Metabolic assessment in pure struvite stones formers: is it necessary? / Avaliação metabólica em formadores de cálculo de estruvita pura: é necessário?

Abstract Background and objective: Magnesium ammonium phosphate stones (MAP), also known as struvite stones, are associated with urinary infection and impairment of renal unit. The aim of this study is to evaluate the urinary metabolic risk factors for recurrence of renal calculi in patients submitted to nephrectomy due to MAP stones. Methods: We retrospectively reviewed the charts of patients > 18 years old submitted to total nephrectomy due to pure MAP stones and pure calcium oxalate (CaOx) stones from July 2006 to July 2016. Urinary metabolic parameters were assessed through 24-hour urine exams ≥ 3 months after nephrectomy. Urinary metabolic parameters and new event related to lithiasis were compared. Results: Twenty-eight and 39 patients were included in MAP and CaOx group, respectively. Abnormalities in 24-hour urine samples were similar between groups. Hypercalciuria occurred in 7.1 and 10.3% of patients in MAP and CaOx group, respectively (p = 0.66), whereas hypocitraturia was present in 65.2 and 59.0% of patients with MAP and CaOx group, respectively (p = 0.41). No significant difference in new events was found between MAP and CaOx groups (17.9 vs. 23.1%, respectively; p = 0.60). Conclusion: A 24-hour urine evaluation should be offered to patients submitted to nephrectomy due to pure MAP stones in order to detect metabolic risk, improve treatment, and prevent stone recurrence.

Resumo Contexto e objetivo: Cálculos de fosfato de amônio e magnésio (FAM), também conhecidos como cálculos de estruvita, estão associados à infecção urinária e ao comprometimento da unidade renal. O objetivo deste estudo é avaliar os fatores de risco metabólico-urinários para recorrência de cálculos renais em pacientes submetidos à nefrectomia devido a cálculo de FAM. Métodos: Revisamos retrospectivamente os prontuários de pacientes > 18 anos submetidos à nefrectomia total devido a cálculos de FAM puro e cálculos de oxalato de cálcio puro (OxCa) de julho de 2006 a julho de 2016. Os parâmetros metabólicos urinários foram avaliados através de exames de urina de 24 horas ≥ 3 meses após a nefrectomia. Os parâmetros metabólicos urinários e um novo evento relacionado à litíase foram comparados. Resultados: Vinte e oito e 39 pacientes foram incluídos nos grupos FAM e OxCa, respectivamente. As anormalidades em amostras de urina de 24 horas foram similares entre os grupos. A hipercalciúria ocorreu em 7,1 e 10,3% dos pacientes nos grupos FAM e OxCa, respectivamente (p = 0,66), enquanto a hipocitratúria esteve presente em 65,2 e 59,0% dos pacientes nos grupos FAM e OxCa, respectivamente (p = 0,41). Nenhuma diferença significativa em novos eventos foi encontrada entre os grupos FAM e OxCa (17,9 vs. 23,1%, respectivamente; p = 0,60). Conclusão: Uma avaliação de urina de 24 horas deve ser oferecida aos pacientes submetidos à nefrectomia devido a cálculos de FAM puro, a fim de detectar risco metabólico, melhorar o tratamento e prevenir a recorrência de cálculos.

X-linked hypophosphatemic rickets: a new mutation / Raquitismo hipofosfatêmico ligado ao X: uma nova mutação

Abstract Phosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient's outcome. Genetic analysis can help to establish a genotype-phenotype correlation.

Resumo O raquitismo fosfopênico pode ser causado por mutações no gene PHEX (ligado ao X do homólogo da endopeptidase que regula o fosfato). Atualmente, mais de 500 mutações no gene PHEX causam raquitismo hipofosfatêmico. Os autores relatam um caso clínico de uma menina de 4 anos com histórico familiar sem relevância, que apresentou falha no crescimento e arqueamento das pernas. Os exames laboratoriais mostraram hipofosfatemia, fosfatase alcalina elevada, cálcio normal, PTH levemente elevado e níveis normais de 25(OH)D e 1,25(OH)D. O estudo radiológico mostrou deformidades ósseas no rádio e no fêmur. O diagnóstico clínico do raquitismo fosfopênico foi realizado e o estudo genético detectou uma provável variante patogênica heterozigótica do gene PHEX: c.767_768del (p.Thr256Serfs*7). Esta variante não foi descrita anteriormente na literatura ou nas bases de dados. O conhecimento sobre novas mutações pode melhorar o desfecho de pacientes. A análise genética pode ajudar a estabelecer uma correlação genótipo-fenótipo.

Analysis of PHEX gene variant and prenatal diagnosis for a Chinese pedigree affected with X-linked hypophosphatemia / 中华医学遗传学杂志

OBJECTIVE@#To detect pathological variant in a Chinese pedigree affected with X-linked hypophosphatemia (XLH).@*METHODS@#Whole-exome sequencing was carried out to screen genetic variants in the proband and her parents. Candidate variant of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) was verified by Sanger sequencing of all members of the pedigree and the 100 healthy controls. Prenatal diagnosis was carried out on chorionic villi sample derived from the fetus of the proband.@*RESULTS@#A c.1256G>A (p. Gly419Glu) variant was identified in the PHEX gene of the proband and all other patients from this pedigree. The same variant was not found among healthy members from this pedigree and the 100 healthy controls. Prenatal diagnosis suggested that the fetus also carried the c.1256G>A (p. Gly419Glu) variant.@*CONCLUSION@#The c.1256G>A (p. Gly419Glu) variant of the PHEX gene probably underlay the pathogenesis of XLH in this family. Discovery of the novel variant has enriched the mutational spectrum of the PHEX gene.

Analysis of PHEX gene variant and prenatal diagnosis for a Chinese pedigree affected with X-linked hypophosphatemia / 中华医学遗传学杂志

OBJECTIVE@#To detect pathological variant in a Chinese pedigree affected with X-linked hypophosphatemia (XLH).@*METHODS@#Whole-exome sequencing was carried out to screen genetic variants in the proband and her parents. Candidate variant of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) was verified by Sanger sequencing of all members of the pedigree and the 100 healthy controls. Prenatal diagnosis was carried out on chorionic villi sample derived from the fetus of the proband.@*RESULTS@#A c.1256G>A (p. Gly419Glu) variant was identified in the PHEX gene of the proband and all other patients from this pedigree. The same variant was not found among healthy members from this pedigree and the 100 healthy controls. Prenatal diagnosis suggested that the fetus also carried the c.1256G>A (p. Gly419Glu) variant.@*CONCLUSION@#The c.1256G>A (p. Gly419Glu) variant of the PHEX gene probably underlay the pathogenesis of XLH in this family. Discovery of the novel variant has enriched the mutational spectrum of the PHEX gene.

Prevalence and clinical characteristics of X-linked hypophosphatemia in Paraná, southern Brazil

ABSTRACT Objective: The aim of this cross-sectional study was to estimate the prevalence of XLH in Paraná, a state in southern Brazil, and report the clinical features and complications of the disease. Materials and methods: We invited all endocrinologists (n = 205), nephrologists (n = 221), orthopedic surgeons (n = 1020), and pediatricians (n = 1000) in Paraná to fill out an electronic survey with information on patients with X-linked hypophosphatemia (XLH), and searched the records of the state's health department for all calcitriol prescriptions in 2018. Results: In all, 244 (10%) specialists responded to the email, of whom 18 (7.4%) reported to be taking care of patients with XLH and answered the online survey. A total of 57 patients with XLH were identified (prevalence 5 per million inhabitants). The median age at diagnosis was 22 years, and 42.2% were children and adolescents. Fifteen patients had genetic testing showing a PHEX mutation. Overall, 91.2% had bone deformities, 30.8% had a history of fragility fractures, and 22.4% had renal complications. Conclusion: This study demonstrated a prevalence of XLH of 5 cases per million inhabitants in the state of Paraná, a rate lower than the one reported in other countries. Manifestations of renal calcification and bone fragility were frequent among the patients. This is the first epidemiological study evaluating the prevalence and clinical presentation of XLH in Latin America.

Novel PHEX gene mutations in patients with X-linked hypophosphatemic rickets: an analysis of 2 cases / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate PHEX gene mutations in 2 patients with X-linked hypophosphatemic rickets (XLH) and their families and to clarify the genetic etiology.</p><p><b>METHODS</b>A retrospective analysis was performed for the clinical data of two patients with XLH. High-throughput sequencing was used to detect the PHEX gene, a pathogenic gene of XLH. PCR-Sanger sequencing was used to verify the distribution of mutations in families.</p><p><b>RESULTS</b>Both patients had novel mutations in the PHEX gene; one patient had a frameshift mutation, c.931dupC, which caused early termination of translation and produced the truncated protein p.Gln311Profs*13; the other patient had a splice site mutation, IVS14+1G>A, which caused the skipping of exon 15 and produced an incomplete amino acid chain. Their parents had normal gene phenotypes.</p><p><b>CONCLUSIONS</b>c.931dupC and IVS14+1G>A are two novel mutations of the PHEX gene and might be the new pathogenic mutations of XLH.</p>

Identification of a novel splicing mutation of PHEX gene in a pedigree affected with X-linked hypophosphatemia / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify potential mutation of PHEX gene in two patients from a family affected with X-linked hypophosphatemia (XLH).</p><p><b>METHODS</b>PCR and Sanger sequencing were performed on blood samples from the patients and 100 healthy controls. Reverse transcription-PCR (RT-PCR) was used to determine the mRNA expression in patient samples.</p><p><b>RESULTS</b>A splicing site mutation, IVS21+2T>G, was found in the PHEX gene in both patients but not among the 100 healthy controls. RT-PCR confirmed that exon 21 of the PHEX gene was deleted.</p><p><b>CONCLUSION</b>The novel splicing mutation IVS21+2T>G of the PHEX gene probably underlies the XLH in this pedigree. At the mRNA level, the mutation has led to removal of exon 21 and shift of the open reading frame (p.Val691fsx), resulting in premature termination of protein translation.</p>

Mutational analysis and prenatal diagnosis in a family affected with hypophosphatemic rickets / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the clinical characteristics and genetic mutation in a family affected with hypophosphatemic rickets.</p><p><b>METHODS</b>Whole exome sequencing (WES) was used to screen potential mutations in genomic DNA extracted from peripheral venous blood sample from the proband. Suspected mutation was confirmed with Sanger sequencing. Amniotic fluid was sampled from the proband for prenatal diagnosis. Potential maternal contamination was excluded by analysis of short tandem repeat (STR) markers.</p><p><b>RESULTS</b>WES has identified a heterozygous c.2058_2059insAGTT (p.L686fs) mutation of the PHEX gene in the proband, which was confirmed by Sanger sequencing in other affected individuals from the family. The mutation was detected in the amniotic fluid sample from the fetus but not among healthy members from the family.</p><p><b>CONCLUSION</b>Identification of the PHEX mutation by WES has facilitated genetic counseling and prenatal diagnosis for the family affected with hypophosphatemic rickets.</p>

X-linked Hypophosphatemic Rickets, del(2)(q37.1;q37.3) Deletion Syndrome and Mosaic Turner Syndrome, mos 45,X/46,X, del(2)(q37.1;q37.3) in a 3-year-old Female

There are currently no published cases that report concomitant Turner syndrome (TS), 2q37 deletion syndrome and X-linked hypophosphatemic rickets (XLH). Interestingly, since the clinical phenotypes of TS and 2q37 deletion syndrome overlap, the correct diagnosis may be missed without a standardized approach to genetic testing consisting of both karyotype and microarray. Both chromosome anomalies have been associated with short stature and a variety of skeletal abnormalities however to date no reports have associated these syndromes in association with a phosphate regulating endopeptidase homolog, X-linked (PHEX) gene deletion resulting in XLH. We report a 3-year-old female with 3 concurrent genetic disorders including a 9.98 Mb terminal deletion of chromosome 2: del(2)(q37.1;q37.3), XLH secondary to a small microdeletion of part of the PHEX gene, and mosaic TS (mos 45,X[32]/46,X[18]). This is the first case report of a patient with 2q37 deletion syndrome and mosaic TS (mos 45,X[32]/46,X[18]) found to have XLH secondary to an interstitial constitutional PHEX gene deletion. Her severe phenotype and multiple genotypic findings reinforce the importance of thorough genetic testing in the setting of complicated phenotypic presentations.

Medium modification with bone morphogenetic protein 2 addition for odontogenic differentiation

Abstract The aim of this study was to evaluate whether medium modification improves the odontogenic differentiation of human dental pulp stem cells (DPSC) in vitro and in vivo. DPSC isolated from human impacted third molar teeth were analysed for clusters of differentiation with flow cytometry. Odontogenic differentiation was stimulated by medium modification with the addition of bone morphogenetic protein 2 (BMP2). The expression of dentin sialophosphoprotein, dentin matrix protein 1, enamelysin/matrix metalloproteinase 20 and the phosphate-regulating gene with homologies to endopeptidases on the X chromosome of the cells were analysed with RT-PCR at 7, 14 and 21 days. Then, DPSC were transplanted on the back of immunocompromised mice via a hydroxyapatite tricalcium phosphate scaffold, and the structure of the formed tissue was investigated. The cells were identified as mesenchymal stem cells with a 98.3% CD73 and CD90 double-positive cell rate. The increase in mineralization capacity and expression of human enamel-dentin specific transcripts proportional to the culture period were determined after differentiation. Six weeks after transplantation, an osteo-dentin matrix was formed in the group in which odontogenic differentiation was stimulated, and the odontogenic characteristics of the matrix were confirmed by histological examination and RT-PCR analysis. Odontogenic differentiation of the isolated and characterized human DPSC was improved with medium modification by the addition of BMP2 in vitro and in vivo. The defined medium and applied technique have a potential use for forming reparative dentin in the future, but the effects of the method should be investigated in long-term studies.

In vivo performance of different scaffolds for dental pulp stem cells induced for odontogenic differentiation

Abstract This study was designed to determine the in vivo performance of three different materials as scaffolds for dental pulp stem cells (DPSC) undergoing induced odontogenic differentiation. An odontogenic medium modified by the addition of recombinant human bone morphogenetic protein 2 was used in the experimental groups to induce differentiation. Mesenchymal stem cell medium was used in the control groups. DPSC were transplanted onto the backs of mice via three scaffolds: copolymer of L-lactide and DL-lactide (PLDL), copolymer of DL-lactide (PDL) and hydroxyapatite tricalcium phosphate (HA/TCP). The expression levels of dentin sialo-phosphoprotein (DSPP), dentin matrix protein-1 (DMP1), enamelysin/matrix metalloproteinase 20 (MMP20) and phosphate-regulating gene with homologies to endopeptidases on X chromosome (PHEX) were analysed using RT-PCR. The expressions in the experimental groups were compared to those in the control groups. The transcript expressions at 6 and 12 weeks were significantly different for all scaffolds (p < 0.05), except for the expression of DSPP in the PLDL group with regard to the time variable. Although there was a decrease in the expression of enamelysin/MMP20 in PLDL and HA/TCP at 12 weeks, all other expressions increased and reached their highest level at 12 weeks. The highest DSPP expression was in the PDL group (p < 0.05). The highest expression of DMP1 was detected in the HA/TCP group (p < 0.05). The highest expression of PHEX was in the PLDL group (p < 0.05). Consequently, PLDL and PDL seemed to be promising scaffold candidates for odontogenic regeneration at least as HA-TCP, when they were applied with the DPSC induced for odontogenic differentiation.

Raquitismo e osteomalácia hipofosfatêmicos de origem genética mediados por FGF23: caracterização molecular, óssea e renal / FGF23-mediated inherited hypophosphatemic rickets: molecular characterization, bone analysis and renal evaluation

Introdução: raquitismo e osteomalácia hipofosfatêmicos de origem genética mediados por FGF23 (RQ/OM-FGF23) são caracterizados pelo aumento patológico dos níveis séricos de FGF23 com consequentes hiperfosfatúria e hipofosfatemia. A forma hereditária mais comum é a ligada ao X dominante (XLHR) ocasionada por mutações inativadoras no gene PHEX. Objetivos: identificar a etiologia molecular; avaliar a densidade mineral óssea (DMO) e a microarquitetura óssea e, determinar a prevalência de nefrocalcinose (NC), nefrolitíase (NL) e de alterações metabólicas urinárias em 47 pacientes com RQ/OM-FGF23 (16 crianças e 31 adultos). Métodos: as análises dos genes PHEX e FGF23 foram realizadas pelos métodos de Sanger e MLPA. A DMO areal (DMOa) foi avaliada por densitometria óssea (DXA), enquanto a DMO volumétrica (DMOv) e os parâmetros de microarquitetura óssea foram analisados por HR-pQCT. A NC foi classificada segundo uma escala de 0-3 (0 = ausência de NC; 3 = NC grave) pelas ultrassonografia (US) e tomografia computadorizada (TC) renais. A presença de NL foi analisada pela TC renal. Fatores de risco para NC e NL foram avaliados pela urina de 24 horas. Resultados: foram identificadas mutações no PHEX em 41 pacientes (87,2%). A avaliação óssea foi realizada em 38 pacientes com XLHR que foram comparados a controles saudáveis. Os pacientes tiveram maior DMOa em L1-L4 (p=0,03) e menor DMOa em 1/3 distal do rádio (p < 0,01). Em rádio distal, a DMOv total (Total.vBMD) e os componentes trabecular (Tb.vBMD) e cortical (Ct.vBMD) foram semelhantes entre os grupos. Na tíbia distal, os pacientes apresentaram menor Total.vBMD em relação aos controles devido ao déficit no Tb.vBMD (p < 0,01). Além do mais, ao separarmos por status metabólico, os pacientes descompensados tiveram menor Ct.vBMD em tíbia distal comparados aos controles (p=0,02). Quanto aos parâmetros estruturais, em rádio distal, os pacientes apresentaram menor número de trabéculas (Tb.N; p=0,01), maior espessura trabecular...

Background: FGF23-mediated hypophosphatemic rickets is a group of diseases characterized by a pathological increase of FGF23 serum levels, resulting in hyperphosphaturia and hypophosphatemia. In this group, the most common form of inheritance is the X-linked dominant (XLHR) caused by inactivating mutations in the PHEX gene. Aims: to identify the molecular basis; to evaluate the bone mineral density and bone microarchitecture; to determinate the prevalence of nephrocalcinosis (NC), nephrolithiasis (NL) and their related metabolic factors in 47 patients with FGF23-mediated hypophosphatemic rickets (16 children and 31 adults). Methods: PHEX and FGF23 were analyzed by conventional Sanger sequencing and MLPA. The areal BMD (aBMD) was evaluated by dual-energy x-ray absorptiometry (DXA), while the volumetric BMD (vBMD) and the bone microarchitecture were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT). NC was investigated by renal ultrasonography (US) and computed tomography (CT) and classified using a 0-3 scale (0= no NC and 3= severe NC). The presence of NL was determined by renal CT. Risk factors for NC and NL were evaluated by 24-hour urinary samples. Results: 41 patients (87.2%) presented mutations in PHEX. The bone analysis was made in 38 XLHR patients compared to healthy controls. XLHR patients presented higher aBMD at L1-L4 (p=0.03) and lower aBMD at the distal third of the radius (p < 0.01). At the distal radius, HR-pQCT showed no differences in the vBMD neither in its trabecular (Tb.vBMD) and cortical (Ct.vBMD) components. At the distal tibia, the XLHR patients showed lower Total.vBMD (p < 0.01) compared to controls due to decreased Tb.vBMD (p < 0.01). Moreover, after XLHR patients were sorted by metabolic status, the noncompensated ones revealed lower Ct.vBMD at the distal tibia compared to their respective controls (p=0.02). Regarding to the microarchitectural parameters, at the distal radius, XLHR...

Three PHEX gene mutations in Chinese subjects with hypophosphatemic rickets and literature review / 中国当代儿科杂志

The clinical data of three Chinese children who had been definitely diagnosed with X-link dominate hypophosphatemic rickets (XLH) by gene mutation analysis of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) were retrospectively studied and the relevant literature was reviewed. PHEX gene mutations were detected in all 3 XLH children; a nonsense mutation (c.58C>T) in one case and splicing mutations (c.1645+1G>A, c.436+1G>A) in the other two cases. Among these mutations, c.436+1G>A was novel. As of January 2014, a total of 329 PHEX gene mutations were reported, primarily within three mutation hot spots, throughout the world. Missense mutations accounted for the highest proportion (24%) among all mutations. There is literature showing geographic differences in the total number of XLH subjects and PHEX mutation types across the world. In the current literature, 89 cases of XLH with 28 types of PHEX mutations have been reported in the population of mainland China. Exon 22 is the most frequent mutation site (18%) and missense mutations are the most common type of mutations (61%). It is concluded that exon 22 is the mutation hot spot and missense mutation is the most common type of mutation in the PHEX gene in Chinese XLH patients and that c.436+1G>A detected in this study is a novel PHEX gene mutation in Chinese with XLH.

Gene mutation analysis of X-linked hypophosphatemic rickets / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the frequency and type of PHEX gene mutations in children with X-linked hypophosphatemic rickets (XLH), the possible presence of mutational hot spots, and the relationship between genotype and clinical phenotype.</p><p><b>METHODS</b>Clinical data of 10 children with XLH was retrospectively reviewed. The relationship between gene mutation type and severity of XLH was evaluated.</p><p><b>RESULTS</b>PHEX gene mutations were detected in all 10 children with XLH, including 6 cases of missense mutation, 2 cases of splice site mutation, 1 case of frameshift mutation, and 1 case of nonsense mutation. Two new mutations, c.2048T>C and IVS14+1delAG, were found. The type of PHEX gene mutation was not associated with the degree of short stature and leg deformity (P=0.571 and 0.467), and the mutation site was also not associated with the degree of short stature and leg deformity (P=0.400 and 1.000).</p><p><b>CONCLUSIONS</b>Missense mutation is the most common type of PHEX gene mutation in children with XLH, and c.2048T>C and IVS14+1delAG are two new PHEX gene mutations. The type and site of PHEX gene mutation are not associated with the severity of XLH.</p>

Analysis of PHEX gene mutation in a hypophosphatasia pedigree / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To screen potential mutations of PHEX gene in a family featuring hypophosphatemic rickets in order to confirm the molecular diagnosis and pathogenetic mechanism.</p><p><b>METHODS</b>Genomic DNA was extracted from peripheral venous blood samples. DNA sequence of PHEX gene was derived from UCSC database, and primers for its coding region were designed with Primer premier 5.0. Potential mutations were detected with PCR amplification and DNA sequence analysis.</p><p><b>RESUTLS</b>A mutation was identified in intron 6 of the PHEX gene in the proband and his mother.</p><p><b>CONCLUSION</b>The c.732+1G>T mutation underlies the hypophosphatemic rickets in this family.</p>

Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts

Neuropathy and bone deformities, lifelong sequelae of leprosy that persist after treatment, result in significant impairment to patients and compromise their social rehabilitation. Phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) is a Zn-metalloendopeptidase, which is abundantly expressed in osteoblasts and many other cell types, such as Schwann cells, and has been implicated in phosphate metabolism and X-linked rickets. Here, we demonstrate that Mycobacterium leprae stimulation downregulates PHEX transcription and protein expression in a human schwannoma cell line (ST88-14) and human osteoblast lineage. Modulation of PHEX expression was observed to a lesser extent in cells stimulated with other species of mycobacteria, but was not observed in cultures treated with latex beads or with the facultative intracellular bacterium Salmonella typhimurium. Direct downregulation of PHEX by M. leprae could be involved in the bone resorption observed in leprosy patients. This is the first report to describe PHEX modulation by an infectious agent.

PHEX Gene Mutations and Genotype-Phenotype Analysis of Korean Patients with Hypophosphatemic Rickets

X-linked hypophosphatemic rickets (XLH) results from mutations in the PHEX gene. Mutational analysis of the PHEX gene in 15 unrelated Korean patients with hypophosphatemic rickets revealed eight mutations, including five novel mutations, in nine patients: two nonsense mutations, two missense mutations, one insertion, and three splicing acceptor/donor site mutations. Of these, c.64G>T, c.1699C>T, c.466_467 insAC, c.1174-1G>A, and c.1768+5G>A were novel mutations. To analyze the correlation between genotype and phenotype, phenotypes were compared between groups with and without a mutation, in terms of mutation location, mutation type, and sex. Skeletal disease tended to be more severe in the group with a mutation in the C-terminal half of the PHEX gene, but no genotype-phenotype correlation was detected in other comparisons. Further extensive studies of the PHEX gene mutations and analyses of the genotype-phenotype relationships are required to understand PHEX function and the pathogenesis of XLH.