RESUMEN
Functional (Nonorganic) Enuresis and Daytime Urinary Incontinence in Children and Adolescents: Clinical Guideline for Assessment and Treatment Abstract: Objective: Enuresis and daytime urinary incontinence are common disorders in children and adolescents and are associated with incapacitation and a high rate of comorbid psychological disorders. This interdisciplinary guideline summarizes the current state of knowledge regarding somatic and psychiatric assessment and treatment. We formulate consensus-based, practical recommendations. Methods: The members of this guideline commission consisted of 18 professional associations. The guideline results from current literature searches, several online surveys, and consensus conferences based on standard procedures. Results: According to the International Children's Continence Society (ICCS), there are four different subtypes of nocturnal enuresis and nine subtypes of daytime urinary incontinence. Organic factors first have to be excluded. Clinical and noninvasive assessment is sufficient in most cases. Standard urotherapy is the mainstay of treatment. If indicated, one can add specific urotherapy and pharmacotherapy. Medication can be useful, especially in enuresis and urge incontinence. Psychological and somatic comorbid disorders must also be addressed. Conclusions: The recommendations of this guideline were passed with a high consensus. Interdisciplinary cooperation is especially important, as somatic factors and comorbid psychological disorders and symptoms need to be considered. More research is required especially regarding functional (nonorganic) daytime urinary incontinence.
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Enuresis Diurna , Enuresis , Enuresis Nocturna , Incontinencia Urinaria , Niño , Adolescente , Humanos , Enuresis Diurna/diagnóstico , Enuresis Diurna/epidemiología , Enuresis Diurna/terapia , Incontinencia Urinaria/diagnóstico , Incontinencia Urinaria/epidemiología , Incontinencia Urinaria/terapia , Enuresis/diagnóstico , Enuresis/epidemiología , Enuresis/terapiaRESUMEN
Nocturnal enuresis (NE) is a common health problem. Approximately 10% of 7-year-old children wet the bed regularly during sleep. Enuresis can be categorized into monosymptomatic (MEN) and nonmonosymptomatic (NMEN) forms. MEN occurs without any other symptoms of bladder dysfunction. NMEN is associated with dysfunction of the lower urinary tract with or without daytime incontinence. The rate of comorbid gastrointestinal, behavioral, and emotional disorders is elevated depending upon the subtype of NE. A careful clinical history is fundamental to the evaluation of enuresis. Diagnostic procedures include medical history and psychological screening with questionnaires, bladder and bowel diary, physical examination, urinalysis, ultrasound, and examination of residual urine. The mainstay of treatment is urotherapy with information and psychoeducation about normal lower urinary tract function, the underlying cause of MEN, disturbed bladder dysfunction in the child with NMEN and instructions about therapeutic strategies. Alarm therapy and the use of desmopressin have been shown to be effective in randomized trials. Children with NMEN first need treatment of the underlying daytime functional bladder problem before treatment of nocturnal enuresis. In patients with findings of overactive bladder, besides urotherapy, anticholinergic drugs may be useful.
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Biorretroalimentación Psicológica/métodos , Antagonistas Colinérgicos/uso terapéutico , Enuresis Nocturna/terapia , Educación del Paciente como Asunto , Vejiga Urinaria/fisiopatología , Síntomas Afectivos/epidemiología , Niño , Comorbilidad , Desamino Arginina Vasopresina/uso terapéutico , Enfermedades Gastrointestinales/epidemiología , Humanos , Enuresis Nocturna/diagnóstico , Enuresis Nocturna/epidemiología , Enuresis Nocturna/fisiopatología , Problema de Conducta , Psicometría , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Ultrasonografía , Urinálisis , Vejiga Urinaria/diagnóstico por imagen , Urodinámica/fisiologíaRESUMEN
BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.
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Hipercalcemia/genética , Mutación , Esteroide Hidroxilasas/genética , Vitamina D/efectos adversos , Animales , Células Cultivadas , Cricetinae , Cricetulus , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hipercalcemia/inducido químicamente , Lactante , Masculino , Linaje , Factores de Riesgo , Esteroide Hidroxilasas/metabolismo , Vitamina D/metabolismo , Vitamina D/uso terapéutico , Vitamina D3 24-HidroxilasaRESUMEN
Acute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1-8 weeks. At follow-up, 14, 15 and 22 months' post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m(2) respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children.
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Lesión Renal Aguda/inmunología , Rechazo de Injerto/inmunología , Isoanticuerpos/sangre , Trasplante de Riñón/inmunología , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Biopsia , Niño , Quimioterapia Combinada , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/terapia , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Donadores Vivos , Plasmaféresis , Diálisis Renal , Rituximab , Factores de Tiempo , Resultado del TratamientoRESUMEN
Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
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Predisposición Genética a la Enfermedad , Laminina/genética , Mutación/genética , Estudios de Asociación Genética , Haplotipos/genética , Humanos , Laminina/química , FenotipoAsunto(s)
Autoanticuerpos/sangre , Enfermedades Autoinmunes/inmunología , Complemento C3b/inmunología , Factor B del Complemento/inmunología , Glomerulonefritis Membranoproliferativa/inmunología , Enfermedades Autoinmunes/terapia , Niño , Femenino , Glomerulonefritis Membranoproliferativa/terapia , Humanos , Masculino , Intercambio Plasmático , Adulto JovenRESUMEN
BACKGROUND: Elimination disorders in childhood are common and treatable. Approximately 10% of 7-year-olds wet the bed at night, and 6% are affected by incontinence during the daytime. Two main types of disturbance are distinguished: nocturnal enuresis and functional (i.e., non-organic) daytime urinary incontinence. Each type contains a wide variety of subtypes. Effective treatment requires precise identification of the subtype of elimination disorder. METHODS: This review is based on a selection of current publications, including principally the German S2k-AWMF guideline and the recommendations of the International Children's Continence Society (ICCS). RESULTS: Diagnostic assessment focuses on the clinical picture, is non-invasive, and can be carried out in most health care settings. If the child is suffering from multiple types of elimination disorder at once, then fecal incontinence or constipation is treated first, daytime urinary incontinence next, and enuresis last. 20-50% of children with elimination disorders have a comorbid mental disorder that also needs to be treated. With standard urotherapy, 56% of patients with daytime urinary incontinence become dry within a year. This conservative, symptom-oriented approach consists of educating the patient and his or her parents to promote behavior changes with respect to drinking and micturition. Elements of specific urotherapy are provided only if indicated. For enuresis, the treatment of first choice is alarm therapy, with which 50-70% of the affected children become dry. Pharmacotherapy, e.g., with desmopressin, can be a helpful adjunctive treatment. In intractable cases, training techniques have been found useful. CONCLUSION: Childhood elimination disorders can be treated effectively after targeted diagnostic evaluation and the establishment of specific indications for treatment. In view of the emotional distress these disorders cause, the associated physical and mental disturbances, and their potential persistence into adolescence, they should be evaluated and treated in affected children from the age of five years onward.
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Enuresis Diurna , Enuresis Nocturna , Adolescente , Niño , Enuresis Diurna/diagnóstico , Enuresis Diurna/terapia , Femenino , Humanos , Enuresis Nocturna/diagnóstico , Enuresis Nocturna/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease). METHODS: We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1. RESULTS: In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (I257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. CONCLUSION: Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.
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Mutación del Sistema de Lectura , Mutación Missense , Monoéster Fosfórico Hidrolasas/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Canales de Cloruro/genética , Creatina Quinasa/sangre , Humanos , L-Lactato Deshidrogenasa/sangre , Masculino , Síndrome Oculocerebrorrenal/genética , Linaje , Fenotipo , Transporte de Proteínas/fisiología , Defectos Congénitos del Transporte Tubular Renal/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADNAsunto(s)
Análisis Mutacional de ADN , Hipercalciuria/genética , Deficiencia de Magnesio/genética , Proteínas de la Membrana/genética , Nefrocalcinosis/genética , Claudinas , Femenino , Genes Recesivos , Tamización de Portadores Genéticos , Genotipo , Homocigoto , Humanos , Hipercalciuria/complicaciones , Deficiencia de Magnesio/complicaciones , Masculino , Proteínas de la Membrana/química , Modelos Moleculares , Mutación , Mutación Missense , Nefrocalcinosis/complicaciones , Conformación ProteicaRESUMEN
BACKGROUND AND OBJECTIVES: Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. RESULTS: Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). CONCLUSIONS: The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA.
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Ciclosporina/uso terapéutico , Resistencia a Medicamentos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/prevención & control , Riñón/efectos de los fármacos , Síndrome Nefrótico/tratamiento farmacológico , Esteroides/uso terapéutico , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Genes del Tumor de Wilms , Predisposición Genética a la Enfermedad , Alemania , Herencia , Hospitales Pediátricos , Hospitales Universitarios , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/genética , Estimación de Kaplan-Meier , Riñón/fisiopatología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/genética , Fallo Renal Crónico/fisiopatología , Laminina/genética , Masculino , Proteínas de la Membrana/genética , Mutación , Síndrome Nefrótico/congénito , Síndrome Nefrótico/etiología , Síndrome Nefrótico/fisiopatología , Selección de Paciente , Fenotipo , Estudios Retrospectivos , Canales Catiónicos TRPC/genética , Canal Catiónico TRPC6 , Factores de Tiempo , Resultado del TratamientoRESUMEN
Acute focal bacterial nephritis (AFBN), formerly known as lobar nephronia, is a rare form of interstitial bacterial nephritis. Most often described in adults with diabetes, there is only limited knowledge of AFBN in children. Ultrasound shows circular hypoechogenic, hypoperfused parenchyma lesions, which may be misdiagnosed as a renal abscess or tumor. From 1984 to 2005, AFBN was diagnosed in 30 children at the University Hospital Münster and the General Hospital Celle, Germany. Data of 25 cases (14 girls, 11 boys) were available for retrospective evaluation. Twenty-five children with AFBN, mean age 4.5 years (range: 0.25-17.5 years), were followed up on average 4.2 years (range: 0.5-11 years). All children were admitted to hospital due to fever and rapid deterioration of clinical condition, initially suspected of having meningitis (four patients), urinary tract infections (five patients), renal tumor (three patients), pneumonia (two patients), appendicitis (one patient), or with only unspecific symptoms (ten patients). AFBN was diagnosed by ultrasound on average 3 days (range: 1-10 days) after onset of symptoms. Pyuria was found in 18/25 children, bacteriuria in 20/25 children, and hematuria in one patient. Blood cultures were negative in all but one patient. Urinary tract abnormalities were found in 12 children, including vesicoureteral reflux (8), megaureter (1), urethral valves (1), unilateral renal hypoplasia (1), and one patient with megacystis, megaureter, caudal dystopic left kidney combined with hypoplasia and dysplasia of the right kidney. High-resolution ultrasound showed AFBN lesions to have resolved completely within 12 weeks after onset of intravenous antibiotic therapy in 20/25 children. Renal parenchymal cysts remained in three cases and focal scarring in two. Blood pressure and renal function was normal in 24/25 cases. AFBN should be suspected in children with fever and rapid deterioration of clinical condition. Residual lesions such as cysts or scarring of renal parenchyma could remain.
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Infecciones Bacterianas/diagnóstico por imagen , Nefritis/diagnóstico por imagen , Nefritis/microbiología , Enfermedad Aguda , Adolescente , Infecciones Bacterianas/terapia , Bacteriuria/diagnóstico por imagen , Bacteriuria/terapia , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Masculino , Nefritis/terapia , Piuria/diagnóstico por imagen , Piuria/microbiología , Piuria/terapia , Estudios Retrospectivos , UltrasonografíaRESUMEN
Hypercalciuria is regarded as a characteristic symptom of Dent disease, an X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure due to mutations in the CLCN5 gene. As the presence of hypercalciuria may affect the decision to consider a CLCN5 mutation in the differential diagnosis, the phenotypic spectrum and the relative frequency of hypercalciuria in patients with CLCN5 mutations was determined. We assessed renal calcium excretion in 34 male patients with proven CLCN5 mutations, who had been referred because of LMW proteinuria and at least one additional symptom of Dent disease. Hypercalciuria was defined as renal calcium excretion exceeding 0.1 mmol/kg per day. Data obtained were compared with all series of CLCN5-positive patients identified by a systematic literature survey. In 7 of our 19 families, at least 1 affected male had normal calcium excretion. Hypercalciuria was observed in 22 of 31 patients tested (71%) compared to 85 of 90 (94.4%) in series from Europe and North America and 74.4% from Japan. LMW proteinuria was present in all CLCN5-positive patients; 25% of the patients in European and North American series, 45% of the Japanese, and 41% in the present series had only two of the four principal symptoms of Dent disease. Therefore, a CLCN5 mutation should be considered irrespective of the presence of hypercalciuria in a patient with LMW proteinuria and one additional symptom of Dent disease.
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Canales de Cloruro/genética , Hipercalciuria/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Diagnóstico Diferencial , Humanos , Hipercalciuria/diagnóstico , Persona de Mediana EdadRESUMEN
BACKGROUND: Adult data suggest that urinary tract infections occur frequently after renal transplantation (RTx) and contribute to mortality and graft loss; data in children are limited. Therefore, we evaluated prevalence, short and long-term morbidity and confounding factors of febrile UTI (fUTI) after paediatric RTx. METHODS: In a retrospective cross-sectional study of three centres, we analysed data on 110 children followed for 4.9+/-3.4 years after successful transplantation. RESULTS: 40/110 (36%) patients had at least one fUTI at a median time of 0.98 years (range 0.02-8.96) after RTx; 11 patients (28%) had recurrent fUTI. Serum creatinine (SCr) rose significantly from 1.15+/-1.13 to 1.83+/-1.69 mg/dl, (P<0.001) during the fUTI, declining to baseline values after treatment. At the last followed-up calculated mean, GFR was comparable between fUTI and non-fUTI groups (75+/-26 vs 71+/-22 ml/min/1.73 m2). During fUTI mean, C-reactive protein (CRP) increased to 123+/-75 mg/l. Febrile UTI were significantly more frequent in girls compared to boys (22/44 vs 18/66, P<0.05) but occurred significantly earlier in boys than in girls [median 0.63 (range 0.02-4.15) vs 1.07 (0.04-8.96) years after RTx; P<0.02]. Also, patients with urinary tract malformations (UTMs) and neurogenic bladder as underlying diagnosis and those with urological surgery prior to transplantation had an increased risk for fUTI. CONCLUSION: fUTI is a frequent complication with significant short-term morbidity especially in girls and children with UTMs, neurogenic bladder and those with urological surgery. Long-term follow-up and prospective studies confirming specific risk factors, preventive measures and impact on graft survival are necessary.
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Fiebre/epidemiología , Trasplante de Riñón , Infecciones Urinarias/epidemiología , Niño , Estudios Transversales , Femenino , Alemania/epidemiología , Humanos , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/microbiología , Fallo Renal Crónico/terapia , Trasplante de Riñón/efectos adversos , Masculino , Prevalencia , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Sistema Urinario/anomalías , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/microbiologíaRESUMEN
The present study was designed to evaluate prothrombotic risk profiles in 59 consecutively recruited white neonates with renal venous thrombosis (RVT). The rates of prothrombotic risk factors (PRs)-for example, the factor V (FV) 1691G> A mutation, the factor II (FII) 20210G> A variant, antithrombin (AT), protein C (PC), protein S (PS), elevated lipoprotein(a) (Lp(a)), total fasting plasma homocysteine (tHcy) levels, and anticardiolipin antibodies (ACAs)-were compared with those of 118 healthy control children. At onset, 32 (54.2%) of the 59 neonates showed underlying clinical conditions; 40 (67.8%) of them and 23 (85.2%) of the 27 infants with idiopathic RVT showed at least one PR. Univariate analysis revealed significantly elevated odds ratios/95% confidence intervals (ORs/95% CIs) for FV and Lp(a). Additionally, PC/AT deficiency and ACAs were found significantly more often in the patient group (P =.04). Multivariate analysis calculated significant ORs/95% CIs only for FV (OR, 9.4; 95% CI, 3.3-26.6) and elevated Lp(a) (OR, 7.6; 95% CI, 2.4-23.8). Of the 59 neonates investigated, 53 revealed renal atrophy, and 13 children additionally suffered from severe arterial hypertension. In conclusion, the present study demonstrates the significance of genetic PR-especially the FV mutation and elevated Lp(a)-for the etiology of neonatal RVT.
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Venas Renales , Trombosis de la Vena/epidemiología , Enfermedad Aguda , Anticoagulantes/uso terapéutico , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Recién Nacido , Masculino , Recurrencia , Factores de Riesgo , Resultado del Tratamiento , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.