[Value of serum fibroblast growth factor 23 in diagnosis of hypophosphatemic rickets in children]. / è¡€æ¸ æˆçº¤ç»´ç»†èƒžç”Ÿé•¿å› å­23å¯¹å„¿ç«¥ä½Žè¡€ç£·æ€§ä½å»ç— çš„è¯Šæ–­ä»·å€¼ç ”ç©¶.

OBJECTIVES: To study the value of serum fibroblast growth factor 23 (FGF23) in the diagnosis of hypophosphatemic rickets in children. METHODS: A total of 28 children who were diagnosed with hypophosphatemic rickets in Children's Hospital of Nanjing Medical University from January 2016 to June 2021 were included as the rickets group. Forty healthy children, matched for sex and age, who attended the Department of Child Healthcare of the hospital were included as the healthy control group. The serum level of FGF23 was compared between the two groups, and the correlations of the serum FGF23 level with clinical characteristics and laboratory test results were analyzed. The value of serum FGF23 in the diagnosis of hypophosphatemic rickets was assessed. RESULTS: The rickets group had a significantly higher serum level of FGF23 than the healthy control group (P<0.05). In the rickets group, the serum FGF23 level was positively correlated with the serum alkaline phosphatase level (rs=0.38, P<0.05) and was negatively correlated with maximum renal tubular phosphorus uptake/glomerular filtration rate (rs=-0.64, P<0.05), while it was not correlated with age, height Z-score, sex, and parathyroid hormone (P>0.05). Serum FGF23 had a sensitivity of 0.821, a specificity of 0.925, an optimal cut-off value of 55.77 pg/mL, and an area under the curve of 0.874 in the diagnosis of hypophosphatemic rickets (P<0.05). CONCLUSIONS: Serum FGF23 is of valuable in the diagnosis of hypophosphatemic rickets in children, which providing a theoretical basis for early diagnosis of this disease in clinical practice.

Twin girls with hypophosphataemic rickets and papilloedema.

A 7 year-old twin girl with hypophosphataemic rickets was evaluated for a recent onset of mild strabismus.She was a homozygous twin sister with hypophosphataemic rickets diagnosed at the age of 2 years, with a mutation in intron 21 of the PHEX gene, which was also present in her sister.The girls' clinical histories were remarkable for an important lower limb varus that progressively improved after starting phosphate supplementation with a galenical solution (Joulies solution 1 mmol phosphate/ml) and vitamin D 1,25 OH.During the examinations, both girls were in good general condition. Physical examinations were unremarkable, except for tibial varus, bilateral fifth finger clinodactyly and bilateral syndactyly of the third and fourth foot fingers. No major head shape abnormalities were noticeable except for a high forehead.One patient presented with a slight strabismus, normal isochoric isocyclic and reactive pupils, no signs of cranial nerve deficit, and no alterations in the rest of the neurological examination. An ophthalmological evaluation showed bilateral papilloedema. A cerebral MRI scan was then performed, suspecting elevated intracranial pressure (figure 1). The same examination was performed on the asymptomatic sister which also demonstrated papilloedema with similar findings on cranial MRI too.

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome.

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.

[Analysis of PHEX gene mutations in three pedigrees affected with hypophosphatemic rickets].

OBJECTIVE: To explore the molecular basis for three pedigrees affected with hypophosphatemia vitamin D resistant rickets (X-linked hypophosphatemia, XLH). METHODS: Peripheral blood samples from the three pedigrees were collected. Following DNA extraction, the 11 exons and flanking regions of the PHEX gene were subjected to PCR amplification and direct sequencing. Pathogenicity of identified mutations was evaluated through genotype-phenotype correlation. RESULTS: For pedigrees 1 and 2, pathogenic mutations were respectively identified in exon 8 (c.871C>T, p.R291X) and exon 15 (c.1601C>T, p.P534L) of the PHEX gene. For pedigree 3, a novel mutation (c.1234delA, p.S412Vfs*12) was found in exon 11 of the PHEX gene, which caused shift the reading frame and premature termination of protein translation. CONCLUSION: The three mutations probably account for the XLH in the affected pedigrees. The discovery of novel mutations has enriched the spectrum of PHEX gene mutations.

[Mutation analysis of four pedigrees affected with hypophosphatemic rickets through targeted next-generation sequencing].

OBJECTIVE: To detect potential mutations of PHEX gene in four pedigrees affected with hypophosphatemic rickets (HR) and provide prenatal diagnosis for a fetus at 13th gestational week. METHODS: The coding regions and exon/intron boundaries of PHEX, FGF23, DMP1, ENPP1, CLCN5 and SLC34A3 genes of the probands were analyzed by targeted next-generation sequencing (NGS). Suspected mutations were verified by Sanger sequencing among unaffected relatives and 200 unrelated healthy individuals. Deletions were confirmed by multiplex ligation-dependent probe amplification (MLPA) detection of probands, unaffected relatives and 20 unrelated healthy individuals. Prenatal diagnosis for a fetus with high risk was carried out through MLPA analysis. RESULTS: Four PHEX mutations were respectively detected in the pedigrees, which included c.850-3C>G, exon 11 deletion, exon 13 deletion and c.1753G>A (p.G585R). Among these, exon 11 deletion, exon 13 deletion and c.1753G>A (p.G585R) were novel mutations and not found among unaffected relatives and healthy controls. In pedigree 3, the same mutation was not found in the fetus. CONCLUSION: Mutations of the PHEX gene probably underlies the disease among the four pedigrees. NGS combined with Sanger sequencing and/or MLPA detection can ensure accurate diagnosis for this disease.

Mosaic NRAS Q61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets.

The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy). We speculate on the apparently rare association of CSHS with CMN compared with EN. We also report the favourable outcome of this patient at the age of 8 years after extensive neonatal curettage of the giant CMN and use of vitamin D and phosphate supplementation.

Hypophosphatemic rickets: lessons from disrupted FGF23 control of phosphorus homeostasis.

Fibroblast growth factor-23 (FGF23) regulates phosphate reabsorption in the kidney and therefore plays an essential role in phosphate balance in humans. There is a host of defects that ultimately lead to excess FGF23 levels and thereby cause renal phosphate wasting and hypophosphatemic rickets. We describe the genetic, pathophysiologic, and clinical aspects of this group of disorders with a focus on X-linked hypophosphatemia (XLH), the best characterized of these abnormalities. We also discuss autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR) and tumor-induced osteomalacia (TIO) in addition to other rarer FGF23-mediated conditions. We contrast the FGF23-mediated disorders with FGF23-independent hypophosphatemia, specifically hypophosphatemic rickets with hypercalciuria (HHRH). Errant diagnosis of hypophosphatemic disorders is common. This review aims to enhance the recognition and appropriate diagnosis of hypophosphatemia and to guide appropriate treatment.

Hypophosphatemic rickets due to perturbations in renal tubular function.

The common denominator for all types of rickets is hypophosphatemia, leading to inadequate supply of the mineral to the growing bone. Hypophosphatemia can result from insufficient uptake of the mineral from the gut or its disproportionate losses in the kidney, the latter being caused by either tubular abnormalities per se or the effect on the tubule of circulating factors like fibroblast growth factor-23 and parathyroid hormone (PTH). High serum levels of the latter result in most cases from abnormalities in vitamin D metabolism which lead to decreased calcium absorption in the gut and hypocalcemia, triggering PTH secretion. Rickets is a disorder of the growth plate and hence pediatric by definition. However, it is important to recognize that the effect of hypophosphatemia on other parts of the skeleton results in osteomalacia in both children and adults. This review addresses the etiology, pathophysiologic mechanisms, clinical manifestations and treatment of entities associated with hypophosphatemic rickets due to perturbations in renal tubular function.

Epidermal nevus syndrome with hypophosphatemic rickets in a young girl.

Epidermal nevus syndrome (ENS) is a rare congenital disorder. It is characterised by epidermal nevi and abnormalities of multiple organs, including central nervous system, skeleton, cardiovascular and genitourinary systems and eyes. Hypophosphatemic rickets-associated ENS has rarely been reported. We report a 46-month-old girl who presented with a classical feature of hypophosphatemic rickets. Examination of skin revealed multiple melanocytic nevi at her trunk, face and both arms with verrucous plaques at both axillae and neck, and yellow plaques at the back along Blaschko's lines. Histopathology of the skin lesions was compatible with epidermal nevi and nevus sebaceous. Therefore, the diagnosis of ENS was made. Apart from typical rickets, the skeletal X-rays interestingly displayed fibrous dysplasia-like lesions along right femur, tibia and fibula. Hypophosphatemic rickets was treated with alfacalcidol and phosphate solution. After 3 months of treatment, clinical improvement of hypophosphatemic rickets was clearly demonstrated. Her blood chemistries were normalised at 5 months following the treatment. In conclusion, hypophosphatemic rickets is a rare presentation of ENS. Our patient also demonstrated an additional abnormal bone finding, fibrous dysplasia-like lesions, associated with rachitic changes. This highlights heterogeneity of this condition and importance of thorough evaluation of patients with ENS.

[Metabolic bone disease osteomalacia]. / Metabolische Knochenkrankheit Osteomalazie.

Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases.

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.

[Updates on rickets and osteomalacia: FGF23-mediated hypophosphatemic rickets/osteomalacia].

Some of the hypophosphatemic rickets/osteomalacia are caused by the increased bioactivity of FGF23, and classified into FGF23-mediated hypophosphatemic rickets/osteomalacia. This group includes various disorders such as X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia, tumor-induced osteomalacia, and rickets/osteomalacia caused by the administration of iron polymaltose or saccharated ferric oxide. Measurement of serum levels of FGF23 is useful for diagnosis of these conditions. In the adult patients with FGF23-mediated hypophosphatemic rickets/osteomalacia, mineralizing enthesoopathy is an often observed complication.

A New de novo Mosaic Mutation of PHEX Gene: A Case Report of a Boy with Hypophosphatemic Rickets.

BACKGROUND: X-linked hypophosphatemia is the most prevalent form of heritable rickets, characterized by an X-linked dominant inheritance pattern. The genetic basis of X-linked hypophosphatemia is a loss-of-function mutation in the PHEX gene (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome), which leads to an enhanced production of phosphaturic hormone FGF23. X-linked hypophosphatemia causes rickets in children and osteomalacia in adults. Clinical manifestations are numerous and variable, including slowdown in growth, swing-through gait and progressive tibial bowing, related to skeletal and extraskeletal actions of FGF23. PHEX gene spans over 220 kb and consists of 22 exons. To date, hereditary and sporadic mutations are known (missense, nonsense, deletions and splice site mutations). CASE PRESENTATION: Herein, we describe a male patient carrying a novel de novo mosaic nonsense mutation c.2176G>T (p.Glu726Ter) located in exon 22 of PHEX gene. CONCLUSION: We highlight this new mutation among possible causative of X-linked hypophosphatemia and suggest that mosaicism of PHEX mutations is not so uncommon and should be excluded in diagnostic workflow of heritable rickets both in male and female patients.

Autosomal recessive hypophosphatemic rickets type 2; a novel mutation in the ENPP1 gene.

BACKGROUND: Hypophosphatemic rickets (HR) is a rare disease caused by several genetic mutations in factors that cause an increase in fibroblast growth factor 23 (FGF23), and renal phosphate transporters. ENPP1 (ectonucleotide pyrophosphatase / phosphodiesterase 1) mutations cause autosomal recessive inheritance hypophosphatemic rickets type 2. CASE: In our study, we present a novel mutation in the ENPP1 gene detected in 4 siblings in a single family. CONCLUSION: Our findings can be applied to further understand molecular pathogenesis and to establish a correlation between genotype and phenotype for HR.

Genetic basis of hereditary hypophosphataemic rickets and phenotype presentation in children and adults.

Hypophosphataemic rickets (HR) is a genetic disorder causing defects in the renal handling of phosphorus, resulting in rickets. HR can be classified into two groups. First- those with excess fibroblast growth factor 23(FGF23) levels, which are due to gene mutations in extrarenal factors and include X-linked dominant hypophosphataemic rickets (XLHR), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR), and hypophosphataemic rickets with hyperparathyroidism. Second- those with normal or low FGF23, which are caused by gene mutations in renal tubular phosphate transporters and include hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and X-linked recessive hypophosphataemic rickets. The radiographical changes and clinical features of rickets in various types of HR are similar but not identical. Short stature, bone deformities mainly in the lower limbs, and dental problems are typical characteristics of HR. Although the initial diagnosis of HR is usually based on physical, radiological, and biochemical features, molecular genetic analysis is important to confirm the diagnosis and differentiate the type of HR. In this review, we describe clinical and biochemical features as well as genetic causes of different types of HR. The clinical and biochemical characteristics presented in this review can help in the diagnosis of different types of HR and, therefore, direct genetic analysis to look for the specific gene mutation.

Hypophosphatemic Rickets with R179W Mutation in FGFR23 Gene - A Rare But Treatable Cause of Refractory Rickets.

Hypophosphatemic rickets is one of the major causes of refractory rickets exhibiting genetic heterogeneity. Most cases are X-linked due to PHEX gene mutations. However recently, autosomal dominant (AD) forms have been described, due to mutations in FGF23. The authors present a 13-year-old girl who had hypophosphatemic rickets due to R179W mutation in FGF23 gene, being the first case in India with this mutation. She presented with bone pains, short stature and osteopenic bones, symptoms appearing after onset of menarche. This presentation is different from that seen in younger children with rickets. Burosumab, an anti-FGF23 antibody is an effective novel therapy for FGF23-related rickets but it is not available in India. High doses of calcitriol and phosphate were required to alleviate the symptoms and signs. The authors aim to alert pediatricians to keep in mind this treatable disorder to prevent diagnostic delays and improve treatment outcome.

Previously Undiagnosed Hypophosphatemic Rickets Presenting Like Ankylosing Spondylitis in Adulthood: A case report.

Hypophosphatemic rickets (HR) is a metabolic bone disease manifesting with a wide variety of musculoskeletal symptoms. Sometimes it can mimic rheumatic diseases; also, it can be seen in the course of rheumatic diseases. In this paper, a 35-years old female patient, previously undiagnosed case of HR presenting first as Ankylosing Spondylitis will be discussed.

Hypophosphataemic Rickets: Similar Phenotype of Different Diseases.

Hypophosphataemic rickets (HR) is a group of rare disorders caused by excessive renal phosphate wasting in which the participation of fibroblast growth factor 23 (FGF23) can be prominent. These diseases pose therapeutic challenges with important consequences for growth and bone development in childhood, with higher risk of fractures and poorer bone healing, dental problems, and nephrolithiasis or nephrocalcinosis. In some cases, the diagnostic delay can be very long; laboratory findings and an exhaustive anamnesis could help distinguish between various pathologies, and FGF23 values-although currently not routinely measured-have implications for the differential diagnosis. Genetic testing is encouraged, especially in sporadic or insidious cases. In this review we discuss the clinical features of HR, with a particular emphasis on the differential diagnosis and the therapeutic implications.