

  https://www.mdpi.com/1422-0067/22/11/5573

  As a result of the FGFR3 receptor mutation, processes involved in the inhibition of cartilage formation are intensified. This is called a gain-of-function mutation. This inhibits the proliferation and maturation of the growth plate and reduces longitudinal bone growth. The mechanism is possibly related to altered integrin expression. Moreover, FGFR3 signaling through MAPK–BMP (bone morphogenetic protein) leads to the premature closure of the synchondrosis, which is associated with the stimulation of bone tissue formation. This results in the narrowing of the spinal canal and the foramen magnum and neurological problems. The authors concluded that medical intervention must be performed prior to synchondrosis closure in order to effectively prevent these complications. […] Another pathogenic mechanism that may be of interest for the treatment of achondroplasia is a defect in targeted lysosomal degradation in the ubiquitination process. As a result of the mutation and the disruption of the degradation process, the FGFR3 receptor does not undergo proteolysis and further participates in amplifying the signal.

• #14 Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006510

  Elevated Fibroblast Growth Factor (FGF) signaling critically contributes to the pathogenesis of limb dwarfism in Evc2 mutant mice. […] Both in vivo and in vitro data demonstrate elevated FGF signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. […] Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. […] Our data demonstrate that a nonsense mutation in Evc2 leads to compromised but not abrogated Hedgehog signaling. […] We conclude that both reduced Hedgehog signaling and elevated FGF signaling play a critical role in the pathogenesis of the unique form of dwarfism that characterizes Evc2 mutants. […] In Evc2 mutants, compromised Hedgehog signaling is possibly due to impaired ciliary accumulation of GLI2; while higher FGF signaling is likely due to elevated Fgfr3 expression in the proliferative zone as a result of compromised Hedgehog signaling, and elevated Fgf18 expression in the perichondrium.

• #15 Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006510

  Taken together, these data demonstrate that compromised Hedgehog signaling mediated by Evc2 mutation only partially contributes to the dwarfism in Evc2 mutants; additionally, elevated FGF signaling, mediated by Evc2 mutation in the perichondrium, plays a critical role in the pathogenesis of dwarfism in Evc2 mutants.

• #16 Dwarfism | Types, Causes, Treatment | Britannica

  https://www.britannica.com/science/dwarfism

  dwarfism, condition of growth retardation resulting in abnormally short adult stature and caused by a variety of hereditary and metabolic disorders. […] Among the common forms of hereditary dwarfism are achondroplasia, hypochondroplasia, and diastrophic dwarfism. […] In achondroplasia, the trunk is of normal size, but, because of a disturbance of the bone-producing cells of the growth plates (epiphyses) of the long bones, the limbs are extremely short; the head tends to be unusually large. […] Pituitary dwarfism, caused by a deficiency of pituitary growth hormone, is the chief endocrine form of dwarfism and may be hereditary; tumours, infections, or infarction (tissue death) of the pituitary can also induce dwarfism. […] In several hormonal disorders and hereditary conditions dwarfism is associated with subnormal intelligence. […] Dwarfism may also result from inadequate nutrition during crucial phases of growth and development.

• #17 Dwarfism | PPT

  https://www.slideshare.net/slideshow/dwarfism-76761121/76761121

  Dwarfism is caused by a deficiency in growth hormone or abnormalities in bones and cartilage. It results in short stature, with adult height usually under 4’10”. The most common form is achondroplasia, which causes short limbs and an average size trunk. Other types include pituitary dwarfism and skeletal dysplasias. Dwarfism can be diagnosed through ultrasounds and genetic testing, though there is no cure – treatment focuses on managing health issues. […] Dwarfism is Hypo-secretion of Growth Hormone Hyposecretion (underproduction) of the Growth Hormone during growing years causes slow bone growth and the epiphyseal plates close before normal height is reached. […] Reduction in GH secretion in infancy or early childhood causes dwarfism. It occurs because of the following reasons: I. Tumor of chromophobes, which compresses and destroys the normal cells secreting GH II. Deficiency of GH-releasing hormone secreted by hypothalamus III. Deficiency of somatomedin C IV. Atrophy or degeneration of acidophilic cells in the anterior pituitary.

• #18

  https://omim.org/entry/262400

  A number sign (#) is used with this entry because isolated growth hormone deficiency type IA (IGHD1A) is caused by homozygous or compound heterozygous mutation in the GH1 gene (139250) on chromosome 17q23. […] Isolated growth hormone deficiency type IA (IGHD1A) is an autosomal recessive disorder characterized by severe growth failure (SDS less than -4.5) by 6 months of age, undetectable growth hormone (GH) concentrations, and a tendency to develop antibodies despite an initial good response to rhGH treatment (summary by Alatzoglou et al., 2014). […] Genetic Heterogeneity of Isolated Growth Hormone Deficiency […] See IGHD1B (617281) and IGHD2 (173100), both caused by mutation in the GH1 gene; IGHD3 (307200), caused by mutation in the BTK gene (300300); and IGHD4 (618157), caused by mutation in the GHRHR gene (139191).

• #19 Pediatric Growth Hormone Deficiency: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/923688-overview

  Pituitary growth hormone secretion is stimulated by growth hormone-releasing hormone (GHRH) from the hypothalamus which may be stimulated by growth hormone-releasing peptides (GHRPs). […] Growth hormone deficiency may result from disruption of the growth hormone axis and may be congenital or acquired. […] Although most instances of isolated growth hormone deficiency are idiopathic, specific etiologies may cause growth hormone deficiency associated with other pituitary deficiencies and may even be associated with sellar developmental defects. […] A mutation in a transcription factor (POUF-1, also known as PIT-1) is known to result in familial growth hormone deficiency. […] Growth hormone deficiency associated with other pituitary deficiencies due to inactivating mutations of the PROP1 (Prophet of PIT-1) transcription factor gene has been reported.

• #20 Pediatric Growth Hormone Deficiency: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/923688-overview

  Congenital growth hormone deficiency may be associated with an abnormal pituitary gland (seen on MRI) or may be part of a syndrome such as septooptic dysplasia (SOD) (de Morsier syndrome), which may include other pituitary deficiencies, optic nerve hypoplasia, and absence of the septum pellucidum; it occurs with an incidence of about 1 in 50,000 births. […] Acquired growth hormone deficiency may result from trauma, infection (eg, encephalitis, meningitis), cranial irradiation (somatotrophs appear to be the most radiation-sensitive cells in the pituitary), and other local or systemic insults or diseases (particularly histiocytosis).

• #21 Dwarfism | PPT

  https://www.slideshare.net/slideshow/dwarfism-76761121/76761121

  This type of dwarfism is associated with other symptoms due to the deficiency of other anterior pituitary hormones. […] Dwarfism is usually caused by a genetic variant; achondroplasia is caused by a mutation on chromosome 4. […] Achondroplasia is average-size trunk and shortened upper parts of their arms and leg. Achondroplasia has a dominant pattern of inheritance. 80% of people with Achondroplasia have average-size parents, so the mutation on the FGFR3 gene is new. […] Laron dwarfism occurs due to the presence of abnormal growth hormone secretagogue (GHS) receptors in liver. GHS receptors become abnormal because of the mutation of genes for the receptors. GH secretion is normal or high. But the hormone cannot stimulate growth because of the abnormal GHS receptors. […] Most types of dwarfism are known as Skeletal Dysplasias-conditions of abnormal bone growth. They’re divided into two types: I. Short-Trunk: -Those have a shortened trunk with more average-sized limbs II. Short-Limb: -Those have an average-sized trunk but shortened arms and legs.

• #22

  https://link.springer.com/article/10.1007/s10354-020-00741-6

  The discovery of the molecular pathogeny of achondroplasia attracted the interest of industry in this rare disease, and strategies for drugs targeting the overactive FGFR3 receptor and downstream signalling pathways started to develop. […] Current strategies include catching FGFR3 ligands, blocking FGFR3, and chemical inhibitors of tyrosine kinase, the intracellular element of the FGFR3 receptor, all of which currently remain in preclinical studies. More advanced are alternative strategies involving C-type natriuretic peptide (CNP), which, via its receptor NPRB, antagonizes the FGFR3-induced activation of the MAPK signalling pathway in growth plate chondrocytes and thus counteract the effects of the FGFR3 mutation. […] The CNP antagonizes FGFR3 downstream signalling by inhibiting the MAPK pathway. The 39-amino acid CNP (CNP-39) analogue BMN111 has an extended plasma half-life due to its resistance to neutral endopeptidase. […] The authors concluded that their results provided proof of concept that BMN 111 might benefit individuals with achondroplasia and hypochondroplasia.

• #23 Achondroplasia Medication: Growth hormone, C-Type Natriuretic Peptide

  https://emedicine.medscape.com/article/1258401-medication

  Growth hormone is used to increase the height of patients with achondroplasia (see Medical Care). However, no long-term studies exist to justify prolonged treatment for short stature. […] Vosoritide, a biologic analogue of C-type natriuretic peptide (CNP), is approved to prevent the inhibition of mineralization of chondrocytes caused by the mutation in the fibroblast growth factor receptor 3 (FGFR3) gene (FGFR3). […] C-type natriuretic peptide (CNP) binds to natriuretic-peptide receptor B (NPR B), which induces synthesis of cyclic guanosine monophosphate (cGMP) molecules, which, in turn, inhibits the mitogen-activated protein kinase (MAPK) pathway. Inhibition of this pathway leads to increased extracellular matrix (ECM), which, in conjunction with chondrocytes, serves as a template for bone via endochondral ossification. Achondroplasia is caused by a mutation in FGFR3, causing it to be permanently active; FGFR3 signaling activates two intracellular signaling cascades that lead to a lower proliferation and differentiation of bone growth plate chondrocytes, through the signal transducer and activator of transcription 1 (STAT1) pathway, and to a lower production of ECM, through the MAPK pathway.

• #24 What is the mechanism of Vosoritide?

  https://synapse.patsnap.com/article/what-is-the-mechanism-of-vosoritide

  Vosoritide is a therapeutic agent designed to address the underlying causes of achondroplasia, a common form of dwarfism. […] This medication works by targeting the molecular mechanisms that drive the abnormal bone growth associated with the condition. […] Achondroplasia results from mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. […] FGFR3 is a critical regulator of bone growth and development. […] However, in individuals with achondroplasia, mutations in FGFR3 cause it to be overactive, leading to severely restricted bone growth and short stature. […] Vosoritide is a synthetic analog of C-type natriuretic peptide (CNP), a naturally occurring peptide that plays a role in regulating bone growth. […] CNP counteracts the inhibitory effects of FGFR3 on chondrocytes.

• #25 First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model | Gene Therapy

  https://www.nature.com/articles/s41434-022-00313-w

  Our findings showed that a single intraperitoneal dose of AAV8-HLP-mGHR (41010 vg/mouse) into 45-week-old Laron dwarf mice resulted in sufficient expression of mGHR in the liver to restore GH signaling resulting in increased circulating IGF1, IGFBP3 and ALS. […] The formation of the ternary IGF complex with IGFBP3 and ALS has been reported to be crucial for postnatal bone acquisition and skeletal response. […] Our treatment of Laron mice resulted in a similar partial restoration of body length where the AAV8-HLP-mGHR treated mice had grown at near normal rates after 3-week post AAV injection but did not display catch up growth to normal. […] Despite its limitations, this study provides evidence that single administration of AAV8-HLP-mGHR viral vector can increase the expression of endogenously circulating IGF1, IGFBP3 and ALS and potentially lead to a useful treatment for patients with LS.

• #26 Dwarfism (Restricted Growth): Types and Causes

  https://patient.info/bones-joints-muscles/restricted-growth-dwarfism

  The outlook (or prognosis) entirely depends on the underlying condition. Overall, most people with dwarfism have no major medical problems, and live full and healthy normal lives. […] Life expectancy is normal in achondroplasia. However, some of the conditions which cause dwarfism can have associated medical issues which can significantly affect abilities and health.

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