Phosphate diabetes

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Phosphate diabetes
X-linked dominant.svg
Phosphate diabetes is X-linked dominant inheritance

Phosphate diabetes is a rare, congenital, hereditary disorder associated with inadequate tubular reabsorption that affects the way the body processes and absorbs phosphate. [1] Also named as X-linked dominant hypophosphatemic rickets (XLH), [2] this disease is caused by a mutation in the X-linked PHEX (phosphate regulating endopeptidase X-linked) gene, [2] which encodes for a protein that regulates phosphate levels in the human body. [3] 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. [4] phosphate diabetes is a condition that falls under the category of tubulopathies, which refers to the pathologies of the renal tubules. [5] The mutated PHEX gene causes pathological elevations in fibroblast growth factor 23 (FGF23), [1] a hormone that regulates phosphate homeostasis by decreasing the reabsorption of phosphate in the kidneys. [6]

Contents

Elevated levels of FGF23 in phosphate diabetes lead to an increase in phosphate excretion through urine, thus reducing the phosphate levels in blood. [5] However, due to impaired activation of vitamin D, which plays a crucial role in increasing intestinal calcium and phosphate absorption, [7] patients with this disorder are unable to replenish the lost phosphate. This results in low absorption of phosphate from the gastrointestinal system, [5] leading to a deficiency of phosphate in the body and disrupting the full calcium-phosphate metabolism process.

Signs and symptoms

Short stature

A common symptom of phosphate diabetes is short stature. [8]

Craniosynostosis in phosphate diabetes Cranialsynostosis.jpg
Craniosynostosis in phosphate diabetes

Delayed growth and development are common symptoms of phosphate diabetes in children, resulting in stunted growth and a shorter stature compared to their peers. This symptom is typically one of the earliest indicators of the disorder and may require treatment with growth hormone therapy to promote normal growth and development.[ citation needed ]

Delayed walking

Children with phosphate diabetes may start to walk late (at the age of one and a half years and later) due to impaired bone development. [9]

Craniosynostosis

Bowed legs in phosphate diabetes XrayRicketsLegssmall.jpg
Bowed legs in phosphate diabetes

Children with phosphate diabetes may have a birth defect in which the bones in a baby's skull fuse together too early before the brain is fully formed. This is known as craniosynostosis that may lead to head deformities. [9]

Dental problems

As phosphate is essential for the formation and maintenance of healthy teeth, phosphate diabetes can lead to a wide range of dental problems, including the formation of cavities, abscesses, and tooth decay. [10]

Muscle weakness

The deficiency of phosphate may affect muscles, resulting in muscle weakness and fatigue. Patients may have difficulties in performing physical activities and may require physical therapy to improve muscle strength and function. [9]

Bowed legs

Curvation of spine (Kyphoscoliosis) in phosphate diabetes Kyphoscoliosis hereditary sensory autonomic neuropathy III.jpg
Curvation of spine (Kyphoscoliosis) in phosphate diabetes

Due to phosphate deficiency, patients' bones in the legs may become fragile and brittle, which leads to a characteristic bowing of the legs. [5]

Bone pain

In phosphate diabetes, the softening of the bones can lead to bone pain, especially in the knees, hips, and lower back. [9]

Deformities of the bones (rickets)

In severe cases of phosphate diabetes, the deficiency of phosphate can lead to deformities of the bones, resulting in conditions like rickets and osteomalacia (softening of the bones which leads to frequent fractures) and kyphoscoliosis (curvature of the spine). [5]

Genetics

Phosphate diabetes that results from mutations in the PHEX gene is an X-linked dominant disorder, [11] where the mutated gene is located on the X chromosome (one of the sex chromosomes). This inheritance trait is dominant, a single copy of the mutation from the parent is sufficient to cause the disorder in the child. [12]

As males have only one X chromosome (and one Y chromosome), while females have two X chromosomes, the inheritance of phosphate diabetes largely depends on the gender of the parent who carries the mutated gene. Affected fathers with phosphate diabetes are unable to pass the disease to their sons, but all of their daughters will be affected. In contrast, affected mothers with phosphate diabetes will pass the disease to half of their sons and half of their daughters statistically. [13] Thus, this disorder most often occurs in females. [14]

While phosphate diabetes is typically inherited through X-linked dominant inheritance, in some rare cases, the disorder may occur sporadically, meaning that there is no family history of the diseased condition. [15] This may happen due to a new mutation in the PHEX gene which arises during fetal development or due to other genetic factors.[ citation needed ]

Pathophysiology

Fibroblast Growth Factor 23 (FGF23) Protein FGF23 PDB 2p39.png
Fibroblast Growth Factor 23 (FGF23)

phosphate diabetes is caused by a genetic mutation in the PHEX gene located on the X chromosome. The PHEX gene encodes for an enzyme called PHEX – phosphate regulating endopeptidase X-linked, which is involved in the regulation of phosphate metabolism in the body. [16]

An occurrence of PHEX gene mutation can lead to an increase in levels of fibroblast growth factor 23 (FGF23), [17] which is a growth factor that regulates phosphate and vitamin D metabolism. Increased levels of FGF23 leads to increase renal phosphate excretion and decrease intestinal phosphate absorption: [18]

Renal phosphate Excretion

FGF23 acts on the kidneys to reduce the expression of sodium/phosphate co-transporters (NaPi-2a and NaPi-2c) in the proximal tubules. [19] As these co-transporters are responsible for reabsorbing phosphate from urine back into the bloodstream, a decrease in their expression would reduce the amount of phosphate being reabsorbed back to blood, hence increasing the phosphate concentration in the urine being excreted (hypophosphatemia).[ citation needed ]

Intestinal phosphate absorption

FGF23 acts on the intestines to reduce the expression of the sodium-phosphate co-transporter (NaPi-2b) in the brush border membrane of enterocytes, [20] which is an important site for nutrient absorption. This transporter facilitates the absorption of phosphate from digested food in the small intestines into the bloodstream. Therefore, reduced activity of the transporter would lower the amount of phosphate being absorbed into the blood, which in turn increases the amount of phosphate excreted in the faeces.[ citation needed ]

In addition, increased levels of FGF23 would affect vitamin D metabolism and inhibit the action of vitamin D. [21] Vitamin D needs to be converted into its activated form, 1,25-dihydroxyvitamin D, to perform its role of regulating calcium and phosphate absorption in the intestines. [22] A series of enzymatic reactions are required for the activation of vitamin D, and enzymes like 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and 1,25-dihydroxyvitamin D-24-hydroxylase (CYP24A1) play an active role in these reactions. [23] However, high levels of FGF23 in blood hinders the activation of vitamin D: [24]

Inhibition of CYP27B1 activity

FGF23 inhibits the catalytic activity of CYP27B1 in activating vitamin D in the kidneys through a signalling pathway that involves the FGF receptor and downstream intracellular signalling molecules (e.g. FGFRs, MAPK, PI3K etc.). [25] This leads to a decreased levels of activated vitamin D (1,25-dihydroxyvitamin D), which lowers the activity of vitamin D and slows down the absorption of calcium and phosphate in the small intestines.[ citation needed ]

Stimulation of CYP24A1 activity

FGF23 stimulates the activity of CYP24A1 in breaking down the activated form of vitamin D. [26] As the availability of activated vitamin D in blood is decreased, the absorption of phosphate into bloodstream is hindered, which further intensifies the systemic phosphate deficiency in the patient's body.[ citation needed ]

Due to the increased phosphate loss through the excretion of urine and faeces, as well as the reduced absorption of phosphate into blood due to the reduced activity of vitamin D, patients' plasma phosphate levels become lower than normal. This results in a chronic systemic phosphate deficiency that may cause a variety of symptoms with varying degrees of intensity.[ citation needed ]

Diagnosis

Consultation with doctors

When the patients' body appear symptoms of phosphate diabetes, they are recommended to go to the hospital for consultation and body check. Doctors specialised in endocrinology and orthopaedics can examine the patient's health condition, and prescribe suitable medicine or arrange referral for further checking.[ citation needed ]

Blood test

In phosphate diabetes patients' blood, the phosphate levels are level while calcium and parathyroid hormone (PTH) levels remain to be normal. Blood tests can be performed to measure if there are any abnormalities with the phosphate levels in blood. [27]

Urine Test

In the urine of phosphate diabetes patients, excess amount of phosphate can be detected due to the impaired reabsorption of phosphate in the kidneys. By testing for the concentration of phosphate in urine, whether the patient is suffering from phosphate diabetes can be determined.[ citation needed ]

X-ray scan

X-ray scans of bones can be useful for doctors to assess abnormalities in bone density and detect bone deformities, [28] such as the bowing of the legs, curvature of spines, which are the symptoms of phosphate diabetes.

Genetic Analysis

Patients with mutations in the PHEX gene usually possess phosphate diabetes. Through the genetic analysis of X chromosome(s) of patients, it can confirm a diagnosis of phosphate diabetes. [29] At the same time, other family members who are at risk of the disease can be identified.[ citation needed ]

Prevention

Genetic screening test

Since phosphate diabetes is an inheritable condition, immediate genetic analysis should be performed on a child after birth if one of the parents has been diagnosed with the disorder during childhood. Earlier diagnosis of the disease can facilitate more effective treatments, hence minimising its impact on the child.[ citation needed ]

Treatment

Epidemiology

phosphate diabetes is a rare condition that affects approximately 1 in 20000-25000 individuals, [33] making it relatively difficult to study epidemiologically. However, advances in genetic testing and improved awareness of the condition have led to increased diagnosis rates in recent years.[ citation needed ]

While phosphate diabetes can affect individuals of any race or ethnicity, [34] it is more common in certain populations, such as those of European and Middle Eastern descent. [35]

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">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<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">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<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">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.

Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and kidney failure.

<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.

Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may include seizures or cardiac arrest such as from torsade de pointes. Those with low magnesium often have low potassium.

<span class="mw-page-title-main">Tertiary hyperparathyroidism</span> Medical condition

Tertiary hyperparathyroidism is a condition involving the overproduction of the hormone, parathyroid hormone, produced by the parathyroid glands. The parathyroid glands are involved in monitoring and regulating blood calcium levels and respond by either producing or ceasing to produce parathyroid hormone.

<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">X-linked hypophosphatemia</span> X-linked dominant disorder that causes rickets

X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets 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. PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting, and local elevations of the mineralization/calcification-inhibiting protein osteopontin in the extracellular matrix of bones and teeth. 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.

<span class="mw-page-title-main">Nephrocalcinosis</span> Medical condition caused by the deposition of calcium salts in the kidneys

Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe the deposition of poorly soluble calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined by progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. It may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium salts.

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">Vitamin D deficiency</span> Human disorder

Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D deficiency can also be caused by inadequate nutritional intake of vitamin D; disorders that limit vitamin D absorption; and disorders that impair the conversion of vitamin D to active metabolites, including certain liver, kidney, and hereditary disorders. Deficiency impairs bone mineralization, leading to bone-softening diseases, such as rickets in children. It can also worsen osteomalacia and osteoporosis in adults, increasing the risk of bone fractures. Muscle weakness is also a common symptom of vitamin D deficiency, further increasing the risk of fall and bone fractures in adults. Vitamin D deficiency is associated with the development of schizophrenia.

An endocrine bone disease is a bone disease associated with a disorder of the endocrine system. An example is osteitis fibrosa cystica.

<span class="mw-page-title-main">Vitamin D</span> Group of fat-soluble secosteroids

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most significant compounds within this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).

Chronic kidney disease–mineral and bone disorder (CKD–MBD) is one of the many complications associated with chronic kidney disease. It represents a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:

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.

<span class="mw-page-title-main">Idiopathic hypercalcinuria</span>

Idiopathic hypercalcinuria (IH) is a condition including an excessive urinary calcium level with a normal blood calcium level resulting from no underlying cause. IH has become the most common cause of hypercalciuria and is the most serious metabolic risk factor for developing nephrolithiasis. IH can predispose individuals to osteopenia or osteoporosis, and affects the entire body. IH arises due to faulty calcium homeostasis, a closely monitored process, where slight deviations in calcium transport in the intestines, blood, and bone can lead to excessive calcium excretion, bone mineral density loss, or kidney stone formation. 50%-60% of nephrolithiasis patients suffer from IH and have 5%-15% lower bone density than those who do not.

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