Primer reporte en Argentina de variante patógena en DMP1 asociada a raquitismo hipofosfatémico autosómico recesivo / First report in Argentina of a pathogenic DMP1 variant associated with autosomal recessive hypophosphatemic rickets

El raquitismo hipofosfatémico hereditario es una condición genética asociada con una mineralización ósea alterada causada por la deficiencia de fosfato. Produce deformidad esquelética y retraso del crecimiento en la infancia. Se describen diferentes patrones de herencia según el locus involucrado. Dado el solapamiento de los fenotipos y la dificultad en analizar genealogías reducidas, los estudios moleculares son importantes para establecer la causa genética y realizar el abordaje familiar. La forma recesiva del raquitismo hipofosfatémico (ARHR, OMIM #241520) es una condición extremadamente poco frecuente reportada en familias de origen europeo y de Oriente Medio. Las mutaciones con pérdida de función del gen DMP1 (dentin matrix acidic phosphoprotein 1) se asocian al raquitismo hipofosfatémico hereditario tipo 1. En este artículo presentamos el primer reporte de una familia argentina con raquitismo hipofosfatémico hereditario por mutación en DMP1

Hereditary hypophosphatemic rickets is a genetic condition associated with impaired bone mineralization caused by phosphate deficiency. It results in skeletal deformity and growth retardation in early childhood. Different inheritance patterns have been described according to the locus involved. Given the phenotypic overlapping and the difficulty in analyzing reduced genealogies, molecular studies are important to establish the genetic cause and implement a family-centered approach. The autosomal recessive form of hypophosphatemic rickets (ARHR, OMIM 241520) is an extremely rare condition reported in families of European and Middle Eastern descent. Loss-of-function mutations in the DMP1 (dentin matrix acidic phosphoprotein 1) gene are associated with hereditary hypophosphatemic rickets type 1. In this article, we describe the first report of an Argentine family with hereditary hypophosphatemic rickets due to a mutation in the DMP1 gene.

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.

Vitamin D-dependent rickets (VDDR) type 1: case series of two siblings with a CYP27B1 mutation and review of the literature / Raquitismo dependente de vitamina D: tipo 1: série de casos de dois irmãos com mutação CYP27B1 e revisão da literatura

Abstract Two siblings presented with clinical and biochemical features of rickets, initially suspected as hypophosphatemic rickets. There was no improvement initially, hence the siblings were reinvestigated and later diagnosed as having vitamin D-dependent rickets (VDDR) type 1 due to a rare mutation in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. Both siblings improved with calcitriol supplementation. The initial presentation of VDDR is often confusing and algorithmic evaluation helps in diagnosis. We also present a brief review of the literature, including genetics.

Resumo Dois irmãos apresentaram características clínicas e bioquímicas do raquitismo, com suspeita clínica inicial de raquitismo hipofosfatêmico. Não houve melhora no início, portanto os irmãos foram reavaliados e, posteriormente, diagnosticados com raquitismo dependente de vitamina D (VDDR) tipo 1 devido a uma rara mutação no gene CYP27B1, que codifica a enzima 1a-hidroxilase. Ambos os irmãos melhoraram com a suplementação de calcitriol. A apresentação inicial do VDDR geralmente é confusa e a avaliação algorítmica ajuda no diagnóstico. Também apresentamos uma breve revisão da literatura, incluindo genética.

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 Compound Heterozygous Mutations in the Vitamin D Receptor Gene in a Korean Girl with Hereditary Vitamin D Resistant Rickets

Hereditary vitamin D resistant rickets (HVDRR) is a rare genetic disorder caused by a mutation of vitamin D receptor (VDR) gene. A number of cases had been reported in many countries but not in Korea. We examined a three-year old Korean girl who had the typical clinical features of HVDRR including rickets, hypocalcemia, hypophosphatemia, elevated serum calcitriol level and secondary hyperparathyroidism. The girl and her father were both heterozygous for the 719 C-to-T (I146T) mutation in exon 4, whereas she and her mother were both heterozygous for 754 C-to-T (R154C) mutation in exon 5 of the VDR gene. In this familial study, we concluded that the girl had compound heterozygous mutations in her VDR gene which caused HVDRR. This is the first report of a unique mutation in the VDR gene in Korea.

Autism and X-linked hypophosphatemia: A possible association.

We herein report the joint occurrence of an autistic disorder (AD) and X-linked hypophosphatemia. X-linked hypophosphatemia (XLH), an X-linked dominant disorder, is the most common of the inherited renal phosphate wasting disorders. Autism is a pervasive developmental disorder that occurs mainly due to genetic causes. In approximately 6-15% of cases, the autistic phenotype is a part of a broader genetic condition called syndromic autism. Therefore, reports of cases with the joint occurrence of a known genetic syndrome and a diagnosis of ASD by a child psychiatrist are relevant. A joint occurrence does not, however, mean that there is always a causal link between the genetic syndrome and the autistic behavioural phenotype. In this case, there are a number of arguments countering a causal link.

Mutations in the vitamin D receptor gene in four patients with hereditary 1, 25-dihydroxyvitamin D-resistant rickets / Mutações no gene do receptor de vitamin D em quatro pacientes com raquitismo hereditário resistente a 1, 25-dihydroxyvitamin D

Mutations in the vitamin D receptor (VDR) are associated to the hereditary 1,25-dihydroxivitamin D-resistant rickets. The objectives of this work are: search for mutations in the VDR and analyze their functional consequences in four Brazilian children presented with rickets and alopecia. The coding region of the VDR was amplified by PCR e direct sequenced. We identified three mutations: two patients had the same mutation in exon 7 at aminoacid position 259 (p.Q259E); one patient had a mutation in exon 8 at codon 319 (p.G319V) and another one had a mutation in exon 3 leading to a truncated protein at position 73 (p.R73X). Functional studies of the mutant receptors of fibroblast primary culture, from patients' skin biopsy treated with increasing doses of 1,25(OH)2 vitamin D showed that VDR mutants were unable to be properly activated and presented a reduction in 24-hydroxylase expression level.

Mutações no receptor de vitamina D (VDR) são associadas a raquitismo hereditário resistente a 1,25-dihidroxivitamina D. Os objetivos deste trabalho foram procurar mutações no VDR e analisar suas conseqüências funcionais em quatro pacientes com raquitismo e alopécia. A região codificadora do VDR foi amplificada por PCR e seqüenciada diretamente. Identificamos três mutações: dois pacientes apresentavam a mesma mutação no éxon 7 na posição protéica 259 (p.Q259E); um paciente apresentava uma mutação no éxon 8 no códon 319 (p.G319V) e o outro apresentava uma mutação no exon 3 resultando em uma proteína truncada na posição 73 (p.R73X). O estudo funcional dos receptores mutados nos extratos de culturas de fibroblasto primárias obtidas de biópsia de pele dos pacientes, tratados com doses crescentes de 1,25(OH)2 vitamina D demonstraram que os receptores mutantes não apresentam ativação adequada apresentando expressão reduzida de 24-hidroxilase.

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.