X-linked hypophosphatemia

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X-linked hypophosphatemia
Other namesX-linked dominant hypophosphatemic rickets, or X-linked Vitamin D-resistant rickets, [1]
X-linked dominant.svg
This condition is inherited in an X-linked dominant manner.
Specialty Endocrinology, pediatrics   OOjs UI icon edit-ltr-progressive.svg
Complications osteomalacia (adults), rickets (children), fractures, enthesopathy, spinal stenosis, abnormal gait, short stature, tinnitus, hearing loss, dental complications, in rare exceptions Chiari malformation can occur.
CausesA genetic mutation of the PHEX gene results in elevated FGF23 hormone.
Medication phosphate, vitamin-D or burosumab

X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow-leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. [2] PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting, [3] and local elevations of the mineralization/calcification-inhibiting protein osteopontin in the extracellular matrix of bones and teeth. [4] [5] An inactivating mutation in the PHEX gene results in an increase in systemic circulating FGF23, and a decrease in the enzymatic activity of the PHEX enzyme which normally removes (degrades) mineralization-inhibiting osteopontin protein; in XLH, the decreased PHEX enzyme activity leads to an accumulation of inhibitory osteopontin locally in bones and teeth to block mineralization which, along with renal phosphate wasting, both cause osteomalacia and odontomalacia. [6] [7]

Contents

For both XLH and hypophosphatasia, inhibitor-enzyme pair relationships function to regulate mineralization in the extracellular matrix through a double-negative (inhibiting the inhibitors) activation effect in a manner described as the Stenciling Principle. [8] [9] Both these underlying mechanisms (renal phosphate wasting systemically, and mineralization inhibitor accumulation locally) contribute to the pathophysiology of XLH that leads to soft bones and teeth (hypomineralization, osteomalacia/odontomalacia). [10] [11] [12] The prevalence of the disease is 1 in 20,000. [13]

X-linked hypophosphatemia may be lumped in with autosomal dominant hypophosphatemic rickets under general terms such as hypophosphatemic rickets. Hypophosphatemic rickets are associated with at least nine other genetic mutations. [14] Clinical management of hypophosphatemic rickets may differ depending on the specific mutations associated with an individual case, but treatments are aimed at raising phosphate levels to promote normal bone formation. [15]

Symptoms and signs

The most common symptoms of XLH affect the bones and teeth, causing pain, abnormalities, and osteoarthritis. Symptoms and signs can vary between children and adults and can include (but not limited to):

Children

Adults

Genetics

XLH affects about 1:20,000 individuals and is the most common cause of inherited phosphate wasting. [26]

It is associated with a mutation in the PHEX gene sequence, located on the human X chromosome at location Xp22.2-p22.1. [1] [2] [29] The PHEX protein regulates another protein called fibroblast growth factor 23 (produced from the FGF23 gene). Fibroblast growth factor 23 normally inhibits the kidneys' ability to reabsorb phosphate into the bloodstream. Gene mutations in PHEX prevent it from correctly regulating fibroblast growth factor 23. The overactivity of FGF-23 reduces vitamin D 1α-hydroxylation and phosphate reabsorption by the kidneys, leading to hypophosphatemia and the related features of ricket. [30] Also in XLH, where PHEX enzymatic activity is absent or reduced, osteopontin [31] —a mineralization-inhibiting secreted substrate protein found in the extracellular matrix of bone [32] —accumulates in bone (and teeth) to contribute to the osteomalacia (and odontomalacia) as shown in the mouse homolog (Hyp) of XLH and in XLH patients. [33] [34] [35]

The disorder is inherited in an X-linked dominant manner. [1] [2] This means the defective gene responsible for the disorder (PHEX) is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder. Males are normally hemizygous for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higher expressivity in males than females.[ citation needed ]

As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked inheritance is determined by the sex of the parent carrying a specific gene and can often seem complex. This is because, typically, females have two copies of the X-chromosome and males have only one copy. The difference between dominant and recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.[ citation needed ]

Diagnosis

The clinical laboratory evaluation of rickets begins with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range.Biochemically, XLH is recognized by hypophosphatemia. [36]

Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0–7.5 mg/dL) is high compared with that for adults (2.7–4.5 mg/dL).[ citation needed ]

Serum parathyroid hormone levels are within the reference range or slightly elevated. calcitriol (1,25-(OH)2 vitamin D3) levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range.[ citation needed ]

The renal tubular reabsorption of phosphate (TRP) in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration. The TRP is calculated with the following formula:[ citation needed ]

1 − [Phosphate Clearance (CPi) / Creatinine Clearance (Ccr)] × 100

Treatment

Conventional therapy consisted of medications including human growth hormone, calcitriol, and oral phosphate, [37] [38] and calcitriol; [37] [38] Unwanted effects of this therapy have included secondary hyperparathyroidism, nephrocalcinosis, kidney stones, and cardiovascular abnormalities.[ citation needed ]

In February 2018 the European Medicines Agency first licensed a monoclonal antibody directed against FGF23, the first drug targeting the underlying cause for this condition, [39] called burosumab. [40] It was then licensed by the US Food and Drug Administration in June 2018 [41] Burosumab is shown to target the major symptoms of XLH by decreasing elevated alkaline phosphatase and normalizing severe hypophosphatemia, leading to substantial improvement of rickets in child and adolescent patients. [42]

The leg deformity can be treated with Ilizarov frames and CAOS. [43] In the event of severe bowing, an osteotomy can be performed to correct the leg shape. [43]

Society and culture

International XLH Alliance – an alliance of international patient groups for individuals affected by XLH and related disorders.

Jennyfer Marques Parinos is a Paralympic bronze medalist from Brazil who has XLH. She competes under a class 9 disability.

See also

Related Research Articles

<span class="mw-page-title-main">Rickets</span> Childhood bone disorder

Rickets, scientific nomenclature: rachitis, is a condition that results in weak or soft bones in children and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone deformities, bone pseudofractures and fractures, muscle spasms, or an abnormally curved spine. The analogous condition in adults is osteomalacia.

<span class="mw-page-title-main">Osteoblast</span> Cells secreting extracellular matrix

Osteoblasts are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function in groups of connected cells. Individual cells cannot make bone. A group of organized osteoblasts together with the bone made by a unit of cells is usually called the osteon.

<span class="mw-page-title-main">Osteomalacia</span> Softening of bones due to impaired bone metabolism

Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization.

<span class="mw-page-title-main">Hypophosphatemia</span> Lack of phosphate in the blood

Hypophosphatemia is an electrolyte disorder in which there is a low level of phosphate in the blood. Symptoms may include weakness, trouble breathing, and loss of appetite. Complications may include seizures, coma, rhabdomyolysis, or softening of the bones.

<span class="mw-page-title-main">Osteocyte</span> Mature osteoblasts which helps in communication between cells and also in molecular synthesis

An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and have an average half life of 25 years. They are derived from osteoprogenitor cells, some of which differentiate into active osteoblasts. Osteoblasts/osteocytes develop in mesenchyme.

<span class="mw-page-title-main">Calcitriol</span> Active form of vitamin D

Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium mainly by increasing the uptake of calcium from the intestines.

<span class="mw-page-title-main">Hypophosphatasia</span> Metabolic bone disease

Hypophosphatasia (; also called deficiency of alkaline phosphatase, phosphoethanolaminuria, or Rathbun's syndrome; sometimes abbreviated HPP) is a rare, and sometimes fatal, inherited metabolic bone disease. Clinical symptoms are heterogeneous, ranging from the rapidly fatal, perinatal variant, with profound skeletal hypomineralization, respiratory compromise or vitamin B6 dependent seizures to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 388 genetic mutations identified to date, in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in the milder forms.

<span class="mw-page-title-main">Osteopontin</span> Mammalian protein found in Homo sapiens

Osteopontin (OPN), also known as bone /sialoprotein I, early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a protein that in humans is encoded by the SPP1 gene. The murine ortholog is Spp1. Osteopontin is a SIBLING (glycoprotein) that was first identified in 1986 in osteoblasts.

<span class="mw-page-title-main">Fibroblast growth factor 23</span> Protein found in humans

Fibroblast growth factor 23 (FGF-23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the FGF23 gene. FGF-23 decreases reabsorption of phosphate in the kidney. Mutations in FGF23 can lead to its increased activity, resulting in autosomal dominant hypophosphatemic rickets.

<span class="mw-page-title-main">Autosomal dominant hypophosphatemic rickets</span> Medical condition

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disease in which excessive loss of phosphate in the urine leads to poorly formed bones (rickets), bone pain, and tooth abscesses. ADHR is caused by a mutation in the fibroblast growth factor 23 (FGF23). ADHR affects men and women equally; symptoms may become apparent at any point from childhood through early adulthood. Blood tests reveal low levels of phosphate (hypophosphatemia) and inappropriately normal levels of vitamin D. Occasionally, hypophosphatemia may improve over time as urine losses of phosphate partially correct.

Metabolic bone disease is an abnormality of bones caused by a broad spectrum of disorders. Most commonly these disorders are caused by deficiencies of minerals such as calcium, phosphorus, magnesium or vitamin D leading to dramatic clinical disorders that are commonly reversible once the underlying defect has been treated. These disorders are to be differentiated from a larger group of genetic bone disorders where there is a defect in a specific signaling system or cell type that causes the bone disorder. There may be overlap. For example, genetic or hereditary hypophosphatemia may cause the metabolic bone disorder osteomalacia. Although there is currently no treatment for the genetic condition, replacement of phosphate often corrects or improves the metabolic bone disorder. Metabolic bone disease in captive reptiles is also common, and is typically caused by calcium deficiency in a reptile's diet.

<span class="mw-page-title-main">PHEX</span> Protein-coding gene in the species Homo sapiens

Phosphate-regulating endopeptidase homolog X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an enzyme that in humans is encoded by the PHEX gene. This gene contains 18 exons and is located on the X chromosome.

<span class="mw-page-title-main">ALPL</span> Protein-coding gene in the species Homo sapiens

Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.

<span class="mw-page-title-main">DMP1</span> Protein-coding gene in the species Homo sapiens

Dentin matrix acidic phosphoprotein 1 is a protein that in humans is encoded by the DMP1 gene.

<span class="mw-page-title-main">MEPE</span> Protein-coding gene in the species Homo sapiens

Matrix extracellular phosphoglycoprotein is a protein that in humans is encoded by the MEPE gene. A conserved RGD motif is found in this protein, and this is potentially involved in integrin recognition.

<span class="mw-page-title-main">Sodium-dependent phosphate transport protein 2C</span> Protein-coding gene in the species Homo sapiens

Sodium-dependent phosphate transport protein 2C is a protein that in humans is encoded by the SLC34A3 gene.

Oncogenic osteomalacia, also known as tumor-induced osteomalacia or oncogenic hypophosphatemic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia and osteomalacia. It may be caused by a phosphaturic mesenchymal tumor. Symptoms typically include crushing fatigue, severe muscle weakness and brain fog due to the low circulating levels of serum phosphate.

<span class="mw-page-title-main">FAM20C</span> Protein-coding gene in the species Homo sapiens

Family with sequence similarity 20, member C also known as FAM20C or DMP4 is a protein which in humans is encoded by the FAM20C gene. Fam20C, a Golgi localized protein kinase, is a serine kinase that phosphorylates both casein and other highly acidic proteins and members of the small integrin-binding ligand, the N-linked glycoproteins (SIBLING) family at the target motif SerXGlu.

Burosumab, sold under the brand name Crysvita, is a human monoclonal antibody medication approved 2018 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia.

Phosphate diabetes is a rare, congenital, hereditary disorder associated with inadequate tubular reabsorption that affects the way the body processes and absorbs phosphate. Also named as X-linked dominant hypophosphatemic rickets (XLH), this disease is caused by a mutation in the X-linked PHEX gene, which encodes for a protein that regulates phosphate levels in the human body. phosphate is an essential mineral which plays a significant role in the formation and maintenance of bones and teeth, energy production and other important cellular processes. phosphate diabetes is a condition that falls under the category of tubulopathies, which refers to the pathologies of the renal tubules. The mutated PHEX gene causes pathological elevations in fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis by decreasing the reabsorption of phosphate in the kidneys.

References

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