FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / X-linked hypophosphatemic rickets (XLHR) is the most common cause of heritable rickets, with an incidence of 1:20,000 live births, representing more than 80% of familial hypophosphatemic rickets. Saliva is the most easily available and accessible body fluid, which makes it one of the most sought after tools in diagnostic pathology. In this context, this thesis, constituted by 4 articles aimed to: (1) describe the main systemic manifestations, oral findings and dental management in 3 generations of an affected family; (2) analyze the mineralization pattern of enamel and dentin in patients affected by XLHR using micro-CT, and to associate enamel and dentin mineralization in primary and permanent teeth with tooth position, gender and presence/absence of this disease; (3) evaluate the peptide profile in the saliva of patients with X-linked hypophosphatemic rickets using high performance liquid chromatography; and (4) characterize salivary proteins in this condition using unidimensional electrophoresis. On study 1, oral exams, laboratorial and histologic evaluations, cone-beam computed tomographies, panoramic and periapical radiographs were performed to properly institute the most adequate treatment strategy. On study 2, teeth were collected from 5 individuals from the same family. Gender, age, tooth position (anterior/posterior) and tooth type (deciduous/permanent) were recorded for each patient. Following collection, teeth were placed in 0.1% thymol solution until Micro-CT scan. Projection images were reconstructed and analyzed. On study 3, unstimulated whole and stimulated parotid saliva were obtained from 8 individuals with (AFF) and 8 healthy individuals, both genders, without (CON) x-linked hypophosphatemic rickets aged from 8 to 66 years. Supernatants were analyzed by high performance liquid chromatography, and the salivary flow rate (ml/min) was calculated. Each major peak in the HPLC chromatogram of each sample was characterized. On study 4, unstimulated whole and stimulated parotid saliva were also obtained, being total protein concentration determined by the Bicinchoninic Acid Protein (BCA) method. Proteins were characterized according to their molecular weights within the unidimensional electrophoresis. The study 1 showed the importance of the knowledge of clinical signs and symptoms of XLHR for the correct diagnosis of this disease, and for the establishment of preventive and comprehensive dental care. On article 2, teeth of all affected patients presented dentin with a different mineralization pattern compared to the teeth of the healthy individual with dentin defects observed next to the pulp chambers. On the third article, whole and parotid salivary flows were significantly different (p = 0.001), being flow of whole saliva higher (0.518  0.282 mL/min) than parotid saliva (0.124  0.086 mL/min). Whole salivary flow rate was higher in the AFF group (0.698  0.229) than in the CON group (0.339  0.210 mL/min) (p = 0.006). Twenty-eight peaks were found in whole and 21 peaks in parotid saliva. Whole saliva of the CON group presented lower number of peaks than AFF group. In parotid saliva, peaks 17 and 28 (retention times: 24 and 39 min) were found exclusively in the AFF group, and peak 13 (retention time: 19 min) exclusively in the CON. Article 4 showed difference concerning to total protein concentration between whole and parotid saliva (p < 0.001), being higher concentration found in whole saliva (102.603  42.336 Âg/mL) than in parotid saliva (0.699  0.438 Âg/mL). Bands with 102 kDa, 48 kDa and 24 kDa presented higher intensity in whole saliva of CON group (p = 0.015, p = 0.043 and p = 0.022). In conclusion, XLHR patients presented specific characteristics in dentin mineralization and salivary proteins and peptides, which can lead to differentiate these patients from healthy individuals, improving the diagnostic field. / Raquitismo hipofosfatÃmico ligado ao cromossomo X (XLHR) à a maior causa de raquitismo hereditÃrio, com uma incidÃncia de 1:20.000 nascidos vivos, representando mais de 80% das formas de raquitismo hipofosfatÃmico familiar. A saliva à o fluido humano mais disponÃvel e de fÃcil acesso, o que faz dela uma das ferramentas mais pesquisadas no diagnÃstico de patologias. Nesse contexto, essa tese, constituÃda de 4 artigos objetivou: (1) descrever as principais manifestaÃÃes sistÃmicas, achados orais e tratamentos dentÃrios em 3 geraÃÃes de uma famÃlia afetada; (2) analisar o padrÃo de mineralizaÃÃo do esmalte e da dentina nos pacientes afetados por XLHR, utilizando microtomografia computadorizada (Micro CT), e associar a mineralizaÃÃo do esmalte e da dentina em dentes decÃduos e permanentes, segundo gÃnero e presenÃa/ausÃncia da doenÃa; (3) avaliar o perfil de peptÃdeos na saliva de pacientes com XLHR, utilizando cromatografia lÃquida de alta performance (HPLC); e (4) caracterizar proteÃnas salivares nessa condiÃÃo, utilizando eletroforese unidimensional. No estudo 1, exames orais, laboratoriais e avaliaÃÃes histolÃgicas, tomografias computadorizadas cone-beam e radiografias periapicais foram realizadas para a apropriada instituiÃÃo da estratÃgia de tratamento mais adequada. No estudo 2, dentes foram coletados de 5 indivÃduos de uma mesma famÃlia. GÃnero, idade, posiÃÃo dentÃria (anterior/posterior) e tipo dentÃrio (decÃduo/permanente) foram registrados para cada paciente. ApÃs a coleta, os dentes foram colocados em soluÃÃo de timol a 0,1% atà a anÃlise atravÃs do Micro CT. As imagens projetadas foram reconstruÃdas e analisadas. No estudo 3, saliva total nÃo estimulada e saliva de parÃtida estimulada foram obtidas de 8 indivÃduos afetados com (AFF) e 8 indivÃduos sem (CON) XLHR, de ambos os gÃneros e idades entre 8 e 66 anos. Sobrenadantes foram analisados por meio de HPLC e o fluxo salivar (mL/min) foi calculado. Os picos que se apresentaram maiores nos cromatogramas do HPLC foram caracterizados. No estudo 4, saliva total nÃo estimulada e saliva de parÃtida estimulada tambÃm foram obtidas, sendo a concentraÃÃo de proteÃnas totais determinada pelo MÃtodo do Ãcido BicinconÃnico (BCA). ProteÃnas foram caracterizadas de acordo com o peso molecular atravÃs de eletroforese unidimensional. O estudo 1 mostrou a importÃncia do conhecimento dos sinais e sintomas clÃnicos do XLHR para o correto diagnÃstico dessa doenÃa, e para o estabelecimento de atendimento odontolÃgico preventivo e abrangente. No artigo 2, os dentes de todos os pacientes afetados apresentaram dentina com padrÃo de mineralizaÃÃo diferente comparado aos dentes de indivÃduos saudÃveis, sendo os defeitos na dentina observados prÃximo Ãs cÃmaras pulpares. No artigo 3, os fluxos salivares da saliva total e de parÃtida foram significativamente diferentes (p=0,001), sendo o fluxo de saliva total maior (0,518  0,282 mL/min) do que o de saliva de parÃtida (0,124  0,086 mL/min). O fluxo salivar da saliva total foi maior no grupo AFF (0,698  0,229) que no grupo CON (0,339  0,210 mL/min) (p = 0,006). Vinte e oito picos foram encontrados em saliva total e 21 em saliva de parÃtida. A saliva total do grupo CON apresentou menor nÃmero de picos que a do grupo AFF. Na saliva de parÃtida, os picos 17 e 28 (tempos de retenÃÃo: 24 e 39 min) foram encontrados exclusivamente no grupo AFF e o pico 13 (tempo de retenÃÃo: 19 min) no CON. Artigo 4 demonstrou diferenÃa relacionada à concentraÃÃo de proteÃnas totais entre saliva total e de parÃtida (p < 0,001), sendo a maior concentraÃÃo encontrada na saliva total (102,603  42,336 Âg/mL) que na saliva de parÃtida (0,699  0,438 Âg/mL). Bandas com 102 kDa, 48 kDa e 24 kDa apresentaram maior intensidade na saliva total do grupo CON (p = 0,015, p = 0,043 e p = 0,022). Em conclusÃo, pacientes com XLHR apresentaram caracterÃsticas especÃficas relacionadas à mineralizaÃÃo dentinÃria e proteÃnas e peptÃdeos salivares que podem levar à diferenciaÃÃo desses pacientes de indivÃduos saudÃveis, avanÃando no campo diagnÃstico.

Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose.

<p>The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.</p>

The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.

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 (Tb.Th; p < 0,01) e maior falta da homogeneidade trabecular (SD.1/Tb.N; p=0,02). Na tíbia distal, eles tiveram menor Tb.N (p < 0,01), maior separação trabecular (Tb.Sp; p < 0,01) e maior SD.1/Tb.N (p < 0,01). A avaliação renal foi feita em 39 pacientes com XLHR. A NC foi diagnosticada em 15 (38,5%) pacientes pelas US e TC, principalmente no grupo pediátrico em uso intensivo de fosfato. A US detectou NC em 37 (94,8%), majoritariamente como grau 1 (97%), enquanto a TC identificou NC medular em 15 (38,5%): 10 (66,7%) como grau 1 e cinco (33,3%) como grau 2. Quatro (10,2%) pacientes adultos tinham NL determinada pela CT. Além da hiperfosfatúria presente em todos os pacientes, a hipocitratúria foi a alteração metabólica mais comum (30,7%); somente dois pacientes apresentaram hipercalciúria (5,1%) e nenhum apresentou hiperoxalúria. Conclusões: nesta casuística, a XLHR foi a principal forma hereditária de RQ/OM-FGF23. A HR-pQCT foi mais informativa do que a DXA e o compartimento ósseo trabecular foi mais afetado pela doença, particularmente na tíbia distal. Finalmente, a NC foi mais prevalente que a NL; o principal fator de risco metabólico foi a hiperfosfatúria e o tratamento intensivo com fosfato parece ser um agravante na formação da NC / 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 patients showed lower trabecular number (Tb.N; p=0.01), greater trabecular thickness (Tb.Th; p < 0.01) and more inhomogeneous trabecular network (SD.1/Tb.N; p=0.02). At the distal tibia, they had lower Tb.N (p < 0.01), larger trabecular separation (Tb.Sp; p < 0.01) and greater SD.1/Tb.N (p < 0.01). The renal assessment was done in 39 XLHR patients. NC was diagnosed in 15 (38.5%) patients by US and CT, mainly in the pediatric group that was in phosphate treatment. US identified NC in 37 (94.8%), mostly as grade 1 (97%), meanwhile CT determined medullary NC in 15 (38.5%) patients: 10 (66.7%) as grade 1 and five (33.3%) as grade 2. Four (10.2%) adults patients had NL determined by CT. Besides hyperphosphaturia present in all XLHR patients, hypocitraturia was the most common metabolic factor (30.7%); hypercalciuria occurred in only two patients (5.1%) and none had hyperoxaluria. Conclusions: in our cohort, XLHR was the most prevalent form of FGF23-mediated inherited hypophosphatemic rickets. HR-pQCT was more informative than DXA and the cancellous bone compartment was the most affected by the disease particularly at the distal tibia. Finally, NC was more prevalent than NL; the main metabolic risk factor was hyperphosphaturia and the intensive treatment with phosphate seems to be an aggravating factor in the formation of NC

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 (Tb.Th; p < 0,01) e maior falta da homogeneidade trabecular (SD.1/Tb.N; p=0,02). Na tíbia distal, eles tiveram menor Tb.N (p < 0,01), maior separação trabecular (Tb.Sp; p < 0,01) e maior SD.1/Tb.N (p < 0,01). A avaliação renal foi feita em 39 pacientes com XLHR. A NC foi diagnosticada em 15 (38,5%) pacientes pelas US e TC, principalmente no grupo pediátrico em uso intensivo de fosfato. A US detectou NC em 37 (94,8%), majoritariamente como grau 1 (97%), enquanto a TC identificou NC medular em 15 (38,5%): 10 (66,7%) como grau 1 e cinco (33,3%) como grau 2. Quatro (10,2%) pacientes adultos tinham NL determinada pela CT. Além da hiperfosfatúria presente em todos os pacientes, a hipocitratúria foi a alteração metabólica mais comum (30,7%); somente dois pacientes apresentaram hipercalciúria (5,1%) e nenhum apresentou hiperoxalúria. Conclusões: nesta casuística, a XLHR foi a principal forma hereditária de RQ/OM-FGF23. A HR-pQCT foi mais informativa do que a DXA e o compartimento ósseo trabecular foi mais afetado pela doença, particularmente na tíbia distal. Finalmente, a NC foi mais prevalente que a NL; o principal fator de risco metabólico foi a hiperfosfatúria e o tratamento intensivo com fosfato parece ser um agravante na formação da NC / 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 patients showed lower trabecular number (Tb.N; p=0.01), greater trabecular thickness (Tb.Th; p < 0.01) and more inhomogeneous trabecular network (SD.1/Tb.N; p=0.02). At the distal tibia, they had lower Tb.N (p < 0.01), larger trabecular separation (Tb.Sp; p < 0.01) and greater SD.1/Tb.N (p < 0.01). The renal assessment was done in 39 XLHR patients. NC was diagnosed in 15 (38.5%) patients by US and CT, mainly in the pediatric group that was in phosphate treatment. US identified NC in 37 (94.8%), mostly as grade 1 (97%), meanwhile CT determined medullary NC in 15 (38.5%) patients: 10 (66.7%) as grade 1 and five (33.3%) as grade 2. Four (10.2%) adults patients had NL determined by CT. Besides hyperphosphaturia present in all XLHR patients, hypocitraturia was the most common metabolic factor (30.7%); hypercalciuria occurred in only two patients (5.1%) and none had hyperoxaluria. Conclusions: in our cohort, XLHR was the most prevalent form of FGF23-mediated inherited hypophosphatemic rickets. HR-pQCT was more informative than DXA and the cancellous bone compartment was the most affected by the disease particularly at the distal tibia. Finally, NC was more prevalent than NL; the main metabolic risk factor was hyperphosphaturia and the intensive treatment with phosphate seems to be an aggravating factor in the formation of NC