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.

Prevalence of oral manifestations of hypophosphatemic rickets in patients treated in a peruvian pediatric hospital / Prevalencia de manifestaciones bucales del raquitismo hipofosfatémico de pacientes atendidos en un hospital pediátrico peruano

Objective: To describe the prevalence of oral manifestations of hypophosphatemic rickets in patients treated in a Peruvian referral pediatric hospital during the years 2012-2016. Material and methods: An observational, descriptive, retrospective, cross-sectional study was carried out. The sample consisted of patients diagnosed with hypophosphatemic rickets who attended the outpatient clinic of the Stomatology Service and the Genetics Service of the National Institute of Child Health (INSN), Lima, Peru, between the years 2012-2016. The research project was assessed and approved by the Research Ethics Committee of the Health Service. Medical records stored in a database of the health institution with the Code CIE E83.3, which corresponds to the diagnosis of Hypophosphatemic Rickets, were requested for the study. Results: Fifteen children received health care, of which only 10 were treated at the Stomatology Service. The distribution of the data was obtained from these 10 patients according to the proposed objective. A higher frequency of gingival lesions was found at the soft tissue level (41.18%); at the bone tissue level, only one case of dentigerous cyst was observed; and at the dental level, 90% of the patients had dental caries. Conclusion: The most frequent oral manifestations of hypophosphatemic rickets in pediatric patients treated at the National Institute of Child Health (2012-2016) were gingivitis and dental caries.

Objetivo:Describir la prevalencia de las manifestaciones bucales del raquitismo hipofosfatémico de pacientes atendidos en un hospital pediátrico de referencia peruano durante los años 2012-2016. Material y Métodos:Se realizó un estudio tipo observacional, descriptivo, retrospectivo, transversal. Para la selección de la muestra se consideró a los pacientes que acudieron a la consulta externa del Servicio de Odontoestomatología y el Servicio de Genética del Instituto Nacional de Salud del Niño, Lima, Perú; en el periodo comprendido entre los años 2012-2016 y que presentaron como diagnóstico Raquitismo Hipofosfatémico. El proyecto de investigación fue evaluado por un Comité de Ética en Investigación del servicio de salud. Se solicitaron las historias clínicas consignadas en una base de datos de la institución de salud con el Código CIE E83.3, que corresponde a este diagnóstico. Resultados: Fueron atendidos 15 niños, de los cuales solo 10 fueron tratados en el Servicio Odontoestomatología; siendo de estos 10 pacientes la distribución de los datos obtenidos según el objetivo propuesto. Se encontró mayor frecuencia de lesiones a nivel de tejido blando de gingivitis con 41.18%, a nivel de tejido óseo solo se presentó un caso de quiste dentígero; y a nivel de tejido dental el 90% de los pacientes presentó caries dental. Conclusión: Las manifestaciones bucales más frecuentes del raquitismo hipofosfatémico de pacientes pediátricos atendidos en el Instituto Nacional de Salud del Niño (2012-2016), fueron la gingivitis y caries dental.

Raquitismo hipofosfatêmico: relato de caso / Hypophosphatemic rickets: case report

RESUMO Objetivo: O raquitismo hipofosfatêmico precisa ser precocemente diagnosticado porque seu tratamento previne sequelas incapacitantes. Este relato alerta para a doença. Relato de caso: Relato de perfil metabólico, depuração de creatinina, estado nutricional e desenvolvimento pôndero-estatural de paciente com características clínico-laboratoriais de raquitismo hipofosfatêmico, atendido em ambulatório de tubulopatias por período de 12 meses. Chegou ao serviço após tempo prolongado acamado, dependente de ventilação mecânica e com perfil metabólico ósseo alterado. Terapêutica consistiu na administração de fósforo (inicial: 65 mg/kg/dia, final: 24,2 mg/kg/dia), cálcio (inicial: 127 mg/kg/dia, final: 48,4 mg/kg/dia) e calcitriol (inicial: 0,06 mcg/kg/dia, final: 0,03 mcg/kg/dia), e a análise constou da descrição das consultas, utilizando-se mediana de exames laboratoriais e dados antropométricos. Observou-se nítida melhora inicial do padrão respiratório do paciente, que evoluiu com ventilação espontânea e deambulação autônoma; com exames laboratoriais: cálcio (mg/dL) inicial 7,1, final 10,1; fósforo (mg/dL) inicial 1,7, final 3,2; magnésio (mg/dL) inicial 1,5, final 2,1; paratormônio (pg/L) inicial 85,8, final 52,7; fosfatase alcalina (UI/L) inicial 12660, final 938; e melhora do desenvolvimento pôndero-estatural (escore Z: E/I inicial: -6,05, final -3,64; P/I: inicial -2,92, final -1,57) com presença de litíase transitória. A depuração de creatinina (mL/min/1,73 m2sc) foi constante durante o seguimento. O tratamento propiciou benefícios clínicos, bioquímicos e nutricionais, mas, apesar da boa resposta inicial, a família abandonou o seguimento por dois anos, apresentando o paciente piora da deambulação e das deformidades esqueléticas. Comentários: Não apenas diagnóstico precoce é necessário, como também a adesão ao tratamento é fundamental para o sucesso na condução dessa patologia.

ABSTRACT Objective: Early diagnosis and immediate treatment of hypophosphatemic rickets is of utmost importance as it may prevent subsequent sequelae. This report aims at warning pediatricians to consider the presence of the disease. Case description: Description of the metabolic profile, creatinine clearance, nutritional status, weight and body structure of a patient who presented the clinical-laboratorial characteristics of hypophosphatemic rickets and was followed in an outpatient clinic for tubulopathies over the period of 12 months. The patient had been bedridden for some time, was dependent on mechanical ventilation and presented an altered metabolic bone condition. Treatment was phosphate (initial: 65 mg/kg/day and final: 24,2 mg/kg/day), calcium (initial: 127 mg/kg/day, final: 48,4 mg/kg/day) and calcitriol (initial: 0.06 mcg/kg/day, final: 0.03 mcg/kg/day). The patient improved, evolving into spontaneous breathing and walking unaided. Laboratory results: calcium (mg/dL) initial 7.1, final 10.1; phosphate (mg/dL) initial 1.7 final 3.2; magnesium (mg/dL) initial 1.5 final 2.1, parathyroid hormone (pg/l) initial 85.8, final 52.7, alkaline phosphatase (UI/l) initial 12660, final 938; there was also improvement in weight/structural development (Z score: H/A initial: -6.05, final -3.64; W/A: initial -2.92, final -1.57) with presence of transitory gallstones. Creatinine clearance (mL/min/1.73m2bsa) was constant. The medication improved his laboratory results and nutritional status, but the patient did not return for two years for follow-up and, during this period, his condition has noticeably deteriorated. Comments: Early diagnosis and follow-up are essential in dealing with this pathology.

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.

A Novel PHEX Gene Mutation in a Patient with Sporadic Hypophosphatemic Rickets

Phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) is a common cause of X-linked hypophosphatemic (XLH) rickets. Diverse PHEX gene mutations have been reported; however, gene mutations in sporadic rickets are less common than in XLH rickets. Herein, we describe a 50-year-old female patient with sporadic hypophosphatemic rickets harboring a novel splicing-site mutation in the PHEX gene (c.663+1G>A) at the exon 5-intron 5 boundary. The patient had recently suffered from right thigh pain and an aggravated waddling gait. She also presented with very short stature, generalized bone pain, and muscle weakness. Despite low serum phosphate levels, her phosphate reabsorption rate was lower than normal. Additionally, her 1,25-dihydroxyvitamin D3 concentration was lower than normal, although FGF23 level was normal. After treatment with alfacalcidol and elemental phosphate, her rachitic symptoms subsided, and callus formation was observed in the fracture site on the right femur.