Stones, bones, and heredity

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine–glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined.

Conclusion

These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.     

以小分子蛋白尿为主要表现的Dent病六例临床及基因分析

目的 分析和总结6例儿童Dent病的临床及基因特征.方法 总结6例Dent患儿的临床资料,采用聚合酶链反应及直接测序的方法检测CLCN5基因.结果 6例患儿均有不同程度的小分子量蛋白尿和高钙尿症.其中3/6有血尿,4/6有肾钙化,3/6有低磷血症,1/6有佝偻病.在这6个家系中发现了6个CLCN5基因突变,包括3个无义突变、1个剪切位点突变、2个错义突变,分别为L594fsX595、R637X、R467X、IVS4-2A>G、S244L和V505G.其中,IVS4-2A>G和V505G是新突变.结论 小分子蛋白尿和高钙尿症是6例Dent病患儿的主要临床特征;Dent病可有Bartter综合征样表现,需要基因诊断进一步确诊.     

Primary hyperoxaluria type 2

Primary hyperoxaluria type 2 (PH2) is a rare disease with only 24 patients reported in the literature so far. It should be considered in any patient presenting with urolithiasis or nephrocalcinosis due to hyperoxaluria. The metabolic defect is deficiency of d-glycerate dehydrogenase/glyoxylate reductase leading to characteristic hyperoxaluria and excretion of l-glycerate, the cornerstone of diagnosis of PH 2. Although development of terminal renal failure seems to be less prevalent than in PH 1, recent reports indicate that chronic as well as terminal renal insufficiency may occur. Therefore specific therapeutic measures should aim at reduction of urinary calcium oxalate saturation by potassium citrate or pyrophosphate to reduce the incidence of nephrolithiasis and nephrocalcinosis and thus improve renal survival. Secondary complications (obstruction, urinary tract infections and pyelonephritis) must be avoided. In patients with terminal renal failure isolated renal transplantation seems to carry a high risk of disease recurrence. Conclusion PH 2 is a rare but important cause of urolithiasis and nephrocalcinosis; long-term follow up is necessary, since the renal prognosis may be worse than previously anticipated. Received: 22 November 1996 / Accepted: 17 January 1997     

Urinary outputs of oxalate,calcium, and magnesium in children with intestinal disorders. Potential cause of renal calculi.

24-hour urinary outputs of oxalate, calcium, and magnesium have been determined in a total of 62 children aged 3 months to 17 years who fell into the following groups: (i) 16 normal controls, (ii) 3 with primary hyperoxaluria, (iii) 9 with small and/or large intestinal resections, (iv) 9 with untreated coeliac disease, (v) 5 with pancreatic dysfunction, and (vi) a miscellaneous group of 20 children with a variety of intestinal disorders. Taken as a whole, 58% of patients with intestinal disorders had hyperoxaluria, and of these 7% had urinary outputs of oxalate which fell within the range seen in primary hyperoxaluria. The proportion of children with hyperoxaluria in the different diagnostic groups was as follows: intestinal resections (78%), coeliac disease (67%), pancreatic dysfunction (80%), and miscellaneous (45%). 35% of the patients with hyperoxaluria had hypercalciuria, whereas magnesium excretion was normal in all subjects studied. In 2 patients treatment of the underlying condition was accompanied by a return of oxalate excretion to normal. These results indicate that hyperoxaluria and hypercalciuria are common in children with a variety of intestinal disorders, and that such children may be at risk of developing renal calculi without early diagnosis and treatment.     

儿童原发性1型高草酸尿症1例并文献复习

目的 总结儿童原发性1型高草酸尿症 (PH 1)临床资料,提高对该病的认识。方法 采集1例PH 1患儿的临床特点、影像学表现,肾结石分析信息;进行家系调查;对该家系相关成员进行AGXT基因外显子及附近调控区域直接测序,分析突变位点;文献综述。结果 女童,3岁时起病,首发症状为肉眼血尿,继腰、背部疼痛,体外震波碎石、排石治疗后结石复发,7年内进展为终末期肾病。腹部B超、X线平片和CT均提示多发双肾脏和输尿管结石。肾结石成份为单水草酸钙。未发现患儿家族有相同疾病的患者。AGXT基因分析发现,患儿存在c.242C>A（p.Ser81X）和c.823_824dupAG（p.Ser275delinsArgAlafs）杂合突变,其父亲携带c.823_824dupAG杂合突变,其母亲携带c.242C>A杂合突变。患儿为AGXT基因复合杂合突变,其中c.242C>A无义突变为首次报道。结论 PH 1为罕见遗传性疾病。经影像学证实为多发和复发性双肾结石,排除其他原因所致,应该考虑原发性高草酸尿症,肾结石成份和AGXT基因分析是PH 1诊断的重要手段,尤其AGXT基因分析在某些情况下可以替代肝穿刺成为PH 1确诊的无创检查;PH 1早期诊断和干预将会延缓肾功能恶化,改善预后。     

Urinary outputs of oxalate, calcium, and magnesium in children with intestinal disorders. Potential cause of renal calculi

24-hour urinary outputs of oxalate, calcium, and magnesium have been determined in a total of 62 children aged 3 months to 17 years who fell into the following groups: (i) 16 normal controls, (ii) 3 with primary hyperoxaluria, (iii) 9 with small and/or large intestinal resections, (iv) 9 with untreated coeliac disease, (v) 5 with pancreatic dysfunction, and (vi) a miscellaneous group of 20 children with a variety of intestinal disorders. Taken as a whole, 58% of patients with intestinal disorders had hyperoxaluria, and of these 7% had urinary outputs of oxalate which fell within the range seen in primary hyperoxaluria. The proportion of children with hyperoxaluria in the different diagnostic groups was as follows: intestinal resections (78%), coeliac disease (67%), pancreatic dysfunction (80%), and miscellaneous (45%). 35% of the patients with hyperoxaluria had hypercalciuria, whereas magnesium excretion was normal in all subjects studied. In 2 patients treatment of the underlying condition was accompanied by a return of oxalate excretion to normal. These results indicate that hyperoxaluria and hypercalciuria are common in children with a variety of intestinal disorders, and that such children may be at risk of developing renal calculi without early diagnosis and treatment.     

Urolithiasis and enteric hyperoxaluria in a child with steatorrhea

Malabsorptive states are frequently associated with increased urinary oxalate excretion. The authors describe a 10-year-old girl with steatorrhea, hyperoxaluria, and a renal calculus in a single functioning kidney. Successful management of steatorrhea corrected both the chronic diarrhea and hyperoxaluria. Enteric hyperoxaluria is a well-known etiology of calcium oxalate urolithiasis in adults. Pediatricians caring for children with malabsorptive conditions should be aware of the risk of urinary calculus formation as a result of increased dietary oxalate absorption.     

Expanding phenotype of mitochondrial depletion syndrome in association with TWNK mutations

Mitochondrial DNA depletion syndromes (MDS) are a group of clinically and genetically heterogeneous autosomal recessive disorders characterized by a reduction of mtDNA. We report two siblings of Armenian origin with early onset neurodegenerative disease characterized by encephalopathy, severe hypotonia, facial dyskinetic movements, abnormal eye movements, severe failure to thrive, and abnormal renal and hepatic function. Sanger sequencing confirmed two variants in the C10orf2 gene (TWNK) and indicated a diagnosis of MDS. Our recent observation confirms that nephrocalcinosis and proximal tubulopathy can be a part of a clinical picture of MDS associated with TWNK mutations and document peculiar ocular and orobuccolingual dyskinesias. Wrist myoclonia and tongue tremor were new clinical features in our patients. We suggest that the above-mentioned clinical constellation could potentially provide the basis for the diagnosis of MDS.     

Dent病研究进展

小儿蛋白尿的原因很多,多数是由于肾小球疾病引起,故往往忽略了肾小管疾病致蛋白尿的出现.Dent病为一种遗传性肾小管疾病,主要表现为低相对分子原量蛋白尿、高钙尿症、肾脏钙化、肾石症及进行性肾衰竭.目前主要发现CLCN5基因和OCRL1基因突变可导致Dent病的发生.Dent病的治疗目前仍以对症支持治疗为主,主要是降低尿钙排泄,减轻肾脏钙化以及延缓肾功能不全的发生.     

Clinical characteristics and metabolic abnormalities in preschool-age children with urolithiasis in southeast Anatolia

ObjectiveData on urolithiasis in preschool-age children are limited. The aim of this study was to investigate the metabolic etiology and clinical findings of preschool-age children with urolithiasis.MethodsThe medical records of 143 preschool-age children (81 boys, 62 girls, aged 2–6 years) with urolithiasis were retrospectively analyzed. Results of physical examination, serum biochemistry, and urine metabolic evaluation (including urinary citrate, oxalate, calcium, uric acid, cystine, and magnesium) were recorded.ResultsThe mean age at diagnosis was 3.7 ± 1.3 years. A family history of stone disease was found in 79.7% of patients, and 37% of parents had consanguineous marriages. The most common presenting symptoms were hematuria (33%) and urinary tract infection (UTI; 29%). Metabolic abnormalities were found in 119 (83.2%) patients, including hyperuricosuria in 24.5%, hypocitraturia in 23.8%, hyperoxaluria in 21.7%, hypercalciuria in 21.0%, cystinuria in 7.7%, and hypomagnesuria in 1.4%. Multiple metabolic abnormalities were found in 24 (16.8%) patients. Results of 28 stone analyses revealed calcium oxalate or phosphate, cystine, and uric acid in 15, nine, and four of the patients, respectively. ^99mTechnetium–dimercaptosuccinic acid renal scintigraphy revealed that 27.8% of the children with UTI had renal parenchymal scarring, with only four of them having vesicoureteral reflux.ConclusionThe most frequent metabolic abnormalities in preschool-age children with urolithiasis were hyperuricosuria and hypocitraturia. A comprehensive investigation of stone disease in children presenting with hematuria and UTI is important to prevent the development of renal parenchymal scarring.     

Dent病1型5例病例系列报告并文献复习

目的 报告5例Dent病1型患儿的临床资料,提高对其认识。 方法 分析5例Dent病1型患儿病史、实验室检查,对先证者进行Dent病相关基因CLCN5、OCRL外显子及附近调控区域的直接测序,验证先证者父母有无相应位点突变,系统复习国内外文献报告的Dent病1型,归纳临床表型与突变类型。 结果 5例患儿实验室检查发现24 h尿蛋白定量33.0~68.9 mg·kg-1,尿α1微球蛋白、尿白蛋白和尿免疫球蛋白均明显升高,均伴有高钙尿症,其中镜下血尿1例、肾钙质沉着2例,行CLCN5、OCRL基因测序各发现了1个CLCN5突变,分别为R637X、Y479X、G530V、W103fsX104和R707X,其中Y479X、G530V和W103fsX104为新发现的突变位点。系统文献检索260篇Dent病相关文献,逐篇筛选,共有72篇Dent病1型病例报告和病例系列报告进入本文分析,均为病例报道或病例系列报道,欧美人群422例,亚洲人群176例。欧美与亚洲国家Dent病1型临床表型低分子量蛋白尿表现一致,差异无统计学意义,高钙尿症、肾钙质沉着、肾积石、佝偻病和肾功能异常差异均有统计学意义,不同的临床表型没有突出显现突变类型（错义、无义、移码、剪切和缺失突变）的优势。 结论 临床提示Dent病1型可能的患儿可通过基因检测以明确诊断,避免不必要的免疫抑制剂治疗。CLCN5突变具有高度异质性,临床表型与CLCN5突变类型没有显现较好的关联性。     

Antibiotic treatment-induced tubular dysfunction as a risk factor for renal stone formation in cystic fibrosis

OBJECTIVES: Our purpose was to characterize the decisive pathophysiologic factors that lead to renal stone formation (nephrolithiasis) in patients with cystic fibrosis (CF). METHODS: Patients with CF (n = 96) were investigated with respect to lithogenic and inhibitory factors of urolithiasis and compared with 30 healthy control patients. They were subdivided into 2 groups, 86 without renal stones and 10 with renal stones. RESULTS: All stones were exclusively composed of calcium oxalate. As a major pathogenic factor, a urinary disequilibrium between promoting and inhibitory components of stone formation, characterized mainly by hypercalciuria, hyperoxaluria, and hypocitraturia, was found in the patients with nephrolithiasis. They tended to have lower plasma phosphate concentrations and an increased urinary phosphate excretion. The citrate/calcium ratio proved to be a valuable means to discriminate patients with renal stones from control patients. Patients with stones had ingested more cotrimoxazole and ceftazidim, cumulatively, than patients without stones. There was an inverse correlation between the amounts of antibiotics ingested and the percentage of tubular phosphate reabsorption (r = -0.91, P <.0046). CONCLUSION: Renal stone formation in patients with CF is caused by a disequilibrium between promoting and inhibitory components of stone formation, which is dominated by hypercalciuria, hyperoxaluria, and hypocitraturia. Treatment with cotrimoxazole and ceftazidim, primarily, may lead to renal proximal tubular damage with an ensuing sequence of phosphate loss, increase of parathyroid hormone secretion, increased 1,25-dihydroxyvitamin D3 formation, and absorptive hypercalciuria.     

Bone disease of primary hyperoxaluria in infancy

A patient with primary hyperoxaluria type I in infancy is reported. He had renal insufficiency, but urolithiasis was absent. Demonstration of diffuse nephrocalcinosis by renal ultrasound contributed to early diagnosis. Prolonged survival leads to extensive extrarenal oxalate deposition. Repeated skeletal surveys showed the development and the progression of severe hyperoxaluria-related bone disease. Translucent metaphyseal bands with sclerotic margins, wide areas of rarefaction at the ends of the long bones, and translucent rims around the epiphyses and the tarsal bones were signs of disordered bone growth. Bone density generally increased with time indicating progressive sclerosis due to oxalate deposition in the previously normal bone structure.     

Polyhydramnios, prematurity, dystrophy, polyuria, constipation, nephrocalcinosis and renal tumor: presentation of a classic tubulopathy

BACKGROUND: A diagnostic workup of a renal mass will rarely lead to the diagnosis of a tubulopathy. We would like to stress the importance of taking a detailed history and of evaluating these findings in the context of the clinical symptoms. CASE REPORT: A 3 year old boy with a renal mass, diagnosed due to urinary tract infection, was referred to exclude renal malignancy. Detailed history revealed polyuria and polydipsia in a child with preterm delivery due to polyhydramnios. These symptoms, together with poor thriving are highly suggestive of a neonatal form of Bartter syndrome. This diagnosis was substantiated by ultrasound findings of nephrocalcinosis and urolithiasis due to hypercalciuria and a renal abscess. Detection of mutations in the KCNJ1-gene confirmed the diagnosis. After unilateral nephrectomy for acute destructive nephritis and under medication with indomethacin and potassium citrate the patient is now thriving well. CONCLUSION: Renal masses suspicious of malignancy may distract from a hereditary tubulopathy. Typical clinical history and presentation with prematurity, polyhydramnios, polyuria, poor thriving and urolithiasis requires diagnostic evaluation of tubular function since routine laboratory tests and urinary dip stick may be normal. Unrecognized, neonatal Bartter syndrome may lead to severe complications including loss of kidney function.     

Case report of paediatric oxalate urolithiasis and a review of enteric hyperoxaluria

The formation of renal calculi secondary to enteric hyperoxaluria is rare in the paediatric population. We present the case of an 8-year-old boy who had short bowel syndrome resulting in enteric hyperoxaluria which led to the development of urolithiasis and bilateral ureteric strictures, both of which resolved with medical management. We also review the literature on enteric hyperoxaluria.     

Bartter综合征分子遗传学研究进展

Bartter综合征是一组以低钾性代谢性碱中毒为主要特征的遗传性肾小管疾病。近期的分子遗传学研究表明,六个编码肾小管离子通道或转运蛋白的基因突变可引起Bartter综合征,根据这些致病基因的不同。Banter综合征进一步分为六个亚型,即Ⅰ-Ⅴ型Bartter综合征和Gitelman综合征。该文从分子遗传学角度阐述了各种类型Bamer综合征的临床特点和可能的发病机制。     

Primary hyperoxaluria in infants: medical, ethical, and economic issues

OBJECTIVES: Survey on the current medical approach to and the economic issues affecting infants with primary hyperoxaluria type 1. METHODS: Questionnaire to specialized centers worldwide. RESULTS: Seventy-eight infants were identified: 44% were of Muslim origin and 56% were not. The consanguinity rate was 76% and 0%, respectively. Thirty-three percent were treated in developing countries (group 1) and 67% in developed countries (group 2). Initial presentation (4.9 +/- 2.8 months) consisted of failure to thrive (22%), urinary tract infection (21%), and uremia (14%). Radiologic findings included nephrocalcinosis (91%), urolithiasis (44%), or both (22%). The diagnosis was based on family history, tissue biopsy, and urine oxalate level in most patients from group 1 and on urine oxalate and glycolate levels, alanine:glyoxalate aminotransferase activity, and DNA analysis in patients from group 2. Therapeutic withdrawal was the final option for 40% of children; financial reasons were given for 10 of 17 patients from group 1 and 0 of 9 from group 2. End-stage renal disease started at 3.2 +/- 6.4 years of age and was present in half of the patients at the time of diagnosis. Fifty-two percent of the patients died: 82% in group 1 versus 33% in group 2; 33% of patients who underwent transplantation died versus 71% of those who did not. CONCLUSION: The management of primary hyperoxaluria type 1 in infants is a major example of the ethical, epidemiologic, technical, and financial challenges that are raised by recessive inherited diseases with early life-threatening onset. In certain circumstances, oxalosis can be regarded as a condition for which therapeutic withdrawal may be an acceptable option.     

A novel CLCN5 mutation in a Chinese boy with Dent’s disease

Background

Dent’s disease is a rare X-linked recessive hereditary disease caused by mutations in either the CLCN5 or OCRL1 genes. This disease is characterized by manifestations of proximal renal tubule dysfunction associated with low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure.

Methods

We report a Chinese boy with Dent’s disease, clinically diagnosed by LMWP and hypercalciuria. Genetic analysis was made of the CLCN5 and OCRL1 genes. Related studies were also reviewed.

Results

A splice site mutation IVS6, +2T>C of the CLCN5 gene was revealed in this case, and it was not reported previously.

Conclusions

Clinical and genetic analysis is valuable for the diagnosis of Dent’s disease. A novel mutation in the CLCN5 gene was identified in our patient.     

Congenital Gaucher disease with nonimmune hydrops/erythroblastosis, infantile arterial calcification, and neonatal hepatitis/fibrosis. Clinicopathologic report with enzymatic and genetic analysis

The findings in a stillborn female fetus of 31 weeks' gestation with congenital Gaucher disease, nonimmune hydrops/erythroblastosis, infantile arterial calcification, and neonatal hepatitis/fibrosis are presented, the first report of this complete constellation. Prior reports describe two similar patients. One lacked the hepatocellular features of giant cell hepatitis although manifesting hepatic fibrosis; the second lacked hepatic pathology. The diagnosis of Gaucher disease herein was established by microscopic examination of the proband, enzymatic analysis of trophoblast, and enzymatic and genetic study of the parents. The father was heterozygous for a recombinant glucocerebrosidase gene; the mother demonstrated a unique frame shift mutation. Thus the fetus is a compound heterozygote for a null and a severe mutation. Studies of parental DNA were negative for the D409H mutation of type IIIc Gaucher disease. Genetic studies were not performed of the ENPP1 gene, mutations of which are associated with idiopathic infantile arterial calcification.     

Natural history of hematuria associated with hypercalciuria in children

Hypercalciuria (HCU) is frequently found during the evaluation of children with hematuria; the long-term implications of untreated HCU in children are uncertain. Since 1981, we have identified HCU (urinary calcium, greater than 0.1 mmol.kg-1.d-1) in 58 patients (41 male) with hematuria; 64% had gross hematuria and 74% had a relative with urolithiasis. Renal HCU was diagnosed in 19 patients and absorptive HCU in 24 patients. In 15 children, the calcium loading test was nondiagnostic. In nine patients (16%), urolithiasis developed, and in one patient, a renal calcification developed. These 10 patients (seven male) were older (10.1 vs 7.5 years) than the other 48 patients and initially presented with gross hematuria (nine of 10). All 10 patients had a family history of urolithiasis. The initial urinary calcium value was similar between the 10 patients with stones (0.15 mmol.kg-1.d-1) and the patients without stones (0.14 mmol.kg-1.d-1); five had absorptive HCU and four had renal HCU. At least one follow-up urinary calcium measurement was available for 23 patients who were not receiving thiazide therapy during 1 to 6 years after diagnosis (mean, 3.1 years). At 1-year follow-up, 12 of 17 patients had HCU and five had hematuria. Twenty-one patients were studied 2 to 3 years from diagnosis; 11 had HCU and eight had hematuria. After 4 years, six of seven patients had HCU and three had hematuria. We concluded that children with HCU and hematuria are at significant risk for urolithiasis, especially if they have gross hematuria and a family history of urolithiasis. Hypercalciuria may be episodic in children with hematuria, and factors other than urinary calcium concentration may be responsible for urinary bleeding.