Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

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OBJECTIVES: To study the diagnosis, treatment, and complications of hypophosphatemic rickets (HR) in children, explore effectiveness evaluation indicators for the disease, and understand the pattern in height growth among these patients. METHODS: A retrospective analysis of the initial clinical data and five-year follow-up data of 85 children with HR treated at Children's Hospital of Nanjing Medical University from January 2008 to December 2022. RESULTS: Among the 85 children with HR, there were 46 males (54%) and 39 females (46%). The age at initial diagnosis ranged from 6 months to 13 years and 9 months, with a median age of 2.75 years. The average height standard deviation score was -2.0±1.1. At initial diagnosis, children exhibited reduced blood phosphate levels and elevated alkaline phosphatase (ALP), with 99% (84/85) presenting with lower limb deformities. The positive rate for PHEX gene mutations was 93% (55/59). One year post-treatment, there was a significant reduction in ALP levels and the gap between the lower limbs (P<0.05). The fastest height growth occurred in the first year after treatment, at 8.23 cm/year, with a peak height velocity (PHV) phase lasting about two years during puberty. The height increased by 9-20 cm in male children during the PHV stage and 10-15 cm in female children. Major complications included nephrocalcinosis and hyperparathyroidism. The incidence rate of nephrocalcinosis in the first year after treatment was 55% (22/40), which increased with the duration of the disease (P<0.001); an increased urinary phosphate/creatinine ratio was positively associated with a higher risk of nephrocalcinosis (OR=1.740, P<0.001). The incidence of hyperparathyroidism in the first year after treatment was 64% (27/42). CONCLUSIONS: For children presenting with lower limb deformities, short stature, and slow growth, early testing for blood levels of phosphate, calcium, and ALP, along with imaging examinations of the lower limbs, can aid in the early diagnosis of HR. Genetic testing may be utilized for definitive confirmation when necessary. ALP combined with improvements in skeletal deformities and annual height growth can serve as indicators of therapeutic effectiveness for HR. Compared to normal children, children with HR demonstrate a lower height increase during the PHV phase, necessitating close follow-up and timely adjustment of treatment plans Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 677-682.

Acquired Forms of Fibroblast Growth Factor 23-Related Hypophosphatemic Osteomalacia.

Fibroblast growth factor 23 (FGF23) is a pivotal humoral factor for the regulation of serum phosphate levels and was first identified in patients with autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia (TIO), the most common form of acquired FGF23-related hypophosphatemic rickets/osteomalacia (FGF23rHR). After the identification of FGF23, many other inherited and acquired forms of FGF23rHR were reported. In this review article, the detailed features of each acquired FGF23rHR are discussed, including TIO, ectopic FGF23 syndrome with malignancy, fibrous dysplasia/McCune-Albright syndrome, Schimmelpenning-Feuerstein-Mims syndrome/cutaneous skeletal hypophosphatemia syndrome, intravenous iron preparation-induced FGF23rHR, alcohol consumption-induced FGF23rHR, and post-kidney transplantation hypophosphatemia. Then, an approach for the differential diagnosis and therapeutic options for each disorder are concisely introduced. Currently, the majority of endocrinologists might only consider TIO when encountering patients with acquired FGF23rHR; an adequate differential diagnosis can reduce medical costs and invasive procedures such as positron emission tomography/computed tomography and venous sampling to identify FGF23-producing tumors. Furthermore, some acquired FGF23rHRs, such as intravenous iron preparation/alcohol consumption-induced FGF23rHR, require only cessation of drugs or alcohol to achieve full recovery from osteomalacia.

Complex phenotype in Fanconi renotubular syndrome type 1: Hypophosphatemic rickets as the predominant presentation.

GATM-related Fanconi renotubular syndrome 1 (FRTS1) is a form of renal Fanconi syndrome (RFS), which is a disorder of solute and water reabsorption caused by defects in the function of the entire proximal tubule. Recent findings reveal the molecular basis of FRTS1: Intramitochondrial fiber aggregation triggered by mutant GATM provides a starting point for proximal tubule damage and drives disease progression. As a rare and newly recognized inherited kidney disease, the complex manifestations of FRTS1 are easily underdiagnosed or misdiagnosed. We discuss the complex phenotype of a 26-year-old woman with onset in infancy and a long history of hypophosphatemic rickets. We also identified a novel heterozygous missense variant in the GATM gene in this patient. The novel variant and phenotype we report expand the disease spectrum of FRTS1. We recommend screening for GATM in children with RFS, especially in patients with resistant rickets who have previously had negative genetic testing. In addition, we found pathological deposition of mutant GATM proteins within mitochondria in the patient's urinary sediment cells by a combination of electron microscopy and immunofluorescence. This unique urine cytology experiment has the potential to be a valuable tool for identifying patients with RRTS1.

Establishing a human-induced pluripotent stem cell line SMUSHi005-A from a patient with hypophosphatemic vitamin D-resistant rickets carrying the PHEX c.1586-1586+1 delAG mutation.

Hypophosphatemic vitamin D-resistant rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. In this report, the SMUSHi005-A human induced pluripotent stem cell (hiPSC) line was successfully established from the PBMCs of a female patient carrying the PHEX mutation with c.1586-1586+1 delAG. The iPSC line has been confirmed to have a normal karyotype. The displayed cells clearly exhibit characteristics similar to embryonic stem cells, expressing pluripotency markers and demonstrating the ability to differentiate into three germ layers.

Hypophosphatemic rickets and short stature.

An 18-month-old male presented with gross motor delay and poor growth (weight z-score -2.21, length z-score -4.26). Radiographs showed metaphyseal irregularities suggesting metaphyseal dysplasia and sagittal craniosynostosis. Biochemical evaluation supported hypophosphatemic rickets [serum phosphorus 2.3 mg/dL (reference range (RR) 4.3-6.8), alkaline phosphatase 754 unit/L (RR 156-369)] due to renal phosphate wasting (TmP/GFR 4.3 mg/dL, normal for age 4.3-6.8), with C-terminal fibroblast growth factor 23 (FGF23) 125 RU/mL (>90 during hypophosphatemia suggests FGF23-mediated hypophosphatemia). Treatment was initiated with calcitriol and phosphate. Genetic analysis showed a pathogenic variant of FGF23: c.527G > A (p.Arg176Gln) indicative of autosomal dominant hypophosphatemic rickets (ADHR). Consistent with reports linking iron deficiency with the ADHR phenotype, low ferritin was detected. Following normalization of ferritin level (41 ng/mL) with oral ferrous sulfate replacement, biochemical improvement was demonstrated (FGF23 69 RU/mL, phosphorus 5.0 mg/dL and alkaline phosphatase 228 unit/L). Calcitriol and phosphate were discontinued. Three years later, the patient demonstrated improved developmental milestones, linear growth (length Z-score -2.01), radiographic normalization of metaphyses, and stabilization of craniosynostosis. While the most common cause of hypophosphatemic rickets is X-linked hypophosphatemia, other etiologies should be considered as treatment differs. In ADHR, normalization of iron leads to biochemical and clinical improvement.

Raquitismo vinculado al uso de fórmulas elementales: Reporte de caso / Rickets associated to the use of elemental formula: A case report

El raquitismo afecta la diferenciación y mineralización del cartílago de crecimiento como consecuencia, en última instancia, de una alteración en los niveles de fósforo y/o calcio. El secundario a la deficiencia de vitamina D es la forma más frecuente (raquitismo carencial). Las manifestaciones clínicas durante los primeros años de vida suelen comprometer en forma más marcada las epífisis de los huesos.Se describe el caso de un lactante de 8 meses con diagnóstico de alergia a la proteína de la leche de vaca que presentó múltiples fracturas patológicas mientras se encontraba bajo tratamiento con fórmulas lácteas a base de aminoácidos. Se efectuó el diagnóstico de raquitismo hipofosfatémico por deficiencia de fósforo y, tras 3 meses de tratamiento con sales de fosfato, calcio, calcitriol, el abandono paulatino de la leche elemental y el descenso gradual de la medicación antiácida, el paciente evolucionó con curación clínico-radiológica del cuadro

The rickets is a disease that affects the differentiation and mineralization of the growth cartilage, as an ultimate consequence of a balance loss in calcium and phosphate levels. Vitamin D deficiency is the most common cause of the rickets (nutritional rickets). Its clinical manifestation during the first years of life involves long bones epiphysis in a more severe way.We report an 8-month-old infant who was diagnosed with cow ́s milk protein allergy and suffered from multiple fractures while receiving elemental formula as part of his treatment. The final etiology was hypophosphatemic rickets secondary to phosphate deficiency, and after 3 months of phosphate, calcium and calcitriol supplementation, in addition to the gradually reduction of the proportion of elemental formula intake and the decline of the antacid doses, clinical and radiological heal was achieved.

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.

Uveítis anterior aguda asociada a raquitismo renal hipofosfatémico / Acute anterior uveítis associated to hypophosphatemic renal ricketts

Los raquitismos hipofosfatémicos hereditarios son un grupo de enfermedades caracterizadas por la pérdida renal de fosfatos. Cursan con hipocrecimiento disarmónico y deformidades óseas. La forma más común es el raquitismo hipofosfatémico ligado al cromosoma X, el cual es causado por mutaciones inactivantes en el gen PHEX. El objetivo de nuestro trabajo fue describir las alteraciones oculares encontradas y la evolución clínica en un paciente con raquitismo hipofosfatémico hereditario y uveítis anterior. Se presenta un niño de 9 años de edad con diagnóstico de raquitismo hipofosfatémico hereditario, valorado en el Servicio de Uveítis del Instituto Cubano de Oftalmología Ramón Pando Ferrer por presentar dolor ocular y molestias a la luz en el ojo derecho. En la exploración oftalmológica se constata una uveítis anterior con hipopión en el ojo derecho y depósitos de cristales en todo el espesor corneal y el iris en ambos ojos. Se indicaron esteroides tópicos con resolución del proceso inflamatorio. Los hallazgos en el segmento anterior del paciente son sugestivos de cistinosis, donde el acúmulo de cristales es la alteración corneal más típica de las manifestaciones oculares, con una incidencia del 90 por ciento en niños menores de un año, y los primeros órganos afectados son los riñones. Los raquitismos hipofosfatémicos hereditarios pueden cursar con depósitos de cristales corneales y procesos inflamatorios de la úvea anterior(AU)

Hereditary hypophosphatemic rickets are a group of diseases characterized by renal loss of phosphates. They appear with disharmonic hypogrowth and bone deformities. The most common form is the X-chromosome-linked hypophosphatemic rickets which is caused by inactivating mutations in PHEX gene. The objective of our work was to describe the ocular alterations and the clinical evolution in a patient with hereditary hypophosphatemic rickets and previous uveitis. Here is the case of a 9 years-old boy diagnosed with hereditary hypophosphatemic rickets, who was seen at the Uveitis Service of Ramon Pando Ferrer Cuban Institute of Ophthalmology. He presented with ocular pain and feeling of discomfort to light in his right eye. The ophthalmological exam yielded anterior uveitis with hypopyon in his right eye and crystal depots in the whole corneal thickness and the iris of both eyes. Topical steroids were prescribed to treat the inflammatory process. The findings in the anterior segment of the patients indicated the presence of cystinosis in which the accumulation of crystals is the most typical corneal alteration among the ocular manifestations. Its incidence reaches 90 percent in under one year-old children and the first affected organs are the kidneys. The hereditary hypophosphatemic rickets may appear with corneal crystal depots and inflammatory processes in the anterior uvea(AU)

Dental manifestations of patient with Vitamin D-resistant rickets

Patients with Vitamin D-resistant rickets have abnormal tooth morphology such as thin globular dentin and enlarged pulp horns that extend into the dentino-enamel junction. Invasion of the pulp by microorganisms and toxins is inevitable. The increased fibrotic content of the pulp, together with a reduced number of odontoblasts, decreases the response to pulp infection. The most important oral findings are characterized by spontaneous gingival and dental abscesses occuring without history of trauma or caries. Radiographic examinations revealed large pulp chambers, short roots, poorly defined lamina dura and hypoplastic alveolar ridge. These dental abscesses are common and therefore the extraction and pulpectomy are the treatment of choice. The purpose of this article is to report a case of Vitamin D-resistant rickets in a 5 year-old boy, describing the dental findings and the treatment to be performed in these cases.

Raquitismo hipofosfatémico ligado al X (XLH):: Presentación de una familia, asociado a una osteoartritis prematura y simulando además una espondiloartropatía seronegativa / X-linked hypophosphatemic rickets: Presentation of a family, associated with premature osteoarthritis, and simulating a seronegative spondyloarthropathy

En este artículo presentamos un enfoque práctico para el diagnóstico diferencial de desórdenes hipofosfatémicos heredados junto a la osteomalacia inducida por tumor (una forma adquirida), profundizando sobre el raquitismo hipofosfatémico ligado al cromosoma X y hacemos la descripción de una familia con este diagnóstico.

In this article we present a practical focus for the differential diagnosis of hypophosphatemic disorders inherited join to the osteomalacia induced by tumor (an acquired form); deepening about the X-linked hypophosphatemic rickets and we present description of a family with this diagnosis.

Informe técnico sobre cobertura en pacientes con diagnóstico de raquitismo renal hipofosfatémico / Technical report on coverage in patients with hypophosphatemic renal rickets

Al respecto de los productos farmacéuticos solicitados se evidencia que en el Petitorio Nacional Único de Medicamentos - PNUME vigente sólo se ha incluido al Calcitriol de 1mcg/mL y el Calcitriol de 0.25 mcg, no encontrándose Solución de Joulie (fosfato disódico+ácido fosfárico), Litiasin (citrato de potasio+ácido cítrico), Solución de Sholl (solución de citratos), K-phos neutral (fosfato de sodio y potasio) y Phospha neutral (anhidrido fosfato de sodio dibásico+fosfato de potasio monobásico+monohidrato fosfato de sodio monobásico), por lo que estos productos deberán contar con la aprobación del Comité Farmacoterapéutico correspondiente para que de corresponder la IPRESS que brinda atención al paciente solicite, de acuerdo a normativa vigente, su evaluación para cobertura SIS.(AU)