62例家族性低磷抗D佝偻病的临床分析

我们对我院1973～1990年收治的62例患儿进行分析,以期作到早期诊断,正确治疗。 1.一般资料:62例均为我院住院患儿。女38例,男24例。1岁内发病4例,1～2岁41例,2～3岁7例,3岁以上5例,发病时间不详5例。发病年龄为8个月～6岁。3岁前确诊12例,3岁后50例。从发病到确诊平均延误4.4年。32例曾在当地误诊为营养性VitD缺乏性佝偻病,其中25例经过系统抗佝缕病治疗。5例误诊为佝偻病后遗症或先天性骨畸     

维生素D及其受体与临床相关疾病的研究

维生素D(Vitamin D,VitD)对人类健康特别是儿童健康具有重要意义,VitD缺乏性佝偻病是我国儿童重点防治的四病之一。临床发现VitD缺乏性佝偻病除骨骼病变外,同时可影响神经、肌肉、造血及免疫等组织器官的功能。近年来对VitD的研究取得了重大进展。     

低血磷抗维生素D佝偻病诊断与治疗:附5例报告

低血磷抗维生素D佝偻病在临床上往往易与营养性佝偻病（维生素D缺乏性佝偻病）相混淆,虽然较少见,但如不及时诊断与治疗,可导致患儿骨骼严重畸形。兹将近四年来在我院儿保门诊就诊的5例低血磷抗维生素D佝偻病的临床资料总结如下。     

表现为类佝偻病的遗传性疾病

总结在发育儿科或儿童保健门诊因腿弯、前囟未闭、头发少等类佝偻病症状就诊的遗传性疾病的临床特点、致病基因及治疗进展,这些遗传性疾病包括低血磷抗维生素D佝偻病、低碱性磷酸酶血症、软骨发育不全、维生素D依赖性佝偻病、致密性骨发育不全和外胚层发育不全。低血磷抗维生素D佝偻病的患儿经常以腿弯、生长迟缓就诊,生化检查血磷明显降低,临床容易诊断。该病治疗与营养性维生素D缺乏性佝偻病不同,需要用1,25羟维生素D3和磷酸盐合剂治疗。低碱性磷酸酶血症特点为碱性磷酸酶明显降低,血钙和磷正常,是由于TNSALP基因突变所致。软骨发育不全患儿除腿弯外,还存在短肢型矮小和特殊面容,血钙、磷和碱性磷酸酶等生化检查均正常,骨骼X线及FGFR3基因检测有助于诊断。维生素D依赖性佝偻病为常染色体隐性遗传,治疗中可选择补充生物活性的维生素D。致密性骨发育不全患儿可因前囟大就诊,此类患儿除了前囟大以外,还伴有下颌角消失、牙齿及指甲发育差等表现,系TSK基因突变所致。外胚层发育不全患儿可因头发少就诊,易误诊为营养性维生素D缺乏性佝偻病,与EDA、EDAR、EDARADD及WNT 10A 4种基因有关。     

6例低血磷性抗D佝偻病误诊分析

在几种抗Ｄ佝偻病中 ,低血磷性抗Ｄ佝偻病较多见 ,其早期表现与最常见的维生素Ｄ缺乏性佝偻病十分相似 ,临床易造成长期误诊。近年来 ,我们在诊治儿童佝偻病时 ,误诊６例 ,现分析如下。临床资料本组男２例 ,女４例 ;年龄２．５～１０岁 ,平均３．５岁。病史最长５年 ,最短６个月 ,平均２．５年。其中来自农村４例 ,城郊２例。临床表现 :大多数以下肢行走无力 ,易摔跤 ,双下肢弯曲畸形 ,甚至出现“Ｘ”或“Ｏ”形腿且进行性加重 ,经一般维生素Ｄ治疗无效而就诊。６例中２例患儿母亲身材矮小 ,也有轻度双下肢“Ｏ”形腿畸形。其他体征如肋外翻…     

维生素D缺乏性佝偻病患儿骨胶原标志物的检测及意义

目的　研究维生素D(VitD)缺乏性佝偻病患儿骨胶原合成与分解的状况 ,探讨其与骨特异性骨碱性磷酸酶 (BALP)之间的相关性。方法　按照佝偻病临床诊断标准确定 2 0 0 1年 11月至 2 0 0 3年 1月河北医科大学附属二院及大同市第一人民医院儿科 14 8例研究对象 (佝偻病组 80例 ,对照组 6 8例 ) ,结合血清 2 5 羟维生素D(2 5 OHD)及BALP检测结果 ,经过两次筛查 ,明确最后研究对象为佝偻病组 4 3例 ,对照组 37例 ,用酶联免疫方法检测其血清I型前胶原羧基末端前肽 (PICP) ,I型胶原羧基末端交联 (crosslaps)水平。结果　佝偻病患儿血清PICP、crosslaps水平均高于正常组 ,且差异均有显著性意义。佝偻病组及正常组除血清BALP、PICP有正相关关系且有统计学意义 ,其他指标间均无相关性。结论　VitD缺乏性佝偻病患儿骨胶原的合成增强 ,并与骨碱性磷酸酶有相关性。PICP可否作为佝偻病早期诊断的指标需进一步研究。VitD缺乏性佝偻病患儿骨胶原的分解增强。佝偻病患儿骨胶原代谢处于高转换状态。     

家族性抗D性佝偻病5例临床分析和长期疗效观察

本文报告5例家族性抗D性佝偻病,并对3～4.5年治疗结果进行分析。5例均为男性,4例有家族史。发病年龄6个月～2岁,诊断年龄2.5～8岁。主要临床表现为骨胳畸形5例,牙齿发育异常4例,身材矮小4例等。均有显著低磷血症、尿磷增加、碱性磷酸酶增高及佝偻病的X线改变。口服磷酸/磷酸氢二钠或磷酸二氢钠/磷酸氢二钠合剂治疗,用量根据年龄、临床和实验室检查结果调整。维生素D用量为1～5万u/d。经随访骨畸形均有不同程度纠正,1例身高恢复正常。早期诊治是改善预后的主要因素。     

儿科住院病人与营养性维生素D缺乏症

本文报告儿科1985年3岁以内住院患儿380人,其中患有VitD 缺乏症者90人,占23.68%;新生儿63人,发现先天性佝偻病2例,患病率为3.2%.90例VitD 缺乏症并存的儿科疾病最多者为肺炎46例(50.5%),上感20例(22.2%),腹泻6例(6.6%)。65/90例作了生化检查,其特点为佝偻病早期,多表现血钙降低(85%),硷性磷酸酶升高(87.5%);激期血钙下降者54.5%,血磷下降者27.3%,碱性磷酸酶升高者54.8%。肺炎合并佝偻病时与单纯肺炎对照,主要症状及体征消退时间及平均住院天数,两组间有显著差异。同时观察肺炎并存佝偻病入院后应用VitD 治疗早晚对疗效亦有显著差异,早期应用可提高肺炎的治愈率。     

维生素D缺乏性佝偻病患儿心功能评价

目的探讨VitD缺乏性佝偻病患儿治疗前后左心收缩功能。方法按佝偻病的生化分类将患儿分为Ⅰ组11例,Ⅱ组12例,Ⅲ组13例。使用彩色多普勒超声诊断仪对佝偻病36例治疗前后进行心功能测定,20例健康儿童作为健康对照组。结果佝偻病患儿治疗前心搏量（SV）、射血分数（EF）、左室射血前期（PEP）、射血时间（LVET）和PEP/LVET的比值与健康对照组比较均有显著差异（Pa〈0.01）;治疗后PEP、PEP/LVET恢复正常,SV、EF、LVET仍有差异（Pa〈0.01）。各组治疗前后比较以Ⅲ组心功能受影响最明显,EF、左室缩短分数（FS）、PEP、LVET和PEP/LVET治疗前、后均有显著差异（Pa〈0.01）。结论VitD缺乏性佝偻病患儿左心的收缩功能可受到影响,特别是佝偻病第3期心功能更易受累,且心功能异常随着佝偻病的治疗可恢复正常。     

儿童 Dent 病Ⅰ型 4 例报告

目的探讨Dent病Ⅰ型的诊断和治疗。方法回顾分析4例Dent病Ⅰ型患儿的临床资料及相关基因CLCN5、OCRL1外显子及附近调控区域的直接测序结果。结果 4例患儿均为男性,发病年龄1.5~4岁,确诊年龄3~10岁;临床皆有蛋白尿表现,其中2例伴佝偻病症状。基因检测均发现CLCN5突变,分别为L263F、R104X、S244L及外显子9-13缺失。S244L为Dent病Ⅰ型患者最为常见的突变,其余均为新发现突变位点。结论 Dent病Ⅰ型主要表现为低分子量蛋白尿,高钙尿症。基因检测有助于早期明确诊断。     

A clinical and molecular genetic study of hypophosphatemic rickets in children

X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria, and tumor-induced osteomalacia share clinical and biochemical features, and are collectively referred to as hypophosphatemic rickets (HR). Recently, the molecular bases of HR were elucidated. A review of medical records and mutational analyses of the PHEX and FGF23 genes were performed on 17 unrelated Korean children with HR. The male-to-female ratio was 3:14, and 5 patients were familial. Initial laboratory tests revealed typical features of HR. Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions. No functional FGF23 mutation was detected in any patient. Patients with the PHEX mutation tended to have more severe skeletal disease than those without. Of the patients with this mutation, no genotype-phenotype correlation and no gene dosage effect were noted. Treatment with vitamin D and phosphate resulted in only a partial growth improvement in most cases, and was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism. Renal glycosuria was detected in six cases and was associated with more severe skeletal disease. We conclude that current HR treatment is not fully safe or effective, and that close monitoring of treatment effectiveness and for complications should be performed during long-term treatment. No genotype-phenotype correlation in XLH was detected in this study, but a large-scaled study on this topic is warranted. The large proportion of patients with a normal genetic study suggests the possibility of other causative gene(s).     

Type III osteogenesis imperfecta associated with hypophosphatemic vitamin D-resistant rickets

In a 7 year old girl presenting with bone deformities, dwarfism, and a history of recurrent fractures osteogenesis imperfecta had been diagnosed at birth. Although she had been hospitalized several times, radiologic signs of rickets remained unnoticed. Laboratory data proved existence of hypophosphatemic vitamin D-resistant type of rickets, which was effectively treated with 1 alpha-hydroxycholecalciferol and phosphorus substitution. The combination of osteogenesis imperfecta type III and hypophosphatemic rickets may be coincident. It proves, however, the necessity to consider the possible simultaneous occurrence of two rare diseases. The therapeutic consequences could be important.     

Treatment of Hypophosphatemic Rickets with Phosphate and Active Vitamin D in Japan: A Questionnaire-based Survey

Hereditary hypophosphatemic rickets represented by X-linked hypophosphatemic rickets (XLH) is a rare disorder characterized by hypophosphatemia, elevated alkaline phosphatase (ALP) and undermineralization of bone. Active vitamin D and phosphate are administered to correct hypophosphatemia and elevation of ALP. Overtreatment with phosphate leads to secondary hyperparathyroidism, and a large dose of active vitamin D has a risk of hypercalciuria. To understand the situation concerning treatment of patients with hereditary hypophosphatemic rickets in Japan, we conducted a questionnaire survey of pediatric endocrinologists. Answers were obtained from 53 out of 68 hospitals where the pediatric endocrinologists worked. One hundred and thirty-five patients were treated in 28 hospitals during November 2009 and May 2010; 126 patients suffered from hereditary hypophosphatemic rickets, and 9 had hypophosphatemia caused by other miscellaneous reasons. The distribution of patient age was as follows: 27 (21%) were between 6 mo and 6 yr of age, 39 (31%) were between 6 and 12 yr of age, and 60 (48%) were more than 12 yr of age. Active vitamin D was given to 123 patients, and phosphate was given to 106 patients. As for the dose of phosphorus, 37.2–58.1 mg/kg/d was given divided into 2 to 6 aliquots. There were various control targets of treatment, including serum phosphate, serum ALP, rachitic change, urinary Ca/Cr, parathyroid hormone and growth. It is very important to avoid side effects of these treatments. No evidence is available about the optimal dose of phosphate or number of administrations in the treatment of patients with hypophosphatemic rickets. Although there is a recommendation for clinical management of patients with hypophosphatemic rickets, we should set a clinical guideline for it in Japan.     

Sagittal synostosis in X-linked hypophosphatemic rickets and related diseases

Background The recent observations of two new cases of X-linked hypophosphatemic rickets associated with premature closure of the sagittal suture prompted a review of similar cases seen in this institution. Objectives To review the clinical records and skull radiographs of 28 children with hypophosphatemic rickets in order to investigate the frequency and type of craniosynostosis and other cranial vault changes seen in these conditions and to review the literature for relevant findings. Materials and methods Clinical and imaging records were reviewed on 28 patients with hypophosphatemic rickets, all younger than 18 years. Most patients had X-linked hypophosphatemic rickets and a few had autosomal-dominant hypophosphatemic rickets or were non-familial cases. Results Of the 28 patients, 13 had sagittal synostosis. Dolichocephaly was present in ten patients. The configuration of the cranial vault in some of these ten patients with dolichocephaly varied somewhat from that seen in nonsyndromic sagittal synostosis. In one patient, a Chiari I malformation was demonstrated by MRI. In another patient with increased intracranial pressure the sagittal suture closure was associated with lambdoidal synostosis. Dolichocephaly was not present in three patients, suggesting that the synostosis started later than in the other patients, probably in the second year of life, a period of slower brain growth than in the first year. The two patients in this group of three showed thickening and sclerosis of the cranial vault of uncertain etiology. Conclusion There is an increased risk of sagittal synostosis in hypophosphatemic rickets and related diseases in children. The appearance of the cranial vault in this type of synostosis can vary from that seen in nonsyndromic synostosis. In this setting, careful clinical and imaging follow-up is warranted.     

Non-azotemic refractory rickets in Indian children

In order to examine the etiology of refractory rickets, we evaluated the case records of patients presenting between 1990 and 2002. Subjects with impaired renal functions were excluded. Of 131 patients, 25.9 % each had hypophosphatemic rickets and distal renal tubular acidosis (RTA), 19.6 %vitamin D dependent rickets (VDDR), 11.3 % proximal RTA, 9.1 % liver disease and 6.1 % malabsorption. A significant proportion of patients with VDDR and proximal RTA showed deformities in the first year of life, whereas those with distal RTA and hypophosphatemic rickets presented later. Patients with hypophosphatemic rickets had predominant involvement of lower limbs; hypercalciuria was found in 4. Distal RTA was associated with marked rickets and normal levels of alkaline phosphatase. Hypophosphatemia and low tubular reabsorption of phosphate, though characteristic of hypophosphatemic rickets, was also seen in patients with VDDR (19.2%) and distal RTA (17.6 %). Our findings suggest that application and interpretation of appropriate investigations are useful in determining the cause of non-azotemic refractory rickets allowing initiation of specific therapy.     

Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions.

A 5-year-old boy was found to have severe rickets in association with hyperpigmented, linear, verrucous, epidermal tumors, typical of the epidermal nevus syndrome. Normocalcemia (9.6 mg/dl), hypophosphatemia (2.0 mg/dl), elevated serum alkaline phosphatase concentration (313 IU), decreased renal tubular reabsorption of phosphorus (35%), radiologic evidence of rickets, and lack of response to usual therapeutic doses of vitamin D suggested hypophosphatemic vitamin D-resistant rickets. Therapy with vitamin D in doses to 750,000 IU and oral phosphate, 2.0 gm/day, failed to induce healing of the rickets. A subtotal parathyroidectomy performed when the patient was 9 years old was also without effect. When he was 12 years old several fibroangiomas on the face and left lower limb were excised. Within three months all biochemical abnormalities resolved and radiologic evidence of healing was observed. A portion of excised tissue was homogenized and injection of the supernate into a 6-week-old puppy induced excessive phosphaturia. The data suggest that the rickets was induced by a phosphaturic substance extractable from the tumors.     

Hyperparathyroidism in patients with X-linked dominant hypophosphatemic rickets--application of the calcium infusion test as an indicator for parathyroidectomy

Two children with X-linked dominant hypophosphatemic rickets treated with vitamin-D metabolites and phosphate supplementation, for prolonged periods, developed hyperparathyroidism with nephrocalcinosis. Calcium infusion tests were performed in both. In one patient, the initial test was done two weeks after all treatment was stopped. Only moderate decrease in the degree of the phosphaturia was recorded. However, a repeat test, performed after all medications were withheld for another four weeks, showed normal anti-phosphaturic response, and she continued to be treated conservatively. In the other patient, the test was done five weeks after withholding treatment. Failure to suppress the phosphaturia provided strong support for the diagnosis of tertiary hyperparathyroidism. He underwent total parathyroidectomy and the parathyroid histology confirmed the diagnosis. In both, control of parathyroid activity stopped the deterioration in kidney function and improved the response of the basic disorder to treatment. It is concluded that in patients with X-linked dominant hypophosphatemic rickets, the calcium infusion test is useful for the differentiation between secondary-reversible and tertiary-irreversible hyperparathyroidism. To avoid continued stimulation of the parathyroid glands by phosphate administration, we recommend that such calcium infusion test be performed and interpreted after at least six weeks have elapsed without phosphate or vitamin-D administration.     

Growth in X-linked hypophosphatemic rickets

Growth failure appears frequently in children with X-linked hypophosphatemic rickets (XLHR) due to hypophosphatemia, disease severity, body disproportion, and primary bone abnormality. Recombinant human growth hormone (rhGH) increases phosphate tubular reabsorption and phosphate level in blood and, thus, constitutes an attractive but controversial therapy in short children with XLHR, those efficacy was demonstrated in small uncontrolled series. Our aim was to report our experience regarding growth in XLHR. Twenty-seven children with XLHR—20 girls, seven boys—diagnosed at a median (md) of 1.46 years of age, (range 0.39–8.5 years), were studied at 10.12 years of age (1.58–18.56), md (range). All received oral treatment with phosphate and calcitriol. At the first visit, grouped Z-height was −1; (−4.58; 0.54) md (range). After 5 years’ follow-up (0.92–15.6), Z-height was −0.91 (− 4.56; 0.17), not different from that at baseline (P = 0.465). In 16 children entirely controlled in our program upon presentation, a “catch up” phenomenon after the rickets had healed (P = 0.823) or throughout the long-term was not observed (P = 0.995). Eight patients had a Z-height ≤ −2SD at the last visit, and impaired linear growth was associated with age >2 years at diagnosis, male gender and non-adherence to treatment. Four children, all boys, received rhGH, and in two cases with sufficient follow up stature normalized. No rhGH side effects were observed, and phosphate and calcitriol doses remained stable. Linear growth failure appeared in a third of XLHR children. Efforts need to be made to reduce the age of diagnosis and to improve adherence to treatment. Treatment with rhGH should be considered early, after the rickets has been controlled, in those patients with impaired growth or delayed diagnosis.     

Regulation of phosphate homeostasis in infants, children, and adolescents, and the role of phosphatonins in this process

PURPOSE OF REVIEW: Unlike calcium metabolism, the control of phosphate homeostasis has long been poorly understood. The identification of 'phosphatonins' in the serum of hypophosphatemic patients, the unveiling of the genetic causes of hypo and hyperphosphatemic diseases in patients, and the creation of finely adapted animal models have revolutionized our understanding of phosphate homeostasis. RECENT FINDINGS: Original reports published in 2006/2007 bring valuable pieces of information that enable better understanding of the physiological regulation of phosphate homeostasis by more precisely defining the interplay between PHEX, vitamin D, and phosphatonins; identification of new genes causing hypophosphatemic rickets, aside from PHEX and fgf23, namely the genes encoding for a renal sodium-phosphate cotransporter, NaPiIIc, and for a bone matrix protein, DmpI; and improved diagnosis of tumor-induced osteomalacia with more precise imaging techniques for tumor localization and more precise fibroblast growth factor 23 assays. SUMMARY: From a clinical point of view, these findings offer new tools for the diagnosis of hypophosphatemic rickets (biologic, genetic, imaging techniques) and open the way to new treatment strategies.     

Hypophosphatemic rickets : Easy to diagnose, difficult to treat

Hypophosphatemic rickets (HR) has generated a lot of interest in recent times. There is need to recognize this disorder and differentiate it from the more common nutritional rickets because the therapy is different. It is also important to emphasize that a detailed clinical examination with pedigree analysis and easily available biochemical tests are adequate to establish the diagnosis in most cases. This report presents three families with hypophosphatemic rickets. Interestingly, many of these patients had a mixed picture of HR and nutritional rickets. Their important features are described with special emphasis on early initiation of treatment with oral phosphate and stringent monitoring of renal functions to prevent development of irreversible renal insufficiency.