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1.
Curr Diab Rep ; 22(12): 571-577, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36401775

RESUMO

PURPOSE OF REVIEW: This review describes the unique pathogenesis of SHORT syndrome, a rare genetic form of insulin resistance syndrome, and recent advances in understanding the underlying mechanisms. SHORT syndrome results from dysfunction of PI3K, but the mechanisms behind the clinical manifestations are not entirely understood. Elucidating these mechanisms may contribute to the understanding of the roles of insulin signaling and PI3K signaling in humans. There are paucity of data on treatment and outcomes. RECENT FINDINGS: The clinical spectrum of the disorder appears wider than previously understood, and overlaps with other clinical syndromes. PI3K malfunction is associated with insulin resistance, decreased lipogenesis, increased energy expenditure, and possible IGF1 resistance. SHORT syndrome may be underdiagnosed, and should be considered in individuals with growth failure, craniofacial dysmorphism, and lipodystrophy. Much is still unknown about the optimal management and long-term outcomes.


Assuntos
Hipercalcemia , Resistência à Insulina , Nefrocalcinose , Humanos , Resistência à Insulina/genética , Fosfatidilinositol 3-Quinases
2.
BMJ Case Rep ; 15(11)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351670

RESUMO

Enamel renal syndrome (ERS) due to loss of function (LOF) mutation of FAM20A gene typically consists of hypoplastic amelogenesis imperfecta (AI) and bilateral nephrolithiasis/nephrocalcinosis. Recent evidence suggests that FAM20A interacts with FAM20C and increases its activity; thus LOF mutation of FAM20A leads to impaired FAM20C action. FAM20C, a golgi casein kinase, phosphorylates fibroblast growth factor (FGF)-23, prevents its glycosylation and makes it more susceptible to degradation by furine proteases. Consequently, inactivating mutations of FAM20C lead to increased concentration of bioactive and intact FGF-23 in circulation and resultant hypophosphataemia. LOF mutation of FAM20A, thus, might also be associated with FGF-23-mediated hypophosphataemia; however, such an association has never been reported in the literature. We describe, for the first time, a triad of AI, bilateral nephrolithiasis and FGF-23-mediated hypophosphataemia in LOF mutation of FAM20A. We suggest that serum phosphate should be measured in all patients with ERS to avoid metabolic and skeletal complications of undiagnosed, hence untreated hypophosphataemia.


Assuntos
Amelogênese Imperfeita , Proteínas do Esmalte Dentário , Hipofosfatemia , Cálculos Renais , Nefrocalcinose , Humanos , Amelogênese Imperfeita/genética , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/metabolismo , Nefrocalcinose/genética , Mutação , Fatores de Crescimento de Fibroblastos/genética , Proteínas do Esmalte Dentário/genética
3.
Kidney360 ; 3(9): 1578-1589, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36245654

RESUMO

Background: Nephron loss dramatically increases tubular phosphate to concentrations that exceed supersaturation. Osteopontin (OPN) is a matricellular protein that enhances mineral solubility in solution; however, the role of OPN in maintaining urinary phosphate solubility in CKD remains undefined. Methods: Here, we examined (1) the expression patterns and timing of kidney/urine OPN changes in CKD mice, (2) if tubular injury is necessary for kidney OPN expression in CKD, (3) how OPN deletion alters kidney mineral deposition in CKD mice, (4) how neutralization of the mineral-binding (ASARM) motif of OPN alters kidney mineral deposition in phosphaturic mice, and (5) the in vitro effect of phosphate-based nanocrystals on tubular epithelial cell OPN expression. Results: Tubular OPN expression was dramatically increased in all studied CKD murine models. Kidney OPN gene expression and urinary OPN/Cr ratios increased before changes in traditional biochemical markers of kidney function. Moreover, a reduction of nephron numbers alone (by unilateral nephrectomy) was sufficient to induce OPN expression in residual nephrons and induction of CKD in OPN-null mice fed excess phosphate resulted in severe nephrocalcinosis. Neutralization of the ASARM motif of OPN in phosphaturic mice resulted in severe nephrocalcinosis that mimicked OPN-null CKD mice. Lastly, in vitro experiments revealed calcium-phosphate nanocrystals to induce OPN expression by tubular epithelial cells directly. Conclusions: Kidney OPN expression increases in early CKD and serves a critical role in maintaining tubular mineral solubility when tubular phosphate concentrations are exceedingly high, as in late-stage CKD. Calcium-phosphate nanocrystals may be a proximal stimulus for tubular OPN production.


Assuntos
Nefrocalcinose , Insuficiência Renal Crônica , Animais , Camundongos , Biomarcadores , Cálcio , Fosfatos de Cálcio , Camundongos Knockout , Osteopontina/genética , Solubilidade
4.
Nephrol Ther ; 18(6): 541-548, 2022 Nov.
Artigo em Francês | MEDLINE | ID: mdl-36216732

RESUMO

INTRODUCTION: The distal renal tubular acidosis of children is characterized by hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria and nephrocalcinosis. It is secondary to the inability of alpha intercalar cells of the distal tubule to acidify urine of genetic origin. OBJECTIVE: To analyse the epidemiological aspects of distal tubular acidosis in Tunisia and study its evolutionary profile. PATIENTS AND METHODS: We conducted a retrospective descriptive study involving 44 patients followed at the paediatrics department of the Charles Nicolle Hospital in Tunis for 28 years (1991-2018). RESULTS: The most common discovery circumstances were growth retardation (88.6%), dehydration (56.8%), ployuro-polydipsic syndrome (47.7%), vomiting (40.9%) and nephrocalcinosis (38.6%). Growth retardation was found in 52.3% of patients. Dehydration was diagnosed in 59.1% of patients on the first exam. Polyuria was constant with an average diuresis of 8 cc/kg/h. All patients had the complete form of distal renal tubular acidosis with an average alkaline reserve of 11.1 mmol/L. Nephocalcinosis was found in 77.3% associated with nepholithiasis in 22.7%. Twenty-four patients had sensorineural deafness, nine of whom had ATP6V1B1/2p13 mutation. The ATP6V0A4/7q33-34 mutation was present in two patients. We used a high alkaline treatment dose with an average maintenance dose of 8.17 mmol/kg/24 hours. In the long term, stunting persisted in 34% of patients. The mean of creatinine's clearance at the last evaluation was 89.38 mL/min/1.73 m2 SC with stage 2 of chronic kidney disease in 50% of patients. CONCLUSION: Distal renal tubular acidosis has long been considered a benign pathology but is responsible for a progressive decline in GFD. Adequate metabolic control is needed to stabilize kidney function.


Assuntos
Acidose Tubular Renal , Nefrocalcinose , ATPases Vacuolares Próton-Translocadoras , Criança , Humanos , Acidose Tubular Renal/complicações , Acidose Tubular Renal/epidemiologia , Acidose Tubular Renal/genética , Nefrocalcinose/epidemiologia , Nefrocalcinose/etiologia , Estudos Retrospectivos , Desidratação/complicações , Transtornos do Crescimento , ATPases Vacuolares Próton-Translocadoras/genética
5.
Turk J Pediatr ; 64(5): 825-838, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36305432

RESUMO

INTRODUCTION: Bartter syndrome (BS) is a group of autosomal-recessive tubular disorders and it is classified into five genetic subtypes. BS can also be classified by phenotype (antenatal, classic). Patients with mutations in the same gene can present different phenotypes. In the present study, target gene sequencing was performed to evaluate the genotype-phenotype relationship. METHODS: Biochemical, clinical and renal ultrasonography results were collected at presentation and the last clinic visit. Genetic analyses were performed. The findings of patients with classical BS (cBS) and antenatal BS (aBS) at presentation and the last visit were compared. RESULTS: Our study included 21 patients (12 female, 57.1%) from 20 families with BS. The median age at diagnosis was 8 months and the median follow-up period was 39 months. The most frequent complaint was growth failure. We have found 18 different types of mutations in four genes, including nine in the CLCNKB gene, seven in the SLCA12A1 gene, one in the KCNJ1 gene and one in the BSND gene. In ten patients, nine different types of CLCNKB gene mutations were detected, five of them were novel. Seven different mutations in the SLC12A1 gene were detected in eight patients, five of them were novel. Compared to patients with aBS and cBS, prematurity was significantly higher in the group with aBS. Nephrocalcinosis was present in only one patient with cBS, all the ten hypercalciuric patients with aBS had nephrocalcinosis at the time of diagnosis and the last visit. The mean height standard deviation score (SDS) of patients with aBS were significantly lower than the cBS group at the time of presentation. The mean weight SDS at the time of presentation was worse in patients with aBS than in patients with cBS. The mean plasma potassium and chloride concentrations were significantly lower in the patients with cBS at the time of diagnosis. CONCLUSIONS: This investigation revealed the mutation characteristics and phenotype-genotype relationship of our patients and provided valuable data for genetic counseling.


Assuntos
Síndrome de Bartter , Nefrocalcinose , Feminino , Humanos , Gravidez , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Canais de Cloreto/genética , Genótipo , Mutação , Fenótipo
6.
Rev Med Suisse ; 18(793): 1606-1613, 2022 Aug 31.
Artigo em Francês | MEDLINE | ID: mdl-36047552

RESUMO

Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.


Le syndrome des télomères courts (STC) est un groupe de maladies rares dues à un défaut dans les gènes de maintenance des télomères, provoquant leur raccourcissement anormal et des manifestations cliniques multiorganiques. Dans l'enfance, le STC se présente par des lésions mucocutanées et gastro-intestinales, une insuffisance médullaire et des néoplasies. À l'âge adulte, une atteinte médullaire aplasiante, hépatique, et une fibrose pulmonaire sont des manifestations cliniques classiques. Les options thérapeutiques pour le STC restent limitées. Le danazol, une hormone androgène synthétique, permet, parfois, de freiner le raccourcissement télomérique et de limiter la progression de la maladie. Finalement, les transplantations hématopoïétique, hépatique et pulmonaire sont discutées dans certaines situations de manière multidisciplinaire.


Assuntos
Doenças da Medula Óssea , Nefrocalcinose , Adulto , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Criança , Transtornos do Crescimento , Humanos , Hipercalcemia , Doenças Metabólicas , Síndrome , Telômero/genética , Telômero/patologia
7.
Pediatr Transplant ; 26(8): e14380, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35979862

RESUMO

BACKGROUND: Although nephrolithiasis (NL) and nephrocalcinosis (NC) are very common features of primary hyperoxaluria type 1 (PH1), the long-term prognosis of NL and NC after preemptive liver transplantation (PLT) has not been elucidated. MATERIAL AND METHODS: We describe the cases of two chronic kidney disease (CKD) stage three patients with different clinical courses after PLT for PH1. RESULTS: The first patient underwent PLT at 7 years of age with an estimated glomerular filtration rate (eGFR) of 47.8 ml/min/1.73 m2 . Two years later, she experienced several episodes of obstructive pyelonephritis due to urolithiasis, and developed septic shock in one of these episodes. At the same time as these episodes, preexisting NL and NC progressively improved, with disappearance on X-ray disappeared at 8 years after transplantation. Her renal function has been maintained with an eGFR of 58.7 ml/min/1.73 m2 . The second patient received PLT at 10 years of age with an eGFR of 58.9 ml/min/1.73 m2 . Her renal function has been maintained with an eGFR of 65.9 ml/min/1.73 m2 . She had repeated urolithiasis which started to appear at 3 years after LT. The radiological findings still show bilateral NL and NC, but the stones in the renal pelvis have shown mild improvement. CONCLUSIONS: Regardless of the regression in NC seen on X-ray, long-term maintenance of the renal function in patients with PH1 with CKD stage 3 can be achieved with PLT. In patients with NL, there is a risk of serious complications due to posttransplant immunosuppressive therapy when obstructive pyelonephritis occurs after LT.


Assuntos
Hiperoxalúria Primária , Hiperoxalúria , Falência Renal Crônica , Transplante de Fígado , Nefrocalcinose , Nefrolitíase , Pielonefrite , Urolitíase , Humanos , Feminino , Nefrocalcinose/etiologia , Nefrocalcinose/complicações , Transplante de Fígado/efeitos adversos , Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/cirurgia , Nefrolitíase/complicações , Nefrolitíase/diagnóstico , Urolitíase/complicações , Pielonefrite/complicações
9.
J Pediatr Endocrinol Metab ; 35(10): 1298-1301, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-35952717

RESUMO

OBJECTIVES: Nephrocalcinosis is associated with conditions that cause hypercalcemia and the increased urinary excretion of calcium, phosphate, and/or oxalate. A monogenic etiology is found in almost 30% of childhood-onset nephrocalcinosis which is also a common manifestation of primary hyperparathyroidism. We discuss a child with nephrocalcinosis and features mimicking primary hyperparathyroidism. CASE PRESENTATION: A 7-year-old girl presented with nephrocalcinosis. Hypercalciuria, hyperphosphaturia, mild hypercalcemia, hypophosphatemia and elevated parathyroid hormone levels along with normal serum creatinine and absence of hypokalemic alkalosis suggested primary hyperparathyroidism. However, she was ultimately diagnosed with Bartter syndrome type 2 based on the presence of homozygous pathogenic variation in KCNJ1gene. CONCLUSIONS: This is the second reported case of late-onset Bartter syndrome type 2 without hypokalemic alkalosis. Patients with Bartter syndrome may present with high parathyroid hormone levels and hypercalcemia in addition to hypercalciuria. Thus, the present case suggests that the KCNJ1 gene should be included in genetic analysis even in older children with isolated nephrocalcinosis.


Assuntos
Alcalose , Síndrome de Bartter , Hipercalcemia , Hiperparatireoidismo Primário , Nefrocalcinose , Alcalose/complicações , Síndrome de Bartter/complicações , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Cálcio , Criança , Creatinina , Feminino , Humanos , Hipercalcemia/etiologia , Hipercalcemia/genética , Hipercalciúria/complicações , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Nefrocalcinose/etiologia , Nefrocalcinose/genética , Oxalatos , Hormônio Paratireóideo , Fosfatos
10.
Rev Med Liege ; 77(7-8): 416-420, 2022 Jul.
Artigo em Francês | MEDLINE | ID: mdl-35924494

RESUMO

Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate transaminase (AGT). Oxalate is a poorly soluble molecule that binds calcium and deposits in the entire organism leading to oxalosis. Its elimination is mainly carried out by kidneys. Hence the first manifestations are frequently of urinary concern and whitout any early care, progression of the disease to end-stage renal failure cannot be avoided. The only etiological treatment has long been combined liver-kidney transplantation because it restaures enzymatic function and replaces pathological kidneys. However, for a few years now, numerous studies are carried out on this subject and promising results have already been published with a new drug, lumasiran. From a clinical case, we describe the different options for the therapeutic management of primary hyperoxaluria type 1.


L'hyperoxalurie primitive de type 1 (HP1) est une maladie autosomale récessive rare entraînant une hyperproduction d'oxalate par déficit d'une enzyme hépatique : l'alanine-glyoxylate aminotransférase. L'oxalate est une petite molécule peu soluble qui se lie au calcium et forme des dépôts d'oxalate calcique dans l'ensemble de l'organisme : c'est l'oxalose. Son élimination est principalement rénale. Dès lors, les premières manifestations sont souvent d'ordre urinaire et, en l'absence de traitement précoce, la maladie évolue inévitablement vers l'insuffisance rénale terminale. Le seul traitement étiologique a longtemps été la transplantation combinée hépatique et rénale qui restaure une activité enzymatique et remplace les reins défaillants. Cependant, depuis quelques années, de nombreuses recherches sont réalisées à ce sujet et des résultats prometteurs ont déjà vu le jour avec le lumasiran. à partir d'un cas clinique, nous décrivons les différentes options de la prise en charge thérapeutique de l'HP1.


Assuntos
Hiperoxalúria Primária , Nefrocalcinose , Humanos , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/diagnóstico , Hiperoxalúria Primária/terapia , Nefrocalcinose/etiologia , Oxalatos/metabolismo , RNA Interferente Pequeno
11.
Urologie ; 61(10): 1099-1109, 2022 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-35925106

RESUMO

BACKGROUND: Nephro- or urolithiasis is a common disease. The prevalence of the disease is increasing in both pediatric and adult patients. The genomic calculation of prevalence may reveal higher levels than the previous diagnosis rates. Monogenic kidney stone disease has been identified in 30% of pediatric and 10% of adult patients. OBJECTIVES: Even if it seems legitimate to assume that there is no specific underlying disease in the case of a one-time stone episode, such a disease must be excluded in the pediatric patient. Therefore, the present study discusses in detail the evaluation and treatment of kidney stones in children. METHODS: Repeated analysis of 24 h urine samples, or multiple spot urine samples in infants and young children, usually provides evidence of the underlying pathology. In addition, any stone removed should be analyzed. These findings are followed by directed genetic diagnostics. Ultrasonography is the preferred diagnostic method. For symptomatic stones, a minimally invasive method of stone removal is chosen if possible, but not every stone needs to be removed. Family workup must be performed, when a specific diagnosis is made in an index case. CONCLUSION: Early diagnosis is important to avoid recurrences despite the few treatment options available. Delayed diagnosis can have catastrophic consequences for patients (e.g., renal failure). Standard treatment with hyperhydration and alkali citrate treatment alone often helps prevent recurrences. New therapeutic options give hope that stone diseases will become more treatable. Finally, early diagnosis often avoids problematic courses.


Assuntos
Cálculos Renais , Nefrocalcinose , Urolitíase , Adolescente , Álcalis , Criança , Pré-Escolar , Citratos , Humanos , Lactente , Cálculos Renais/diagnóstico , Nefrocalcinose/diagnóstico
12.
J Fish Dis ; 45(11): 1645-1658, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35862221

RESUMO

Nephrocalcinosis is a common disorder in farmed Atlantic salmon, but the consequences for the fish physiology are not well understood. We performed a transcriptome study in kidneys of Atlantic salmon (Salmo salar) smolts without and with severe chronic nephrocalcinosis (NC). The study revealed that numerous genes are differentially expressed in fish with NC compared with healthy salmon. The most evident changes in gene expression patterns in the NC group were a massive downregulation of metabolism and energy production, upregulation of signalling pathways important for tissue repair and function maintenance and upregulation of inflammatory responses. Overall, the extensive tissue damage and the gene regulation responses that affect salmon with severe nephrocalcinosis are highly likely to have dramatic consequences on fish survival.


Assuntos
Doenças dos Peixes , Nefrocalcinose , Salmo salar , Animais , Doenças dos Peixes/genética , Regulação da Expressão Gênica , Nefrocalcinose/genética , Nefrocalcinose/veterinária , Salmo salar/genética , Transcriptoma
13.
J Bone Miner Res ; 37(10): 1926-1935, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35879818

RESUMO

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to activating variants of the calcium-sensing receptor gene (CASR). Inherited or de novo activating variants of the CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. Conventional therapy includes calcium and activated vitamin D, which can worsen hypercalciuria, resulting in renal complications. A systematic literature review, using published reports from 1994 to 2021, was conducted to catalog CASR variants, to define the ADH1 clinical spectrum, and to determine the effect of treatment on patients with ADH1. There were 113 unique CASR variants reported, with a general lack of genotype/phenotype correlation. Clinical data were available in 191 patients; 27% lacked symptoms, 32% had mild/moderate symptoms, and 41% had severe symptoms. Seizures, the most frequent clinical presentation, occurred in 39% of patients. In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed. Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients (6.8 ± 0.7 versus 7.6 ± 0.7 mg/dL [mean ± SD]; p < 0.0001), and the age of presentation was significantly lower in severely symptomatic patients (9.1 ± 15.0 versus 19.3 ± 19.4 years; p < 0.01). Assessments for complications including nephrocalcinosis, nephrolithiasis, renal impairment, and brain calcifications in 57 patients on conventional therapy showed that 75% had at least one complication. Hypercalciuria was associated with nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications (odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.4-37.2; p < 0.01). In 27 patients with urine calcium measures before and after starting conventional therapy, the incidence of hypercalciuria increased by 91% (p < 0.05) after therapy initiation. ADH1 is a condition often associated with severe symptomatology at presentation with an increase in the risk of renal complications after initiation of conventional therapy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Hipocalcemia , Hipoparatireoidismo , Nefrocalcinose , Nefrolitíase , Humanos , Hipercalciúria/genética , Hipercalciúria/tratamento farmacológico , Hipocalcemia/genética , Hipocalcemia/tratamento farmacológico , Receptores de Detecção de Cálcio/genética , Cálcio , Nefrocalcinose/genética , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/genética , Hormônio Paratireóideo/uso terapêutico , Vitamina D/uso terapêutico
14.
Allergol Immunopathol (Madr) ; 50(4): 1-9, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35789397

RESUMO

Monoallelic loss-of-function (LOF) mutations in the phosphatidylinositol 3-kinase (PIK3R1) gene affecting the inter-Src homology 2 domain of the p85α regulatory subunit of phosphoinositide--3-kinase δ (PI3Kδ) cause the activated PI3K δ syndrome (APDS2). APDS2 is defined as a primary antibody deficiency, developmental abnormalities within the B and T lymph cell compartments, and immune dysregulation. The genetic defect of APDS2 is shared with that of the SHORT syndrome, characterized by short stature, joint hyperextensibility, ocular depression, Rieger anomaly, and delayed tooth eruption. LOF variants in an intronic splice site (c.1425+1G.C/A/T) in the PI3KR1 gene have been identified in patients affected with both APDS2 and SHORT syndrome. Herein, we report a novel c.1644-1648del (p.Asp548Glufs*6) variant in a pediatric patient with the APDS2-related immunodeficiency, who presents with mild phenotypic features of the SHORT syndrome, congenital chest wall deformity, and IgE-mediated food allergy. The same variant was also identified in the patient's hitherto asymptomatic mother, implicating an incomplete penetrance. Regular monitoring by a multidisciplinary team under the pediatric clinical immunologist's supervision to implement appropriate diagnostic procedures and treatment modalities is of paramount importance. Further studies are required to better define the genotype-phenotype correlation in patients with the PIK3R1 gene mutations and to better delineate the mutual relationship between APDS2 and the SHORT syndrome.


Assuntos
Fosfatidilinositol 3-Quinases , Doenças da Imunodeficiência Primária , Criança , Classe I de Fosfatidilinositol 3-Quinases , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Transtornos do Crescimento , Humanos , Hipercalcemia , Doenças Metabólicas , Mutação/genética , Nefrocalcinose , Penetrância , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Fatores de Transcrição/genética
15.
Urolithiasis ; 50(4): 439-445, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35678848

RESUMO

Autosomal recessive disorders are prevalent in Pakistan, a developing South Asian country where consanguineous marriages are common. This study seeks to determine the prevalence of monogenic causes in children presenting with nephrocalcinosis and nephrolithiasis at a dialysis and transplant center in Karachi, Pakistan. A retrospective analysis was conducted in children aged 1-18 years presenting with nephrocalcinosis, between 2010 and 2019. Demographic information, clinical profile, laboratory parameters and stone analysis were collected, on a pre-designed questionnaire. One hundred and twenty-six children were included, with 11 and 3 diagnosed with renal tubular acidosis and Bartter's syndrome respectively. Next-generation sequencing and Sanger sequencing was performed on 112 children. Eighty-seven patients were diagnosed with primary hyperoxaluria, with mutations in alanine-glyoxylate-aminotransferase gene found in 73, followed by glyoxylate reductase/hydroxy-pyruvate reductase in 13, and 4-hydroxy-2-oxaloglutarate aldolase in 1. Twenty-five patients reported negative for mutations. Sixty-four percent were males, with a statistically significant difference (p < 0.05). History of parental consanguineous marriage was found in 98% of the cohort. Fifty-four and 40 patients presented to the clinic with Chronic Kidney Disease Stage 1 and Stage 5, respectively, with a statistically significant difference p = 0.007. Mutations noted in our cohort are different and more severe than those reported in the developed world. The disease poses a major disease burden in developing world context with the only treatment option of combined liver-kidney transplantation not available in Pakistan.


Assuntos
Hiperoxalúria Primária , Hiperoxalúria , Cálculos Renais , Nefrocalcinose , Criança , Efeitos Psicossociais da Doença , Feminino , Ligação Genética , Humanos , Hiperoxalúria/complicações , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/epidemiologia , Hiperoxalúria Primária/genética , Cálculos Renais/complicações , Masculino , Nefrocalcinose/epidemiologia , Nefrocalcinose/genética , Paquistão/epidemiologia , Estudos Retrospectivos
16.
J Bone Miner Res ; 37(8): 1580-1591, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35689455

RESUMO

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) represents an FGF23-independent disease caused by biallelic variants in the solute carrier family 34-member 3 (SLC34A3) gene. HHRH is characterized by chronic hypophosphatemia and an increased risk for nephrocalcinosis and rickets/osteomalacia, muscular weakness, and secondary limb deformity. Biochemical changes, but no relevant skeletal changes, have been reported for heterozygous SLC34A3 carriers. Therefore, we assessed the characteristics of individuals with biallelic and monoallelic SLC34A3 variants. In 8 index patients and 5 family members, genetic analysis was performed using a custom gene panel. The skeletal assessment comprised biochemical parameters, areal bone mineral density (aBMD), and bone microarchitecture. Pathogenic SLC34A3 variants were revealed in 7 of 13 individuals (2 homozygous, 5 heterozygous), whereas 3 of 13 carried monoallelic variants of unknown significance. Whereas both homozygous individuals had nephrocalcinosis, only one displayed a skeletal phenotype consistent with HHRH. Reduced to low-normal phosphate levels, decreased tubular reabsorption of phosphate (TRP), and high-normal to elevated values of 1,25-OH2 -D3 accompanied by normal cFGF23 levels were revealed independently of mutational status. Interestingly, individuals with nephrocalcinosis showed significantly increased calcium excretion and 1,25-OH2 -D3 levels but normal phosphate reabsorption. Furthermore, aBMD Z-score <-2.0 was revealed in 4 of 8 heterozygous carriers, and HR-pQCT analysis showed a moderate decrease in structural parameters. Our findings highlight the clinical relevance also of monoallelic SLC34A3 variants, including their potential skeletal impairment. Calcium excretion and 1,25-OH2 -D3 levels, but not TRP, were associated with nephrocalcinosis. Future studies should investigate the effects of distinct SLC34A3 variants and optimize treatment and monitoring regimens to prevent nephrocalcinosis and skeletal deterioration. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Raquitismo Hipofosfatêmico Familiar , Nefrocalcinose , Cálcio/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem , Raquitismo Hipofosfatêmico Familiar/genética , Humanos , Hipercalciúria/complicações , Hipercalciúria/tratamento farmacológico , Hipercalciúria/genética , Nefrocalcinose/genética , Fosfatos , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética
17.
Iran J Kidney Dis ; 16(3): 162-170, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35714210

RESUMO

INTRODUCTION: Bartter syndrome (BS) is a salt losing tubulopathy due to impairment of the transport mechanisms at the thick ascending limb of the Henle's loop. The aim of this study was to report the clinical course of patients with BS. METHODS: Patients with BS were followed from 1996 to 2020 and enrolled to a systematic protocol to confirm primary BS by evaluating the metabolic derangements, nephrolithiasis and nephrocalcinosis. Treatment was based on standard guidelines. Comparisons were made between data at baseline and at the last visit. RESULTS: A total of 13 patients (7 males) with primary BS were analyzed. Two patients had a mutation of the KCNJ1 gene. Age at diagnosis was 3 ± 4.5 years and the follow-up period was 11.19 ± 6.76 years. Metabolic alkalosis was initially detected in 76.92% and remained stable at the last visit (P > .05). Hypokalemia was present in 61.5% of patients at diagnosis, but sustained in 38.46% at the last visit (P < .05). Urine calcium level was 13.3 ± 9.6 mg/ kg/d at the first visit, and significantly reduced to 3.7 ± 2.0 mg/ kg/d at the last visit (P < .05). Nephrocalcinosis was detected by first kidney ultrasonography in 53.8% of patients. Kidney function was preserved, with a glomerular filtration rate of 120.1 ± 28.7 mL/min/ 1.73m2 at last visit. Growth was completely recovered in 71.42% and partially improved in 14.28% of patients after treatment, respectively. All patients received indomethacin and potassium chloride salts. CONCLUSIONS: Long-term follow-up of this cohort of BS showed favorable outcomes after treatment resulting in metabolic normalization and growth catch-up in most patients.  DOI: 10.52547/ijkd.6657.


Assuntos
Alcalose , Síndrome de Bartter , Hipopotassemia , Nefrocalcinose , Síndrome de Bartter/complicações , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/terapia , Humanos , Masculino , Nefrocalcinose/diagnóstico , Nefrocalcinose/terapia , Potássio
18.
Iran J Kidney Dis ; 16(3): 209-213, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35714216

RESUMO

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is characterized by renal magnesium wasting, hypercalciuria and eventually kidney failure which mostly affects children and young aged adults. Mutation of genes of claudin-16 and claudin-19 are involved in the pathogenesis of this disorder, which leads to renal magnesium and calcium wasting. A 35-year-old man with end-stage kidney disease (ESKD) was referred to our clinic due to bilateral nephrocalcinosis, detected by ultrasonographic study, for further evaluation. Detailed investigations revealed that his siblings had also similar presentations of hypomagnesemia, hypercalciuria, nephrocalcinosis and chronic kidney disease (CKD). Sanger sequencing showed a novel mutation (c.338G > A: p.C113Y) at the second exon of the CLDN16 gene. The patient underwent kidney transplantation and his siblings received only medical treatment. In young patients with ESKD and concomitant nephrocalcinosis, especially where there is a family history of CKD/ESKD, genetic evaluation is strongly recommended.  DOI: 10.52547/ijkd.6845.


Assuntos
Claudinas , Falência Renal Crônica , Nefrocalcinose , Insuficiência Renal Crônica , Adulto , Criança , Claudinas/genética , Humanos , Hipercalciúria/complicações , Hipercalciúria/diagnóstico , Hipercalciúria/genética , Irã (Geográfico) , Falência Renal Crônica/complicações , Falência Renal Crônica/genética , Magnésio , Masculino , Pessoa de Meia-Idade , Mutação , Nefrocalcinose/complicações , Nefrocalcinose/genética , Nefrocalcinose/terapia , Insuficiência Renal Crônica/complicações
19.
Trials ; 23(1): 499, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710560

RESUMO

BACKGROUND: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels. METHODS: The FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10-60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)2D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria. DISCUSSION: The current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the "off-label" use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04495608 . Registered on July 23, 2020.


Assuntos
Nefrocalcinose , Nefrolitíase , Insuficiência Renal Crônica , Adulto , Fluconazol/efeitos adversos , Humanos , Hipercalciúria/diagnóstico , Hipercalciúria/tratamento farmacológico , Hipercalciúria/etiologia , Fosfatos , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Vitamina D/metabolismo
20.
J Clin Endocrinol Metab ; 107(8): e3159-e3166, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35569070

RESUMO

BACKGROUND: Pharmacological therapy may be useful in the treatment of moderate to severe hypercalcemia in patients with infantile hypercalcemia-1 (HCINF1) due to pathogenic variants in the cytochrome P450 24 subfamily A member 1 (CYP24A1). Rifampin is an antituberculosis drug that is a potent inducer of cytochrome P450 3 subfamily A member 4, which is involved in an alternative catabolic pathway of vitamin D. The efficacy of rifampin in improving hypercalcemia was previously reported, but many questions remain on the long-term efficacy and safety. The aim of the study is to test the long-term efficacy and safety of rifampin in a patient with HCINF1. METHODS: We report clinical, biochemical, and imaging features of a 23-year-old man affected by HCINF1 with moderate hypercalcemia (12.9 mg/dL), symptomatic nephrolithiasis, nephrocalcinosis, and impaired kidney function [estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2] treated with rifampin for an overall period of 24 months. Kidney, liver, and adrenal function were evaluated at every follow-up visit. RESULTS: In 2 months, rifampin induced a normalization of serum calcium (9.6 mg/dL) associated with an improvement of kidney function (eGFR 92 mL/min/1.73 m2) stable during the treatment. After 15 months, rifampin was temporally withdrawn because of asthenia, unrelated to impairment of adrenal function. After 3 months, the timing of drug administration was shifted from the morning to the evening, obtaining the remission of asthenia. At the end of follow-up, the nephrolithiasis disappeared and the nephrocalcinosis was stable. CONCLUSIONS: Rifampin could represent an effective choice to induce a stable reduction of calcium levels in patients with HCINF1, with a good safety profile.


Assuntos
Hipercalcemia , Cálculos Renais , Nefrocalcinose , Adulto , Astenia/complicações , Cálcio , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/genética , Masculino , Nefrocalcinose/tratamento farmacológico , Nefrocalcinose/genética , Rifampina/efeitos adversos , Vitamina D , Vitamina D3 24-Hidroxilase/genética , Adulto Jovem
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