RESUMO
Hereditary hypophosphatemic rickets with hypercalciuria is an autosomal recessive phosphate-wasting disorder, associated with kidney and skeletal pathologies, which is caused by pathogenic variants of SLC34A3. In this issue, Zhu et al. describe a pooled analysis of 304 individuals carrying SLC34A3 variants. Their study underscores the complexity of hereditary hypophosphatemic rickets with hypercalciuria, as kidney and bone phenotypes generally do not coexist, heterozygous carriers of SLC34A3 variants also can be affected, and the response to oral phosphate supplementation is dependent on the genetic status.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Humanos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Hipercalciúria/diagnóstico , Hipercalciúria/genética , Medicina de Precisão , Mutação , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética , FosfatosRESUMO
Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Humanos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Hipercalciúria/diagnóstico , Hipercalciúria/tratamento farmacológico , Hipercalciúria/genética , Rim/metabolismo , Fosfatos , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/metabolismoRESUMO
X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Perda Auditiva , Hiperparatireoidismo , Hipofosfatemia , Nefrocalcinose , Osteoartrite , Criança , Adulto , Humanos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Nefrocalcinose/genética , Nefrocalcinose/complicações , Fatores de Crescimento de Fibroblastos/genética , Hipofosfatemia/epidemiologia , Hipofosfatemia/genética , Fosfatos , Hiperparatireoidismo/complicações , Obesidade/complicações , Perda Auditiva/complicações , Perda Auditiva/tratamento farmacológicoRESUMO
Abnormalities associated with phosphate metabolism can lead to thoracic deformities that result in respiratory failure, which is conventionally managed by means of supplemental oxygenation, positive airway pressure and physiotherapy. However, when these measures fail, the clinician faces a dilemma, since many patients cannot tolerate a major surgical procedure. A minimally invasive technique, insertion of an endobronchial stent, might offer a solution.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Insuficiência Respiratória , Raquitismo Hipofosfatêmico , Humanos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico/complicações , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Stents/efeitos adversosRESUMO
BACKGROUND: Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. METHODS: By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17-55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ≤2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). RESULTS: We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. CONCLUSION: Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Hipofosfatemia/genética , Hipofosfatemia/complicações , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fósforo , Fatores de Crescimento de FibroblastosRESUMO
Alopecia in hereditary vitamin D resistant rickets (HVDRR) has some correlation with severe rickets and poor overall response. However, these observations are based on small series. Hence, we aim to assess the genotypic spectrum of HVDRR and its correlation with alopecia and clinical response. Seven genetically-proven HVDDR patients from five unrelated families and 119 probands from systematic review were analysed retrospectively for phenotypic and genotypic data and overall response to therapy. In our cohort mean age at rickets onset was 12 (± 3.4) months. Alopecia was present in all patients but one. All patients had poor overall response to oral high-dose calcium and calcitriol and most required intravenous calcium. Genetic analyses revealed four novel variants. On systematic review, alopecia was present in majority (81.5%) and preceded the onset of rickets. Patients with alopecia had higher serum calcium (7.6 vs.6.9 mg/dl, p = 0.008), lower 1, 25(OH)2 D (200 vs.320 pg/ml, p = 0.03) and similar overall response to oral therapy (28.7% vs. 35.3%, p = 0.56). Alopecia was present in 51.4% of non-truncating (NT) ligand-binding domain (LBD) variants, whereas it was universal in truncating LBD and all DNA binding-domain (DBD) variants. Overall response to oral therapy was highest in LBD-NT (46.4%) as compared to 7.6% in LBD-truncating and 19% in DBD-NT variants. Among LBD-NT variants, those affecting RXR heterodimerization, but not those affecting ligand affinity, were associated with alopecia. Both alopecia and overall response have genotypic correlation. Age at diagnosis and overall response to oral therapy were similar between patients with and without alopecia in genetically proven HVDRR.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Humanos , Lactente , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/complicações , Receptores de Calcitriol/genética , Cálcio , Ligantes , Estudos Retrospectivos , Alopecia/genética , Alopecia/complicações , Alopecia/tratamento farmacológico , Mutação , Vitamina D/uso terapêuticoRESUMO
BACKGROUND: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate-lipid metabolism, could be involved. METHODS: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min-max)). RESULTS: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4-99) in SOC, 47 (9-98) in burosumab, and 28 (1-94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate-lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). CONCLUSION: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018-2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipertensão , Hipofosfatemia , Adolescente , Humanos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Anticorpos Monoclonais , Estudos Transversais , Estudos Prospectivos , Hipertensão/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , ObesidadeRESUMO
Cutaneous skeletal hypophosphatemia syndrome (CSHS) is an ultra-rare mosaic disorder manifesting as skeletal dysplasia and FGF23-mediated hypophosphatemia, with some experiencing extra-osseous/extra-cutaneous manifestations, including both benign and malignant neoplasms. Like other disorders of FGF23-mediated hypophosphatemia including X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), patients with CSHS have low serum phosphorus and active 1,25-dihydroxyvitamin D levels. Current treatment options for patients with CSHS include multiple daily doses of oral phosphorus and one or more daily doses of active vitamin D analog to correct the deficits. Recently, the fully human monoclonal antibody against FGF23 burosumab received US approval for the treatment of XLH and TIO, two rare diseases characterized by FGF23-mediated hypophosphatemia leading to rickets and osteomalacia. Given the similarities between the pathobiologies of these disorders and CSHS, we investigated the impact of burosumab on two patients, one pediatric and one adult, with CSHS who participated in separate, but similarly designed trials. In both the pediatric and adult patients, burosumab therapy was well-tolerated and contributed to clinically meaningful improvements in disease outcomes including normalization of phosphorus metabolism and markers of bone health, and improvements in skeletal abnormalities, fractures, and physical function. Reported adverse events were minimal, with only mild injection site reactions attributed to burosumab therapy. Together, these findings suggest that burosumab therapy is a promising therapeutic option for patients with CSHS.
Assuntos
Anticorpos Monoclonais Humanizados , Hipofosfatemia , Adulto , Criança , Humanos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia/tratamento farmacológico , Osteomalacia/tratamento farmacológico , Fósforo , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
X-linked hypophosphatemia (XLH) is a rare genetic disorder with X-linked dominant inheritance. Mutations in the PHEX gene increase fibroblast growth factor 23 (FGF23) concentrations, causing loss of phosphorus at the proximal tubule. Most pediatric patients debut in the first two years with short stature and bowed legs. Conventional treatment consists of oral supplements with phosphorus and calcitriol. Since 2018, burosumab has been approved as a novel therapeutic option for XLH, with promising results. The purpose of this study was to share our experience with two cases of XLH treated with burosumab. These patients presented with a broad phenotypical differences. One had the most severe radiological phenotype and developed left ventricular hypertrophy (LVH) and left ventricular dysfunction with preserved ejection fraction. Treatment with burosumab was well-tolerated and was followed by radiological stability and a striking improvement in both blood biochemistry and quality of life. The LVH was stable and left ventricular function normalized in the patient with cardiac involvement. In recent years many studies have been carried out to explain the role of FGF23 in cardiovascular damage, but the exact pathophysiological mechanisms are as yet unclear. The most intensively studied populations are patients with XLH or chronic kidney disease, as both are associated with high levels of FGF23. To date, cardiovascular involvement in XLH has been described in patients treated with conventional treatment, so it would be of interest to investigate if early use of burosumab at the time of diagnosis of XLH would prevent the occurrence of cardiovascular manifestations.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Fatores de Crescimento de Fibroblastos/genética , Humanos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Fósforo/uso terapêutico , Qualidade de VidaRESUMO
X-linked hypophosphatemia (XLH) is a rare genetic phosphate disorder caused mainly by PHEX mutations. Unlike for children, knowledge of the disease's manifestations in adults is limited. Musculoskeletal symptoms are the main feature of the disease in young adults associated with a heavy burden on patients' life. They include fractures and pseudofractures, pain, joint stiffness, osteoarthritis, enthesopathies, and muscle weakness, eventually leading to impaired quality of life. Conventional treatment with phosphate supplements and vitamin D analogs is indicated in symptomatic patients. Appropriate rehabilitation is also a key to the management of the disease to improve physical function and decrease pain, stiffness, and fatigue. Regarding the incidence and consequences of musculoskeletal features in XLH, all patients should be assessed by a bone disease specialist and, if necessary, managed by a multidisciplinary team.
Assuntos
Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/terapia , Entesopatia/etiologia , Entesopatia/fisiopatologia , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Humanos , Mutação/genética , Osteoartrite/etiologia , Osteoartrite/fisiopatologia , Endopeptidase Neutra Reguladora de Fosfato PHEX/genéticaRESUMO
X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient's needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.
Assuntos
Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/terapia , Fator de Crescimento de Fibroblastos 23/metabolismo , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Sociedades Médicas/organização & administração , Fosfatase Alcalina/metabolismo , Anticorpos Monoclonais Humanizados/administração & dosagem , Bélgica , Consenso , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/genética , Humanos , Hipofosfatemia/complicações , Hipofosfatemia/genética , Comunicação Interdisciplinar , Osteomalacia/complicações , Osteomalacia/genética , Índice de Gravidade de Doença , Resultado do Tratamento , Vitamina DRESUMO
Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D3. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH)2 vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.
Assuntos
Densidade Óssea , Colestanotriol 26-Mono-Oxigenase/deficiência , Raquitismo Hipofosfatêmico Familiar/complicações , Adolescente , Adulto , Consanguinidade , Família 2 do Citocromo P450 , Humanos , Vitamina D/sangueRESUMO
X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FG-F23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, enthesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood but FGF23 excess and deficient production of calcitriol likely contributes to its development. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF-23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries.
Assuntos
Raquitismo Hipofosfatêmico Familiar/terapia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Doenças Cardiovasculares/epidemiologia , Doenças do Sistema Endócrino/epidemiologia , Raquitismo Hipofosfatêmico Familiar/complicações , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/fisiologia , Humanos , Hiperparatireoidismo/prevenção & controle , Doenças Metabólicas/epidemiologia , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/uso terapêutico , Gravidez , Vitamina D/uso terapêuticoRESUMO
Autosomal dominant hypophosphatemic rickets (ADHR) is remarkable among the hypophosphatemic rickets syndromes for its variable age of presentation and periods of quiescence during which serum phosphate and fibroblast growth factor 23 (FGF 23) levels are normal without therapy. In contrast, hypophosphatemia in X-linked hypophosphatemic rickets (XLH) manifests soon after birth and requires lifelong therapy. This suggests that there are environmental factors which can alter FGF 23 activity in ADHR but not in XLH. We present an adult with ADHR in whom resolution of hypophosphatemia was achieved by correcting iron deficiency without the need for phosphate supplementation. Serial iron and FGF 23 levels revealed an inverse relationship (r=-0.79, p<0.04). All patients with ADHR who present with hypophosphatemia and worsening symptoms should be screened for iron deficiency. If iron deficiency is detected, therapy with a combination of calcitriol and iron supplementation should be considered without phosphate supplementation.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Adulto , Calcitriol , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Humanos , Ferro , FosfatosRESUMO
OBJECTIVE: To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). STUDY DESIGN: Multicentre prospective clinical study on pediatric patients included in the RenalTube database ( www.renaltube.com ) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study's protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. RESULTS: Twenty-four patients (17 females, from 1 to 17 years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60 mg/dl and 58.3 ± 26.8 pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45 pg/ml (normal < 60 pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were + 0.77 ± 0.77 and + 0.94 ± 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 ± 19.18 g/m2.7, and four patients, in addition to the obese one, had values greater than 51 g/m2.7, indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations. CONCLUSIONS: XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.
Assuntos
Doenças Cardiovasculares/etiologia , Raquitismo Hipofosfatêmico Familiar/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Lactente , MasculinoRESUMO
X-Linked hypophosphatemia (XLH) is the most common form of hereditary rickets caused by loss-of function mutations in the PHEX gene. XLH is characterized by hypophosphatemia secondary to renal phosphate wasting, inappropriately low concentrations of 1,25 dihydroxyvitamin D and high circulating levels of fibroblast growth factor 23 (FGF23). Short stature and rachitic osseous lesions are characteristic phenotypic findings of XLH although the severity of these manifestations is highly variable among patients. The degree of growth impairment is not dependent on the magnitude of hypophosphatemia or the extent of legs´ bowing and height is not normalized by chronic administration of phosphate supplements and 1α hydroxyvitamin D derivatives. Treatment with growth hormone accelerates longitudinal growth rate but there is still controversy regarding the potential risk of increasing bone deformities and body disproportion. Treatments aimed at blocking FGF23 action are promising, but information is lacking on the consequences of counteracting FGF23 during the growing period. This review summarizes current knowledge on phosphorus metabolism in XLH, presents updated information on XLH and growth, including the effects of FGF23 on epiphyseal growth plate of the Hyp mouse, an animal model of the disease, and discusses growth hormone and novel FGF23 related therapies.
Assuntos
Raquitismo Hipofosfatêmico Familiar/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Transtornos do Crescimento/metabolismo , Animais , Raquitismo Hipofosfatêmico Familiar/complicações , Fator de Crescimento de Fibroblastos 23 , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/etiologia , HumanosRESUMO
X-linked hypophosphatemia (XLH) is a rare genetic skeletal disease where increased phosphate wasting in the kidney leads to hypophosphatemia and prevents normal mineralization of bone and dentin. Here, we examined the periodontal status of 34 adults with XLH and separated them according to the treatment they received for hypophosphatemia. We observed that periodontitis frequency and severity were increased in adults with XLH and that the severity varied according to the hypophosphatemia treatment. Patients who benefited from an early and continuous vitamin D and phosphate supplementation during their childhood presented less periodontal attachment loss than patients with late or incomplete supplementation. Continued hypophosphatemia treatment during adulthood further improved the periodontal health. Extracted teeth from patients with late or incomplete supplementation showed a strong acellular cementum hypoplasia when compared with age-matched healthy controls. These results show that XLH disturbs not only bone and dentin formation but also cementum and that the constitutional defect of the attachment apparatus is associated with attachment loss.
Assuntos
Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Periodontite/prevenção & controle , Fosfatos/uso terapêutico , Vitamina D/uso terapêutico , Adulto , Estudos de Casos e Controles , Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Periodontite/diagnóstico por imagem , Estudos Prospectivos , Radiografia Panorâmica , Resultado do TratamentoRESUMO
OBJECTIVE: Hereditary hypophosphatemias (HH) are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response, and complications of treatment in the Norwegian population of children with HH. DESIGN: Retrospective national cohort study. METHODS: Sanger sequencing and multiplex ligand-dependent probe amplification analysis of PHEX and Sanger sequencing of FGF23, DMP1, ENPP1KL, and FAM20C were performed to assess genotype in patients with HH with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family, exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype. RESULTS: Twety-eight patients with HH (18 females and ten males) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by 1st January 2010 was 1,109,156, giving an XLHR prevalence of â¼1 in 60,000 Norwegian children. FAM20C mutations were found in two brothers and SLC34A3 mutations in one patient. In XLHR, growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis tended to be slightly more common in patients starting treatment before 1 year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance. CONCLUSIONS: We present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.
Assuntos
Transtornos do Crescimento , Hipofosfatemia Familiar , Nefrocalcinose , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Fator de Crescimento de Fibroblastos 23 , Genótipo , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Humanos , Hipofosfatemia Familiar/complicações , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/epidemiologia , Hipofosfatemia Familiar/genética , Lactente , Masculino , Nefrocalcinose/tratamento farmacológico , Nefrocalcinose/epidemiologia , Nefrocalcinose/etiologia , Nefrocalcinose/genética , Noruega/epidemiologia , Linhagem , Fenótipo , Fósforo/uso terapêutico , Prevalência , Estudos Retrospectivos , Fatores Sexuais , Vitamina D/uso terapêuticoRESUMO
Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd3+)-based contrast agents (GBCAs) in patients with kidney disease. The release of toxic Gd3+ from GBCAs likely plays a major role in NSF pathophysiology. The cause and etiology of Gd3+ release from GBCAs is unknown. Increased Acidic Serine Aspartate Rich MEPE-associated peptides (ASARM peptides) induce bone mineralization abnormalities and contribute to renal phosphate-handling defects in inherited hypophosphatemic rickets and tumor-induced osteomalacia. The proteolytic cleavage of related bone matrix proteins with ASARM motifs results in release of ASARM peptide into bone and circulation. ASARM peptides are acidic, reactive, phosphorylated inhibitors of mineralization that bind Ca2+ and hydroxyapatite. Since the ionic radius of Gd3+ is close to that of Ca2+, we hypothesized that ASARM peptides increase the risk of NSF by inducing release of Gd3+ from GBCAs. Here, we show 1) ASARM peptides bind and induce release of Gd3+ from GBCAs in vitro and in vivo; 2) A bioengineered peptide (SPR4) stabilizes the Gd3+-GBCA complex by specifically binding to ASARM peptide in vitro and in vivo; and 3) SPR4 peptide infusion prevents GBCA-induced NSF-like pathology in a murine model with increased ASARM peptide (Hyp mouse). We conclude ASARM peptides may play a role in NSF and SPR4 peptide is a candidate adjuvant for preventing or reducing risk of disease.
Assuntos
Meios de Contraste , Proteínas da Matriz Extracelular/metabolismo , Gadolínio DTPA , Glicoproteínas/metabolismo , Rim/metabolismo , Meglumina/análogos & derivados , Dermopatia Fibrosante Nefrogênica/prevenção & controle , Compostos Organometálicos , Endopeptidase Neutra Reguladora de Fosfato PHEX/farmacologia , Fragmentos de Peptídeos/farmacologia , Fosfoproteínas/metabolismo , Animais , Citoproteção , Modelos Animais de Doenças , Estabilidade de Medicamentos , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fator de Crescimento de Fibroblastos 23 , Rim/diagnóstico por imagem , Rim/patologia , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Dermopatia Fibrosante Nefrogênica/induzido quimicamente , Dermopatia Fibrosante Nefrogênica/diagnóstico , Dermopatia Fibrosante Nefrogênica/genética , Dermopatia Fibrosante Nefrogênica/metabolismo , Endopeptidase Neutra Reguladora de Fosfato PHEX/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Microtomografia por Raio-XRESUMO
BACKGROUND: Hereditary vitamin D-resistant rickets (HVDRR) is a rare genetic disorder caused by mutations in the vitamin D receptor (VDR) gene, which result in end-organ resistance to 1,25-(OH)2D3. PATIENTs with HVDRR are mostly treated using i.v. calcium therapy with a central catheter. However, central catheter-related complications have been reported. PATIENT: The patient was a 3-year-old boy presenting with waddling gait and alopecia. He had hypocalcemia [8 mg/dl (2 mmol/l)], hyperparathyroidism (1,232 ng/l), and elevated 1,25-(OH)2D3 levels (>250 pmol/l). DNA sequence analyses of the VDR gene showed a homozygous C-T transition at codon 152, resulting in a non-sense mutation in exon 5. INTERVENTIONS AND OUTCOMES: The patient was initially treated with calcitriol (80 ng/kg/day) and high-dose oral calcium (150 mg/kg/day) for one year. At the end of the first year, intermittent (5 days per month) i.v. calcium therapy without a central catheter was initiated because of insufficient clinical and radiological improvement. After 2 years of intermittent i.v. calcium therapy, there was a clear improvement based on clinical progress and on X-ray and biochemical findings. No peripheral complications were reported either. CONCLUSION: HVDRR with a non-sense mutation in the ligand-binding domain and alopecia was successfully treated with intermittent i.v. calcium without a central catheter.