Metabolic Bone Disease: An Overview.

Metabolic bone diseases are a heterogenous group of conditions that all result in aberrant bone mineral homeostasis with resulting skeletal disease. The underlying causes are variable, ranging from nutritional deficiencies to pathogenic variants in skeletal genes. To properly diagnose and treat these conditions, a clinician needs to understand bone metabolism as well as recognize the signs of disease in a patient.

Transmembrane protein 53 craniotubular dysplasia (OMIM # 619727): The skeletal disease and consequent blindness of this new disorder.

Craniotubular dysplasia, Ikegawa type (OMIM #619727) denotes the autosomal recessive skeletal disease identified in 2021 featuring blindness acquired in childhood. Five young members of four Indian families harbored a homozygous indel within TMEM53 (OMIM *619722), the gene that encodes transmembrane protein 53 (TMEM53). When intact, TMEM53 spans the nuclear envelope of osteoprogenitor cells, dampens BMP-SMAD signaling, and thereby slows bone formation.

Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort.

Neutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme.

Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period.

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88.

Pyridoxine challenge reflects pediatric hypophosphatasia severity and thereby examines tissue-nonspecific alkaline phosphatase's role in vitamin B metabolism.

Alkaline phosphatase (ALP) is detected in most human tissues. However, ALP activity is routinely assayed using high concentrations of artificial colorimetric substrates in phosphate-free laboratory buffers at lethal pH. Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the ALP isoenzyme expressed in bone, liver, kidney, and elsewhere and is therefore designated "tissue-nonspecific" ALP (TNSALP).

Predicting Rates of Angular Correction After Hemiepiphysiodesis in Patients With X-Linked Hypophosphatemic Rickets.

Purpose: Patients with X-linked hypophosphatemic rickets (XLH) often develop coronal plane knee deformities despite medical treatment. Hemiepiphysiodesis is an effective way to correct coronal plane knee deformities in skeletally immature patients, but a full understanding of the rate of angular correction after hemiepiphysiodesis in XLH patients, compared with idiopathic cases is lacking.

Methods: We retrospectively reviewed charts of 24 XLH patients and 37 control patients without metabolic bone disease who underwent hemiepiphysiodesis.

X-Linked Hypophosphatemia Caused by the Prevailing North American Variant c.*231A>G; Exon 13-15 Duplication Is Often Misdiagnosed as Ankylosing Spondylitis and Manifests in Both Men and Women.

Inactivating mutations of the gene coding for phosphate-regulating endopeptidase homolog X-linked (PHEX) cause X-linked hypophosphatemia (XLH). A novel variant, c.*231A>G; exon 13-15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation.

Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia.

Context: Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown.

Objective: This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH.

Health Care Transition From Pediatric- to Adult-Focused Care in X-linked Hypophosphatemia: Expert Consensus.

Context: X-linked hypophosphatemia (XLH) is an inherited skeletal disorder that can lead to lifelong deleterious musculoskeletal and functional consequences. Although often perceived as a childhood condition, children and adults both experience the negative effects of XLH. Adolescents and young adults (AYAs) benefit from effective health care transition (HCT) preparation to support the transfer from pediatric- to adult-focused care.

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.

Purpose: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.

COVID-19 in a Subset of Hospitalized Children in Israel.

Background: Most pediatric coronavirus disease 2019 (COVID-19) is mild. We assessed nationally severe COVID-19, including pediatric inflammatory multisystem syndrome (PIMS), in hospitalized children.

Methods: An ongoing, prospective, national surveillance was conducted from March 2020 through March 2021, at 20 hospitals treating children <18 years across Israel (~75% of Israeli hospitals).

Vitamin B deficiency with normal plasma levels of pyridoxal 5'-phosphate in perinatal hypophosphatasia.

Pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B (B), is elevated in the plasma of individuals with hypophosphatasia (HPP). HPP is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of ALPL, the gene that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). PLP accumulates extracellularly in HPP because it is a natural substrate of this cell-surface phosphomonoester phosphohydrolase.

Coalescing expansile skeletal disease: Delineation of an extraordinary osteopathy involving the IFITM5 mutation of osteogenesis imperfecta type V.

In 2003, we briefly reported the remarkable osteopathy of a 12-year-old boy who at age two months began fracturing his limbs with subsequent hyperplastic callus formation and expansion and fusion of appendicular bones. By age ten years he had coalesced his lumbosacral spine, pelvis, femurs, and leg and foot bones as a single structure. Computed tomography of expanded bone revealed a thin cortical shell, diminished irregular trabeculae, and cystic areas.

Persistent idiopathic hyperphosphatasemia from bone alkaline phosphatase in a healthy boy.

Alkaline phosphatase (ALP) in humans comprises a family of four cell-surface phosphomonoester phosphohydrolase isozymes. Three genes separately encode the "tissue-specific" ALPs whereas the fourth gene encodes ubiquitous homodimeric "tissue-nonspecific" ALP (TNSALP) richly expressed in bone, liver, kidney, and developing teeth. TNSALP monomers have five putative N-linked glycosylation sites where different post-translational modifications account for this isozyme's distinctive physicochemical properties in different organs.

Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7).

Juvenile Paget's disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphatasemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos.

Healing of vitamin D deficiency rickets complicating hypophosphatasia suggests a role beyond circulating mineral sufficiency for vitamin D in musculoskeletal health.

Hypophosphatasia (HPP) is the metabolic bone disease caused by loss-of-function mutation(s) of the ALPL gene that encodes the cell-surface tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate (PPi), a TNSALP natural substrate and inhibitor of biomineralization, often leads to rickets or osteomalacia despite normal or sometimes elevated circulating levels of calcium (Ca) and inorganic phosphate (Pi). We report an infant girl with vitamin D deficiency rickets subsequently healed by cholecalciferol administration alone before receiving TNSALP-replacement therapy for accompanying HPP.

X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3'-UTR Mutation c.*231A>G (A Retrospective Case-Control Study).

X-linked hypophosphatemia (XLH), the most prevalent heritable renal phosphate (Pi) wasting disorder, is caused by deactivating mutations of PHEX. Consequently, circulating phosphatonin FGF23 becomes elevated and hypophosphatemia in affected children leads to rickets with skeletal deformity and reduced linear growth while affected adults suffer from osteomalacia and forms of ectopic mineralization. In 2015, we reported uniquely mild XLH in six children and four of their mothers carrying the non-coding PHEX 3'-UTR mutation c.

Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation.

Bruck syndrome (BRKS) is the rare disorder that features congenital joint contractures often with pterygia and subsequent fractures, also known as osteogenesis imperfecta (OI) type XI (OMIM # 610968). Its two forms, BRKS1 (OMIM # 259450) and BRKS2 (OMIM # 609220), reflect autosomal recessive (AR) inheritance of FKBP10 and PLOD2 loss-of-function mutations, respectively. A 10-year-old girl was referred with blue sclera, osteopenia, poorly-healing fragility fractures, Wormian skull bones, cleft soft palate, congenital fusion of cervical vertebrae, progressive scoliosis, bell-shaped thorax, restrictive and reactive pulmonary disease, protrusio acetabuli, short stature, and additional dysmorphic features without joint contractures.

Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years.