Hereditary Rickets Research Articles

Hereditary Rickets: A Quick Guide for the Pediatrician.

With the increased discovery of genes implicated in vitamin D metabolism and the regulation of calcium and phosphate homeostasis, a growing number of genetic forms of rickets are now recognized. These are categorized into calciopenic and phosphopenic rickets. Calciopenic forms of hereditary rickets are caused by genetic mutations that alter the enzymatic activity in the vitamin D activation pathway or impair the vitamin D receptor action. Hereditary forms of phosphopenic rickets, on the other hand, are caused by genetic mutations that lead to increased expression of FGF23 hormone or that impair the absorptive capacity of phosphate at the proximal renal tubule. Due to the clinical overlap between acquired and genetic forms of rickets, identifying children with hereditary rickets can be challenging. A clear understanding of the molecular basis of hereditary forms of rickets and their associated biochemical patterns allow the health care provider to assign the correct diagnosis, avoid non-effective interventions and shorten the duration of the diagnostic journey in these children. In this mini-review, known forms of hereditary rickets listed on the Online Mendelian Inheritance in Man database are discussed. Further, a clinical approach to identify and diagnose children with hereditary forms of rickets is suggested.

Refractory rickets: A case of X-linked hypophosphatemic rickets (PHEX gene variation)

Hypophosphatemic rickets is a type of hereditary rickets distinguished by both hypophosphatemia and hyperphosphaturia. X-linked hypophosphatemic rickets (XLH) is the most prevalent type of heritable hypophosphatemic rickets. We describe a 3-year-old child whose phosphate-regulating endopeptidase homolog X-linked (PHEX) gene variation resulted in lower limb abnormalities and short stature. A similar history was noted in the father. We highlight the significance of a prompt diagnosis and initiation of treatment to prevent subsequent sequelae.

Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Spectrum of PHEX Mutations and FGF23 Profiles in a Taiwanese Cohort With X-Linked Hypophosphatemia Including 102 Patients.

X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.

A Pair of Siblings with Vitamin D Dependent Rickets (VDDR) Type 1A: More Than Dairy and Sunshine

Vitamin D-dependent rickets (VDDR) type 1A, owing to 1-alpha-hydroxylase deficiency, albeit rare, is an important diagnosis to consider in children with rickets not responding to conventional doses vitamin D and calcium. In this case report, we describe two siblings who presented with multiple fractures since childhood. A low 1,25-dihydroxyvitamin D (1,25(OH)2D) despite a sufficient 25-hydroxyvitamin D (25OHD) level was suggestive of 1-alpha-hydroxylase deficiency. Genetic testing confirmed a mutation in the CYP27B1 gene on chromosome 12q13.3, which produces 1-alpha-hydroxylase. The inability to convert 25OHD to 1,25 (OH)2D leads to hypocalcemia and severe rickets. Treatment requires a pharmacologic dose of activated hydroxylated vitamin D and adequate calcium intake. Rare forms of hereditary rickets should be suspected in severe rickets. Early recognition of VDDR type 1A is imperative to ensure adequate healing of rickets during childhood. Establishing a diagnosis also helps to ensure compliance with the high doses of active vitamin D metabolite required in this condition.

Abstract 12982: Between a Rock and a Hard Place: Stiff Left Atrial Syndrome in a Patient With Hereditary Rickets

Introduction: Stiff left atrial syndrome (SLAS) is an uncommon cause of pulmonary hypertension (PH) that has been described as a complication of ablation for atrial fibrillation; here we describe a unique case of SLAS in the setting of extensive left atrial calcification from the treatment of hereditary hypophosphatemia (HH). Case Presentation: A 44-year-old woman with a history of HH presented for evaluation of progressive exertional dyspnea. Previous treatment with calcitriol and phosphate had been complicated by severe calcific mitral and aortic stenosis requiring aortic and mitral valve replacement eight years prior. She reported initial improvement in her symptoms after surgery, but more recently had noted worsening dyspnea and edema despite escalating her home diuretic dose. TTE was notable for moderately severe PH with no evidence of valvular or ventricular dysfunction. Chest CT showed extensive left atrial mural calcification (Figure A) with corresponding calcium visible in the wall of the left atrium on TTE (Figure B). The patient was admitted and underwent IV diuresis followed by RHC confirming mPAP of 41mmHg with a PCWP of 20mmHg and prominent V waves to 33mmHg (Figure C-D). PCWP was confirmed by wedge oxyhemoglobin saturation. Symptoms were improved but not resolved with additional diuresis. Discussion: In this patient with metastatic calcinosis related to the treatment of her HH, we believe her PH is most likely secondary to SLAS due to marked circumferential left atrial calcification. SLAS is characterized by decreased left atrial compliance, leading to large V waves in the absence of mitral regurgitation or an elevated LVEDP. Beyond diuresis, there are no proven treatments for PH due to SLAS.

X-Linked Hypophosphataemic Rickets and Growth.

X-linked hypophosphataemia (XLH) is the most prevalent form of hereditary rickets characterized by an alteration of phosphate metabolism which frequently leads to the appearance of fractures, bone deformities and growth delay. Although the mechanism of growth impairment in patients with XLH still needs to be clarified, it is known that this alteration is not due to genetic or endocrine factors. A potential explanation for the impairment of growth in this disease is the alteration of the growth plate, a structure responsible for longitudinal growth of bones. Some of the findings in the growth plate of patients with XLH include atypical organization of chondrocytes due to low rates of proliferation and apoptosis and disturbance of chondrocyte hypertrophy, overactivation of the mitogen-activated protein kinase (MAPK) signalling pathway and upregulation of phosphorylated extracellular signal-regulated kinase (pERK). Conventional treatment of XLH (consisting of oral phosphate supplements and active vitaminD analogues) is often insufficient for the longitudinal growth of bone, but other strategies based on recombinant growth hormone or therapies targeting fibroblast growth factor23 (FGF23) or its receptor, such as burosumab, have shown promising results. This article briefly describes the relationship between XLH and growth retardation, and how to address this alteration in patients with XLH.

Rickets in a Crab-eating Fox (Cerdocyon thous)

Background : Calcium is essential for the healthy development of animals, especially regarding bone formation. Diverse factors influence calcium metabolism, and failure in any of these points may result in metabolic bone diseases. Rickets is an uncommon disease of growing bones occurring exclusively in young animals, it is a characterized by the failure of osteoid to calcify and can be a result of lack of vitamin D, imbalance of calcium and phosphorus or hereditary conditions. Nutritional origin is more frequent in veterinary medicine, but it has become rarer after the availability of balanced commercial rations. This report describes the diagnosis and treatment of rickets in a crab-eating fox puppy. Case : A 3-month-old male crab-eating fox was presented with ataxia and angular deviation of the tibia and radius/ulna with suspected osteometabolic disease. It was part of a group of three orphan siblings hand-raised. The other two siblings did not present any clinical signs. All three animals presented pale mucous membranes and were infected by ancylostoma, coccidia, toxocara, and sarcocystis. Radiographic findings of the affected animal showed generalized osteopenia of the entire skeleton associated with widening radiolucent distal physeal plates and cupping of the metaphysis, changes classical of rickets. The other two siblings presented no skeletal alterations and complete blood count and biochemistry of all three animals were taken for comparison, including serum vitamin D and PTH. All three animals presented lymphopenia (5.4-9.3 x 10³/uL, reference range 10.3-16.5 x 10³/uL), hypoproteinemia (5.1-5.3 g/dL, reference range 5.9-8.2 g/dL), low levels of creatinine (0.4-0.6 mg/dL, reference range 0.7-1.2 mg/dL), increased ALP (181-285 U/L, reference range 209.7-267 U/L) and CK (421-500 U/L, reference range for domestic dogs 16-140 U/L). The affected fox presented ionized calcium (10.9 mg/dL, reference range for domestic dogs 9.3-11.5 mg/dL) and vitamin D (26.4 ng/mL, reference range for domestic dogs 9.5-129 ng/mL) close to the inferior limits associated with elevated phosphorus (8.8 mg/dL, reference range for domestic dogs 2.5-5.6 mg/dL) and PTH (4.3 pg/mL, reference range for domestic dogs < 2.82 pg/dL). Besides that, the affected animal presented the quickest development (weight gain) among the offspring. Discussion : Recent reports of rickets in veterinary medicine are not common. The advent of balanced commercial rations and improvement in animal husbandry reduced the frequency of this condition. Wild species are more frequently reported to present metabolic bone disease due to inadequate nutrition management of the different species. Bone formation and growth are result of the deposition of hydroxyapatite crystals and it depends on calcium intake or absorption, adequate serum vitamin D levels and proper calcium and phosphorus balance. All these three situations were breached in this case report, resulting in a multifactorial scenario for development of rickets in this crab-eating-fox. Radiographic exam, complete blood count, biochemistry, and clinical response to dietary correction confirmed the diagnosis of rickets with nutritional origin. Hereditary rickets had been described in people and a domestic dog, but not in wildlife species. The animal responded well to clinical and nutritional management, presenting clinical response within a couple of weeks. This is the first report of rickets in this species as well as dosage of serum vitamin D and PTH in crab-eating foxes.

Functional analysis of 22 splice-site mutations in the PHEX, the causative gene in X-linked dominant hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the PHEX gene and is the most common form of hereditary rickets. The splice-site mutations account for 17% of all reported PHEX mutations. The functional consequence of these splice-site mutations has not been systemically investigated. The current study was undertaken to functionally annotate previously reported 22 splice-site mutations in the PHEX gene. PHEX mini-genes with different splice-site mutations were created by site-directed mutagenesis and expressed in HEK293 cells. The mRNA transcripts were analyzed by RT-PCR, cloning, and sequencing. These splicing mutations led to a variety of consequences, including exon skipping, intron retention, and activation of cryptic splice sites. Among 22 splice-site mutations, exon skipping was the most common event accounting for 73% (16/22). Non-canonical splice-site mutations could result in splicing errors to the same extent as canonical splice-site mutations such as c.436+3G>C, c.436+4A>C, c.436+6T>C, c.437-3C>G, c.850-3C>G, c.1080-3C>A, c.1482+5G>C, c.1586+6T>C, c.1645+5G>A, c.1645+6T>C, c.1701-16T>A, c.1768+5G>A, and c.1899+5G>A. Interestingly, non-canonical (c.436+6T>C and c.1586+6T>C) and canonical splice-site mutations (c.1769-1G>C) could generate partial splicing errors (both wild-type and mutant transcripts were detected), resulting in incomplete inactivation of PHEX gene, which may explain the mild disease phenotype reported previously, providing evidence of genotype-phenotype correlation. c.1645C>T (p.R549*) had no impact on pre-mRNA splicing although it is located next to canonical splice donor site GT. Exon skipping is the most common outcome due to splice-site mutations. Both canonical and non-canonical splice-site mutations can result in either severe or mild RNA splicing defects, contributing to phenotype heterogeneity. Non-canonical splice-site mutations should not be overlooked in genetic screening especially those located within 50 bp from canonical splice site.

Identification of a p.Trp403* nonsense variant in PHEX causing X-linked hypophosphatemia by inhibiting p38 MAPK signaling.

X-linked hypophosphatemia (XLH) is the most common hereditary rickets, caused by mutations in PHEX encoding the phosphate regulating endopeptidase homolog X-linked. Here, we report a nonsense variant in exon 11 of PHEX (c.1209G>A p.Trp403*) cosegregating with XLH in a Chinese family with a LOD score of 2.70. Real-time reverse transcription polymerase chain reaction analysis demonstrated that p.Trp403* variant did not cause nonsense-mediated mRNA decay (NMD), but significantly increased the expression level of FGF23 mRNA in the patients. Interestingly, p.Trp403* significantly reduced phosphorylation of p38 mitogen-activated protein kinase (MAPK) but not ERK1/2. Moreover, overexpression of FGF23 significantly decreased phosphorylation of p38 MAPK, whereas knockdown of FGF23 by siRNA significantly increased phosphorylation of p38 MAPK. These data suggest that p.Trp403* may not function via an NMD mechanism, and instead causes XLH via a novel signaling mechanism involving PHEX, FGF23, and p38 MAPK. This finding provides important insights into genetic and molecular mechanisms for the pathogenesis of XLH.

New insights on Final Epigravettian funerary behavior at Arene Candide Cave (Western Liguria, Italy).

We gained new insights on Epigravettian funerary behavior at the Arene Candide cave through the osteological and spatial analysis of the burials and human bone accumulations found in the cave during past excavations. Archaeothanathological information on the human skeletal remains was recovered from diaries, field pictures and notes, and data from recent excavations was integrated. The secondary deposits have traditionally been interpreted as older burials that were disturbed to make space for new inhumations. Our results suggest that those disturbances were not casual: older burials were intentionally displaced to bury younger inhumations. Subsequently, some skeletal elements, especially crania, were arranged around the new burial; these were often placed within stone niches. Based on the composition of some clusters, which contain the bones of two individuals displaced together, it is possible that a double burial composed of two adults was originally present at the site. This would be a burial type that had not been recognized at Arene Candide until now. Strikingly, this potential double burial contained an individual showing pathological bowing of the limbs, a finding which is not infrequent in skeletons from Gravettian and Epigravettian multiple burials. In addition, the crania and other skeletal elements derived from this burial were intentionally placed around a new inhumation, whose skeleton possibly shows a milder form of the same disease (possibly hereditary rickets). This and other observations suggest that the five individuals belonging to the second phase of this "cemetery" (AMS dates spanning 12,030 -11,180 cal BP) might have been buried over a relatively brief time span. Our study demonstrated similar behaviors in the first phase of mortuary use of the cave (12,820-12,420 cal BP), indicating a remarkable persistence in Final Epigravettian funerary models despite their archaeologically apparent rarity and intermittent nature.

HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA (CASE REPORT)

Hereditary hypophosphatemic rickets with hypercalciuria is a very rare autosomal recessive disease, pathogenic base of which is phosphorus reabsorption disorder in proximal nephron with following development of hypophsphatemia, hypercalciuria calcitriol level increase, decrease of parathyroid hormone, osteopenia and bony deformity. This disease refers to hypophosphatemic rickets, due to mutations in the SLC34A3 gene that encodes the sodium-phosphate cotransporter NaPi-IIc, which is responsible for phosphorus reabsorption in the proximal nephron. In this article, we present a clinical observation for a child with atypical manifestations of hereditary hypophosphatemic rickets with hypercalciuria. The clinical examination showed non constant hypophosphatemia, normal values of maximum tubular phosphate transport, absence of calcitriol serum concentrations increase, rachitic changes and bone mineral disorders during a long period of observation. It didn’t allow clinically to identify one of the variants of hypophosphatemic rickets in a child. The diagnosis was confirmed by the results of complete exome sequencing which revealed previously undescribed compound heterozygous mutation c.1382G&gt; A (p.Trp461Ter) in exon 13 and p.1094-3C&gt; T in intron 10 of the SLC34A3 gene. A correct diagnosis allowed us to reconsider the approaches of the treatment: in hereditary rickets recommended only phosphorus supplementation and prescription of vitamin D due to its increased endogenous production.

X-linked vitamin D-resistant rickets: 12 years of follow-up

Rickets are abnormalities of mineralization that can lead to bone fractures and deformities. Vitamin-resistant rickets is defined as any rickets not prevented by regular, early and prolonged administration of vitamin D and not cured by a sufficient total dose. The aim of our work is to describe the clinical, paraclinical and therapeutic aspects of X-linked hypophosphatemic rickets (XLHR), which is the most common cause of hereditary rickets and on the other hand to highlight the interest not only of the early care but also the regular long-term monitoring of these children.

Genetic Causes of Rickets.

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.

X-linked hypophosphatemia and growth.

X-Linked hypophosphatemia (XLH) is the most common form of hereditary rickets caused by loss-of function mutations in the PHEX gene. XLH is characterized by hypophosphatemia secondary to renal phosphate wasting, inappropriately low concentrations of 1,25 dihydroxyvitamin D and high circulating levels of fibroblast growth factor 23 (FGF23). Short stature and rachitic osseous lesions are characteristic phenotypic findings of XLH although the severity of these manifestations is highly variable among patients. The degree of growth impairment is not dependent on the magnitude of hypophosphatemia or the extent of legs´ bowing and height is not normalized by chronic administration of phosphate supplements and 1α hydroxyvitamin D derivatives. Treatment with growth hormone accelerates longitudinal growth rate but there is still controversy regarding the potential risk of increasing bone deformities and body disproportion. Treatments aimed at blocking FGF23 action are promising, but information is lacking on the consequences of counteracting FGF23 during the growing period. This review summarizes current knowledge on phosphorus metabolism in XLH, presents updated information on XLH and growth, including the effects of FGF23 on epiphyseal growth plate of the Hyp mouse, an animal model of the disease, and discusses growth hormone and novel FGF23 related therapies.

Hypophosphatemic Rickets in Siblings: A Rare Case Report.

Hypophosphatemic rickets (HR) is a type of hereditary rickets characterized by persistent hypophosphatemia and hyperphosphaturia. The most predominant type is inherited in an X-linked fashion and caused by mutation in the gene encoding the phosphate-regulating endopeptidase homolog, X-linked (PHEX), identified in 1995. The X-linked hypophosphatemic (XLH) rickets is a rare hereditary metabolic disorder with a prevalence of 1 in 20,000 and causes deficient calcification of mineralized structures such as bones and teeth resulting in dental problems in terms of delayed eruption, spontaneous periapical infections, and exfoliation. We report one such unique case of hypophosphatemic vitamin D-resistant rickets in siblings exhibiting classical features of rickets with emphasis on its treatment and dental considerations.

Progress in the diagnosis and treatment of X-linked hypophosphatemic rickets

X-linked hypophosphatemic rickets is the most common hereditary rickets and easy to misdiagnosis or missed.The treatment is more complicated compared with the general rickets.In this paper, the clinical features, genes and treatment of X-linked hypophosphatemic rickets are reviewed. Key words: X-linked hypophos-phatemic rickets; PHEX gene; Growth hormone

Tumor-Induced Rickets Presenting in an Adolescent: A Case Report and Review of the Literature.

Rickets of any etiology is rarely encountered in modern clinical practice, and a primary presentation in an adolescent is even less common. Most cases of rickets are due to abnormalities in vitamin D intake, absorption, activity, or metabolism; others are related to phosphate deficiency from excessive renal excretion (e.g., X-linked dominant hypophosphatemic rickets). When a patient presents with no evidence of hereditary rickets and a standard workup fails to reveal the cause, unusual etiologies must be considered. Tumor-induced hypophosphatemia is a paraneoplastic condition that typically presents with osteomalacia in adults in their fifth decade of life1. We present a case of tumor-induced rickets in a previously healthy adolescent. The patient and his family were informed that data concerning the case would be submitted for publication, and they provided consent. A fourteen-year-old black adolescent presented to the pediatrician with the vague symptoms of bilateral knee and ankle pain, as well as generalized weakness. His mother was concerned that he “walked like a 70-year-old man.” He had no history of trauma or related family history. At the time of presentation, his height was at the 70th percentile and his weight was above the 90th percentile for age. He had no overt skeletal deformities. The pain was initially attributed to “growing pains.” He was prescribed nonsteroidal anti-inflammatory drugs, physical therapy, and shoe insoles. When the pain did not remit over the subsequent seven months, he was referred to a primary care sports medicine clinic where he was diagnosed with bilateral patellofemoral syndrome and bilateral pes planus. Radiographs of the knees obtained at that time demonstrated notable physeal widening and generalized demineralization of the cortices bilaterally (Fig. 1). Laboratory assessment was initiated (Table I). He was diagnosed with vitamin D deficiency and hypophosphatemic rickets and was prescribed calcitriol as well as sodium …

Evaluation of treatment of hereditary rickets in Egyptian children

Evaluation of treatment of hereditary rickets in Egyptian children

Hereditary Rickets. How Genetic Alterations Explain the Biochemical and Clinical Phenotypes

The reemergence of vitamin D deficiency in the industrialized countries resurrects the "threat" of nutritional rickets, especially among pediatric populations, a fact that may lead to underdiagnosis of hereditary rickets. Today, hereditary rickets may be subdivided into two main groups according to their biochemical profile: the one associated with defects in vitamin D synthesis and action and the second associated with abnormal phosphorus metabolism. The classification of the patients in a particular group of hereditary rickets is determinative of the treatment to follow. This review, through the recent advances on vitamin D and P metabolism, discusses the molecular and biochemical defects associated to each group of inherited rickets, as well as the clinical phenotypes and the recommended therapeutic approaches.