Primary care pediatrician knowledge of nutritional rickets

OBJECTIVE: The purpose of this study is to determine primary care pediatricians' level of awareness in the diagnosis and management of rickets. The information will be useful in assessing the need for provider education related to appropriate advice regarding vitamin D supplementation for infants. STUDY DESIGN: A one-page questionnaire was sent to a sample of 510 pediatricians in states surrounding the Great Lakes. These physicians were chosen depending based on practice listings from local telephone directories. Results were analyzed using the Chi-squared (chi2) test. RESULTS: Of the 248 respondents, 43% (n = 105) had encountered at least one actual or suspected case of rickets in the past five years. Sixty-nine percent of respondents chose vitamin D deficiency rickets-specific diagnostic tests, 24% chose rickets-specific tests, and 7% chose tests that are not specific to diagnosing rickets. Ninety-four percent of respondents chose treatments specific to vitamin D deficiency rickets, while 6% chose treatments not specific to rickets. CONCLUSION: Most primary care pediatricians from major metropolitan areas in the Great Lakes region are aware of the appropriate methods to diagnose and treat vitamin D-deficiency rickets. However, educational interventions are still necessary for both physicians and parents to promote widespread use of vitamin D supplementation in all breastfed infants.     

Incidental finding of vitamin-D deficient rickets in an otherwise healthy infant--a reappraisal of current vitamin-D supplementation guidelines

In an effort to prevent rickets and vitamin-D deficiency in healthy infants, the American Academy of Pediatrics recommends a supplement of 200 IU per day of vitamin D to all breastfed and nonbreastfed infants unless they consume at least 500 ml per day of vitamin-D-fortified formula or milk. Case reports of infantile vitamin-D-deficient rickets secondary to maternal vitamin-D deficiency have been reported but focused on mothers who had predictable risk factors for such a deficiency. We report on an infant with vitamin-D-deficient rickets who did not have nutritional risk factors and whose mother did not have nutritional or medical risk factors for such a deficiency. We conclude that the current vitamin-D supplementation guidelines be extended to all infants, regardless of feeding volume or source, or at least to all infants born to dark-skinned mothers.     

The role of dietary calcium in the etiology of childhood rickets in the past and the present

For more than two centuries, lack of sunlight has been understood to cause vitamin D deficiency and documented as a primary cause of rickets. As such, evidence of rickets in the archeological record has been used as a proxy for vitamin D status in past individuals and populations. In the last decade, a clinical global consensus has emerged wherein it is recognized that dietary calcium deficiency also plays a role in the manifestation of rickets and classic skeletal deformities may not form if dietary calcium is normal even if vitamin D is deficient. This disease is now clinically called “nutritional rickets” to reflect the fact that rickets can take calcium deficiency-predominant or vitamin D deficiency-predominant forms. However, there are currently no paleopathological studies wherein dietary calcium deficiency is critically considered a primary etiology of the disease. We review here the interplay of calcium, vitamin D, and phosphorous in bone homeostasis, examine the role of dietary calcium in human health, and critically explore the clinical literature on calcium deficiency-predominant rickets. Finally, we report a case of rickets from the late Formative Period (~2500–1500 years ago) of the Atacama Desert and argue the disease in this infant is likely an example of calcium deficiency-predominant rickets. We conclude that most archeological cases of rickets are the result of multiple micronutrient deficiencies that compound to manifest in macroscopic skeletal lesions. For clinicians, these factors are important for implementing best treatment practice, and for paleopathologists they are necessary for appropriate interpretation of health in past communities.     

Genetic and clinical profile of patients with hypophosphatemic rickets

Nutritional vitamin D deficiency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23 related), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D dependent rickets. Hypophosphatemia is a feature in all these forms. The diagnosis relies on a combination of clinical, biochemical and radiological features, but genetic testing is required to confirm the diagnosis. We screened 66 patients with hypophosphatemic rickets referred to this center between May 2015 and July 2019 using whole exome sequencing (WES) in addition to the measurement of their intact serum fibroblast growth factor 23 (FGF23) levels. WES revealed 36 pathogenic and 28 likely pathogenic variants in 16 different genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) in 63 patients which helped differentiate between the various forms of hypophosphatemic rickets. Intact serum FGF23 levels were significantly higher in patients with variations in PHEX, FGF23, DMP1 or ENPP1 genes. The major genetic causes of rickets were classic hypophosphatemic rickets with elevated FGF23 levels, distal renal tubular acidosis, and vitamin D dependent rickets. Based on the present results, we propose a customized gene panel for targeted exome sequencing, which will be useful for confirming the diagnosis in most patients with hypophosphatemic rickets.     

Studies on the pathogenesis of avian rickets. I. Changes in epiphyseal and metaphyseal vessels in hypocalcemic and hypophosphatemic rickets.

Growth plate morphometry and measurements of serum chemistry were correlated to clarify the pathogenesis of hypocalcemic and hypophosphatemic avian rickets. Accumulation of proliferating and maturing cartilage in hypocalcemic chicks is accompanied by increased length and increased variation in length of perforating epiphyseal vessels, decreased number and abnormal arrangement of marrow spaces, an increased proportion of cells to blood vessels in marrow spaces, and a change in the distribution but not the total number of DNA-synthesizing chondrocytes per unit width of growth plate. Accumulation of hypertrophic cartilage in hypophosphatemic rickets is accompanied by no change in length, distribution, or number of perforating epiphyseal vessels, elongation but no change in number or arrangement of marrow spaces, an increase in the relative proportion of blood vessels to cells in the marrow spaces, and no change in distribution but a decrease in total number of DNA-synthesizing chondrocytes per unit width of growth plate. Both types of rickets have decreased amounts of calcified cartilage. These results provide further evidence that hypocalcemia and hypophosphatemia cause morphologically distinct types of rickets in birds. The data indicate that the thickness of the proliferating and maturing region and hence the distance of the hypertrophic zones from the epiphysis are anatomically and temporally related to length of perforating epiphyseal vessels and serum calcium levels. They indicate that in hypocalcemic rickets accumulation of proliferating and maturing cartilage is unlikely to be the result of increased chondrocyte replication and that the relative rates of chondrocyte hypertrophy and resorption of hypertrophic cartilage by marrow are equal. They support the concept that delayed chondrocyte hypertrophy is the major cause of growth plate thickening in hypocalcemic rickets. Data presented in this study, when considered together with data from the literature on hypophosphatemic rickets, support the long-held concept that growth plate thickening in this disease is caused primarily by a decreased rate of resorption of hypertrophic cartilage by marrow relative to the rates of chondrocyte proliferation, maturation, and hypertrophy. The data further support the concepts that growth of cartilage into marrow is a biphasic process including longitudinal growth effected mainly by blood vessels, and resorption of the lateral walls of marrow spaces effected mainly by marrow cells, and that it is the latter phase that is defective in hypophosphatemia.     

High Incidence of Rickets in Extremely Low Birth Weight Infants with Severe Parenteral Nutrition-Associated Cholestasis and Bronchopulmonary Dysplasia

Risk factors for rickets of prematurity have not been re-examined since introduction of high mineral formula, particularly in ELBW infants. We analyzed the incidence and the risk factors of rickets in extremely low birth weight (ELBW) infants. As a retrospective case-control study from 2004 to 2008, risk factors were analyzed in 24 patients with rickets versus 31 patients without. The frequency of rickets in ELBW infants was 24/55 (44%). Infants with rickets were diagnosed at 48.2 ± 16.1 days of age, and improved by 85.3 ± 25.3 days. By radiologic evaluation, 29% were grade 1 rickets, 58% grade 2 and 13% grade 3. In univariate analysis, infants with rickets had significantly higher incidence of patent ductus arteriosus, parenteral nutrition associated cholestasis (PNAC), severe PNAC and moderate/severe bronchopulmonary dysplasia (BPD). In multiple regression analysis, after adjustment for gestation and birth weight, rickets significantly correlated with severe PNAC and with moderate/severe BPD. Serum peak alkaline phosphatase levels were significantly elevated in rickets (P < 0.001). In ELBW infants, the incidence of rickets of prematurity remains high and the incidence of severe PNAC and moderate/severe BPD was significantly increased 18 and 3 times, respectively.     

A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children.

BACKGROUND: Nutritional rickets remains prevalent in many tropical countries despite the fact that such countries have ample sunlight. Some postulate that a deficiency of dietary calcium, rather than vitamin D, is often responsible for rickets after infancy. METHODS: We enrolled 123 Nigerian children (median age, 46 months) with rickets in a randomized, double-blind, controlled trial of 24 weeks of treatment with vitamin D (600,000 U intramuscularly at enrollment and at 12 weeks), calcium (1000 mg daily), or a combination of vitamin D and calcium. We compared the calcium intake of the children at enrollment with that of control children without rickets who were matched for sex, age, and weight. We measured serum calcium and alkaline phosphatase and used a 10-point radiographic score to assess the response to treatment at 24 weeks. RESULTS: The daily dietary calcium intake was low in the children with rickets and the control children (median, 203 mg and 196 mg, respectively; P=0.64). Treatment produced a smaller increase in the mean (+/-SD) serum calcium concentration in the vitamin D group (from 7.8+/-0.8 mg per deciliter [2.0+/-0.2 mmol per liter] at base line to 8.3+/-0.7 mg per deciliter [2.1+/-0.2 mmol per liter] at 24 weeks) than in the calcium group (from 7.5+/-0.8 [1.9+/-0.2 mmol per liter] to 9.0+/-0.6 mg per deciliter [2.2+/-0.2 mmol per liter], P<0.001) or the combination-therapy group (from 7.7+/-1.0 [1.9+/-0.25 mmol per liter] to 9.1+/-0.6 mg per deciliter [2.3+/-0.2 mmol per liter], P<0.001). A greater proportion of children in the calcium and combination-therapy groups than in the vitamin D group reached the combined end point of a serum alkaline phosphatase concentration of 350 U per liter or less and radiographic evidence of nearly complete healing of rickets (61 percent, 58 percent, and 19 percent, respectively; P<0.001). CONCLUSIONS: Nigerian children with rickets have a low intake of calcium and have a better response to treatment with calcium alone or in combination with vitamin D than to treatment with vitamin D alone.     

骨碱性磷酸酶对婴幼儿佝偻病早期诊断的临床研究

目的探讨骨碱性磷酸酶（BALP）在婴幼儿佝偻病早期诊断中的临床意义。方法对123例维生素D（VitD）缺乏性佝偻病患儿进行BALP检测并设立正常对照组，对BALP≥250u／L者，结合临床进行血清钙（Ca）、磷（P）、碱性磷酸酶（AKP）和X线比较分析。结果BALP检测具有敏感、特异、简单、快速、经济等优点。结论BALP是目前佝偻病早期诊断有价值实验方法，值得普及和推广。     

Alopecia with rickets: an end organ unresponsiveness to 1,25-dihydroxyvitamin D--a case report

Two siblings of a rare syndrome of vitamin D dependent type II rickets are reported for the first time from India. The clinical and biochemical picture was characterised by florid rickets, alopecia, hypocalcemia and resistance to therapy with high dosages of vitamin D3. Due to lack of facilities for estimation of 1,25(OH)2D, alopecia remains the only clue to the diagnosis of this rare syndrome in association with resistant rickets.     

Morbidity, rickets and long-bone growth in post-medieval Britain--a cross-population analysis

BACKGROUND: Vitamin D deficiency rickets is associated with skeletal deformities including swollen rib junctions, bowing of the legs, and the flaring and fraying of the wrist and long-bone metaphyses. There is, however, scarce information on the direct effect of rickets on skeletal growth in either present or past populations. AIM: The study investigated the effect of vitamin D deficiency rickets on long-bone growth in two post-medieval skeletal populations from East London (Broadgate and Christ Church Spitalfields). Subsequently, inter-population growth variations in relation to non-specific environmental stress (dental enamel defects), industrialization, urbanization and socio-economic status during infancy (birth to 3 years) and early childhood (3-7 years) were examined. SUBJECTS AND METHODS: Data on long-bone diaphyseal length dimensions and stress indicators of 234 subadults from Anglo-Saxon, late medieval and post-medieval archaeological skeletal samples were analysed using both linear and non-linear growth models. RESULTS: Rickets had no effect on the growth curves for any of the long bones studied. However, pronounced variations in growth between the four populations were noted, mainly during infancy. The diaphyseal length of long bones of Broadgate were significantly smaller-per-age than those of Spitalfields and the other samples up to the age of 4 years, and were associated with a high prevalence of enamel defects during early infancy. CONCLUSION: Socio-economic status, rather than urbanization, industrialization or rickets, was the central factor behind the observed differences in growth among the post-medieval populations. The observed inter-population growth variations were only significant during infancy.     

Transient hyperthyroxinemia associated with rickets

The case of an 8-month-old infant with rickets and hyperthyroxinemia is described. Hyperthyroxinemia resolved following the treatment of the rickets. This association has not been reported previously.     

维生素D受体基因多态性与维生素D缺乏性佝偻病遗传关联性Meta分析

目的评价维生素D受体（VDR）基因多态性与维生素D缺乏性佝偻病（佝偻病）的遗传关联性。方法制定原始文献的纳入标准及检索策略,检索PubMed、Springer、Science Direct、Web of Science、中国期刊全文数据库、维普中文科技期刊数据库和万方数据库,收集VDR基因FokⅠ、ApaⅠ、BsmⅠ和TaqⅠ位点多态性与佝偻病相关性的病例对照研究,以佝偻病患儿为病例组。依据NHI-NHGRI研究工作组2007年制定的遗传关联性研究报告规范为基础,并依据相关文献选取其中的14条标准用于评价文献偏倚。以基因型频率为指标,提取数据后先确定最佳遗传模型,采用Stata 11.0软件进行Meta分析,计算合并的OR值及其95%CI。结果 19篇病例对照研究进入Meta分析。①FokⅠ位点采用共显性模型（FF基因型vsff基因型;FF基因型vsFf基因型）分析,病例组704例,对照组596例。Meta分析结果显示,亚洲人群FF基因型较ff基因型（OR=4.59,95%CI：2.98~7.07）和Ff基因型（OR=2.58,95%CI：1.79~3.73）患佝偻病的风险显著增加;高加索人群FokⅠ位点与佝偻病无显著关联性（FF基因型vsff基因型,OR=2.50,95%CI：0.76~8.19;FF基因型vsFf基因型,OR=1.18,95%CI：0.66~2.10）;非洲人群FF基因型较ff基因型患佝偻病的风险显著增加（OR=5.81,95%CI：1.21~27.98）。②ApaⅠ位点采用显性模型（AA＋Aa基因型vsaa基因型）分析,病例组338例,对照组459例。亚洲人群和非洲人群ApaⅠ位点与佝偻病均无显著关联性,OR分别为1.04（95%CI：0.72~1.49）和0.98（95%CI：0.57~1.71）;高加索人群AA＋Aa基因型患佝偻病的风险增高（OR=5.50,95%CI：1.22~24.75）。③BsmⅠ位点采用显性模型（bb基因型vsBb＋BB基因型）分析,病例组822例,对照组736例。亚洲人群BsmⅠ位点bb基因型较Bb＋BB基因型患佝偻病的风险降低（OR=0.46,95%CI：0.23~0.92）,非洲人群BsmⅠ位点与佝偻病无显著关联性（OR=1.65,95%CI：0.95~2.88）。④TaqⅠ位点采用隐性模型（TT基因型vsTt＋tt基因型）分析,病例组519例,对照组513例。亚洲人群（OR=1.22,95%CI：0.82~1.82）、高加索人群（OR=0.91,95%CI：0.35~2.35）和非洲人群（OR=1.18,95%CI：0.68~2.05）TaqⅠ位点与佝偻病无显著关联性。结论现有证据表明,亚洲人群FokⅠ位点FF基因型为患佝偻病的危险因素,而BsmⅠ位点bb基因型为佝偻病轻微的保护因素,尚不能认为ApaⅠ和TaqⅠ位点与佝偻病有关联性;由于高加索人群和非洲人群研究较少,VDR基因多态性与佝偻病的关联性尚不明确。     

Effects of therapy in X-linked hypophosphatemic rickets.

BACKGROUND. Patients with X-linked hypophosphatemic rickets, which is clinically manifested by growth failure and bowing of the legs, are usually treated with phosphate and a vitamin D preparation. However, the efficacy of this treatment has been disputed, and nephrocalcinosis is a recognized complication of therapy. METHODS. We studied 24 patients with X-linked hypophosphatemic rickets (9 boys and 15 girls) ranging in age from 1 to 16 years (median, 5.3). The duration of combination therapy ranged from 0.3 to 11.8 years (median, 3.0). We measured height as a standard-deviation (SD) score (the number of SDs from the mean height for chronologic age). Measurements made before the age of two years or after the onset of puberty were excluded. We compared the results with those reported in 1971 for 16 untreated prepubertal Australian patients. We also determined the severity of nephrocalcinosis (on a scale of 0 to 4, with 0 indicating no abnormalities and 4 stone formation) with renal ultrasonography and whether it could be related to the dosage of phosphate or vitamin D or to other factors. RESULTS. Patients treated for at least two years before the onset of puberty (n = 19) had a mean height SD score of -1.08, as compared with -2.05 in the untreated historical controls. The 13 patients who had been treated with calcitriol and phosphate for at least two years had an increase in the mean height SD score of 0.33, from -1.58 to -1.25 (95 percent confidence interval, 0 to 0.67; P = 0.05). Nineteen of the 24 patients (79 percent) had nephrocalcinosis detected on renal ultrasonography. The grade of nephrocalcinosis was significantly correlated with the mean phosphate dose (r = 0.60, P = 0.002), but not with the dose of vitamin D or the duration of therapy. All patients had normal serum creatinine concentrations. CONCLUSIONS. Therapy with calcitriol and phosphate may increase the growth of children with X-linked hypophosphatemic rickets. Nephrocalcinosis in these children represents a complication of therapy and is associated with the dose of phosphate received.     

Experimental hypophosphataemia in growing pigs: effects on endochondral ossification in comparison to osteochondrosis.

Hypophosphataemia was induced in growing pigs by dietary supplementation with aluminium hydroxide. The effect on endochondral ossification was studied morphologically in comparison with normophosphataemic pigs given aluminium phosphate or left untreated. The aim of the investigation was to elucidate further the role of nutritional factors in the pathogenesis of disturbed endochondral ossification, occurring in osteochondrosis. In all pigs, focal arrestment of endochondral ossification with subsequent cartilage retention in the epiphyseal or metaphyseal growth zones was seen. In normophosphataemic pigs, focal degenerative cartilage changes were associated with impairment of vascular penetration. The lesions had morphological characteristics of early osteochondrosis. In hypophosphataemic pigs, a more generalized disturbance, endochondral ossification, was seen with impaired vascular penetration and excessive deposition of osteoid in the primary spongiosa. Focal cartilage retentions were associated with necrotic changes in the primary spongiosa and not with cartilage degeneration. The lesions were similar to rickets and it was concluded that hypophosphataemia is not an aetiological factor in the development of osteochondrosis. The differentiation between the cartilage retention seen in early stages of osteochondrosis and rickets must be based on histological examination.     

骨骼畸形儿童的临床研究

目的探讨骨骼畸形与晚发性佝偻病(DR)的关系.方法采用病例对照,结合临床调查,检测了85例骨骼畸形儿童及50例健康儿童的血钙、血磷、碱性磷酸酶(ALP)、骨碱性磷酸酶(BALP)、X线.结果85例5～16岁骨骼畸形儿童的临床症状主要为多汗、肢体疼痛、肢体无力、肌肉痉挛;体征以鸡胸和X形腿为多见;血钙、血磷、碱性磷酸酶检测阳性率均低,BALP测定阳性率(BALP>250U/L)为14.1%,诊断为DR,并与对照组比较,差异有显著性意义(p<0.05).结论要重视骨骼畸形儿童的诊断及DR的诊断和防治工作.     

Static and dynamic bone changes in hospitalized patients suffering from rickets — a histomorphometric study

Aims : The aim of this study was to assess static and dynamic bone changes in patients suffering from rickets. Methods and results : Transcortical iliac crest biopsies of 15 hospitalized children with rickets were taken after labelling new bone formation with two cycles of tetracycline administration 10 days apart. Undecalcified sections were prepared, appropriately stained and histomorphometric analysis performed. Static and dynamic bone changes were measured including the volume of bone and osteoid, trabecular and cortical bone dimensions and resorptive and mineralization activities. The results were compared with normal values. The nature of the mineralization fronts was noted. Trabecular osteoid volumes of all but one patient was above the normal range of 1.9% (± 0.4%). This patient suffered rickets associated with the Kwashiorkor–Marasmus syndrome. Tetracycline labelling was found to be more sensitive than subjective evaluation of the nature of the mineralization fronts. Despite a balanced hospital diet, a bone formation rate of zero was found in three cases, indicating a need for vitamin D and mineral supplementation. Seven cases had decreased mineralization lag times, indicating response to the balanced diet. Conclusions : This study showed that histometric analysis of labelled bone biopsies is a helpful adjunct to the diagnosis but particularly assessment of response to management of deficiency states in children.     

Phagocytosis in vitamin D deficient rickets

Summary Children with rickets have been shown to have impaired phagocytosis of Escherichia coli. It has been proven, that the serum opsonizing activity is responsible for this fact. Dependence of phagocytosis on age and Ca × P index in rickets have been observed. The findings provide a possible explanation on diminished resistence to infection in rickets.

---

Zusammenfassung 1. Es wurde gezeigt, daß Kinder mit Rachitis eine verminderte Phagocytose von Escherichia coli zeigen. Für diese Phagocytoseverminderung ist die Serum-Opsonisations-Aktivität verantwortlich.2. Außerdem wurde eine Abhängigkeit der Phagocytose vom Alter und vom Ca × P-Index festgestellt.Diese Befunde können möglicherweise als Begründung für die verminderte Infekt Resistenz bei Rachitis dienen.

     

自制血清快速分离板在儿童碱性磷酸酶检测中的应用

目的用研制成功的血清快速分离板检测儿童碱性磷酸酶（ALP）,评价其应用价值。方法选取天津市儿童医院门诊体检儿童和住院佝偻病患儿共200例,年龄1个月-7岁,其中男性138例,女性62例;从每例受试者手指分别取30μl末梢血同时用血清快速分离板和市售的骨源性碱性磷酸酶（BALP）试剂盒检测,进行结果比对。结果用血清快速分离板检测ALP,显示结果准确度、重复性良好,显色稳定;200例样本经两种方法比对,结果差异无统计学意义（P〉0．05）。结论利用自行研制的血清快速分离板检测儿童ALP,操作简便,试剂稳定,结果易于判别且成本低廉,有利于儿童佝偻病和钙缺乏的诊断和治疗。     

Fibroblast growth factor (FGF) 23 works as a phosphate-regulating hormone and is involved in the pathogenesis of several disorders of phosphate metabolism

Fibroblast growth factor (FGF) 23 was identified as the latest member of the FGF family. Subsequent studies showed that FGF23 reduces the serum phosphate level by suppressing proximal tubular phosphate reabsorption. This phosphaturic action of FGF23 derives from the suppressive effect of FGF23 on the expression of type 2a and 2c sodium-phosphate cotransporter in the brush border membrane of proximal tubules. At the same time, FGF23 reduces the serum level of 1,25-dihydroxyvitamin D [1,25(OH)2D] which results in suppressed intestinal phosphate absorption. Establishment of an enzyme-linked immunosorbent assay for FGF23 indicated that excess actions of FGF23 result in hypophosphatemic rickets/osteomalacia such as X-linked, autosomal dominant, autosomal recessive hypophosphatemic rickets/osteomalacia, and tumor-induced rickets/osteomalacia. In contrast, deficiency of FGF23 action causes hyperphosphatemic tumoral calcinosis. These results indicate that FGF23 is a hormone regulating serum phosphate and 1,25(OH)2D levels.     

Dentin noncollagenous matrix proteins in familial hypophosphatemic rickets

Familial hypophosphatemic rickets is transmitted in most cases as an X-linked dominant trait and results from the mutation of the PHEX gene predominantly expressed in osteoblast and odontoblast. Patients with rickets have been reported to display important dentin defects. Our purpose was to explore the structure, composition and distribution of noncollagenous proteins (NCPs) of hypophosphatemic dentin. We collected teeth from 10 hypophosphatemic patients whose mineralization occurred either in a hypophosphatemic environment or in a corrected phosphate and vitamin environment. Teeth were examined by scanning electron microscopy, immunohistochemistry and Western blot analysis. An abnormal distribution (accumulation in interglobular spaces) and cleavage of the NCPs and particularly of matrix extracellular phosphoglycoprotein were observed in deciduous dentin. In contrast, it was close to normal in permanent dentin mineralized under corrected conditions. In conclusion, dentin mineralization in a corrected phosphate and vitamin D environment compensates the adverse effect of PHEX mutation.