The correct answers are A, B, and D

Comment: Muscle weakness, failure to thrive, radiographic evidence of rickets, and bone pain are classic clinical features of chronic hypophosphatemia. Hypophosphatemia-induced muscle weakness involves skeletal muscle and may cause proximal myopathy, dysphasia, ileus, and even respiratory failure.

The correct answer is A

Comment: The first step in the diagnostic approach to hypophosphatemia is to establish whether hypophosphatemia is caused by inadequate dietary phosphate intake, reduced intestinal phosphate absorption, or excessive urinary losses of phosphate and this is done by evaluating the FEPO ₄ .

In this patient, the random urine phosphate and creatinine excretion were 60 and 33 mg, respectively, and the FEPO ₄ was 28.6% (reference range, 10% to 15%).

The correct answers are E, F, G, and H

Comment: The elevated FEPO ₄ signifies excessive urinary losses of phosphate. Renal phosphate wasting can result from genetic or acquired renal disorders. Acquired renal phosphate wasting syndromes can result from vitamin D deficiency, hyperparathyroidism, oncogenic osteomalacia, and FS. The genetic disorder of renal hypophosphatemic disorders generally manifest in infancy and are usually transmitted as XHR. The choice “A” is a wrong answer as serum calcium concentration is elevated in patients with primary hyperparathyroidism. Choices “B, C, and D” are also incorrect because of the inappropriately high FEPO ₄ . The choice “I” is a wrong answer because hyperventilation lowers serum phosphate level by promoting a shift of phosphate into the cells, leading to respiratory alkalosis and the FEPO ₄ is appropriately low.

The correct answer is B

Comment: The condition appears to be genetic (strong family history of rickets) and the 1,25-dihydroxyvitamin D levels are very low, consistent with this diagnosis. X-linked hypophosphatemic rickets is the most common inherited form of familial hypophosphatemic rickets and is characterized by growth retardation, defective bone mineralization, hypophosphatemia secondary to renal phosphate wasting, and inappropriately low serum concentration of 1,25-dihydroxyvitamin D. Patients with XHR have mutations in PHEX. It has been postulated that PHEX plays a major role in osteoblast cell differentiation and bone mineralization. It also increases renal phosphate reabsorption and promotes conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D through activation of 1-α-hydroxylase enzymes. Choice “A” is incorrect because FS is associated with generalized aminoaciduria and glucosuria. Choices “C and D” are not the correct answers, because of a strong family history of rickets.

The correct answer is B

Comment: Mutation in PHEX is associated with an increase in serum concentration of phosphatonin, including FGF23. The mechanism by which this mutation leads to elevation in FGF23 is unknown. The elevated level of FGF23 inhibits renal and intestinal absorption of phosphate directly by inhibition of sodium-potassium-II cotransporters. It also inhibits activation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D through inhibition of 1-α-hydroxylase enzyme directly. Autosomal dominant hypophosphatemic rickets has similar clinical manifestations, with hypophosphatemia, clinical rickets, and inappropriately low levels of 1,25-dihydroxyvitamin D. Genetic studies have identified mutation in FGF23 as the cause of ADHR. The diagnosis of X-linked hypophosphatemic rickets was made based on the available laboratory data.

The correct answers are A and B

Comment: The goal of therapy is to improve growth, reduce the severity of bone disease, and minimize activity limitations. Phosphate supplements and calcitriol are the mainstays of therapy. Phosphorus administration lowers the level of ionized calcium in plasma and decreases calcitriol synthesis, leading to secondary hyperparathyroidism. Increased levels of PTH further aggravate urinary phosphate loss. Therefore, calcitriol administration is necessary to increase the intestinal absorption of calcium and phosphorus and to prevent secondary hyperparathyroidism. Therapy with calcitriol is initiated at 15 ng/kg/day to 20 ng/kg/day. The dose is gradually increased over several weeks to 30 ng/kg/day to 60 ng/kg/day. Phosphate salts are given between 0.5 and 4.0 g/day in divided doses every 4 hours. Healing typically starts in 6 to 8 months after the start of therapy. The patient was treated with calcitriol and sodium phosphate, which led to significant improvement in the radiological signs of rickets after 6 months of therapy, and his serum phosphate level returned to normal.

The correct answer is B

Comment: Oncogenic osteomalacia is a paraneoplastic syndrome characterized by osteomalacia, hypophosphatemia, renal phosphate wasting, bone pain, and muscle weakness. These patients usually have benign tumors of mesenchymal origin that produce phosphatonins, phosphaturic peptides. Identification of the tumor can involve total body magnetic resonance imaging or scintigraphy using octreotide with indium-111 (since the tumors typically express somatostatin receptors). Patients with this syndrome require a combination of oral phosphate and calcitriol. This is because the use of phosphate alone may lower ionized calcium and lead to secondary hyperparathyroidism. Therapy should continue until the tumor can be identified and removed. Removal of the tumor leads to prompt reversal of the biochemical abnormalities and healing of the bone disease. The vast majority of tumors are benign and do not recur. Prognosis is excellent for complete recovery.

The correct answer is D

Comment: The presence of multiple defects in renal proximal tubular reabsorption, including glycosuria, proteinuria, hypophosphatemia, hyperphosphaturia, hyperuricosuria, and hypouricemia without non-anion gap metabolic acidosis, hypokalemia, and polyuria with episodes of dehydration were suggestive of FS.

The differential diagnosis of FS in a young child includes inherited diseases and acquired causes. Cystinosis is the most common disease among inherited etiologies. The others are galactosemia, hereditary fructose intolerance, tyrosinemia, Wilson’s disease, Lowe syndrome, Dent’s disease, and mitochondrial cytopathies. Acquired causes of FS include the disorders that affect the proximal tubule such as drugs used in chemotherapy, toxins, dysproteinemia, glomerulonephritis, and acute kidney injury.

When examined for inherited diseases, corneal examination and intracellular cystine concentration in white blood cells for cystinosis were normal. Galactosemia was excluded with the lack of vomiting, diarrhea, cataract, and hepatic pathologies. There was not any vomiting, hypoglycemia, or convulsion after the ingestion of fructose, so hereditary fructose intolerance was excluded as well. Hereditary tyrosinemia type I, also known as hepatorenal tyrosinemia, is a tyrosine metabolism defect, affecting the kidneys and peripheral nerves but especially the liver. Hepatomegaly, jaundice, hypoglycemia, or hepatitis was not presented in this patient. Clinical findings of Wilson’s disease are usually related to hepatic or central nervous system involvement. The clinical spectrum is variable and rarely presents before the age of 5 years. Hepatic disorders, neuropsychiatric pathologies, or both may predominantly is the initial diagnosis. In our patient, these pathologic findings that suggest Wilson’s disease were not present. Lowe and Dent’s disease are both X-linked disorders and they are common in males. Congenital glaucoma, cataracts, and mental retardation characterize Lowe syndrome. In Dent’s disease, affected males have aminoaciduria, glycosuria, hypercalciuria and nephrocalcinosis, but hemizygous females have only mild aminoaciduria and hypercalciuria. Our patient has a normal mental status and no glaucoma or cataract. It was distinguished from Dent’s disease by the absence of hypercalciuria. Mitochondrial cytopathies are a group of diseases with abnormalities in multiple systems including neurologic disorders, pancreatic and hepatic diseases, and cardiomyopathy. No additional systemic involvement suggesting mitochondrial disease was found in our patient’s history, physical examination, and laboratory evaluations. Medication is an important cause of acquired FS. A number of chemotherapeutic drugs especially ifosfamide (IFO) and cisplatin are the common causes of FS. Since our patient had a history of immature teratoma, chemotherapy regimen should be questioned. Among chemotherapeutics, IFO is a well-known responsible agent for generalized proximal tubulopathy. When medical records were evaluated, FS was observed after the fourth cycle of neoadjuvant chemotherapy including etoposide (100 mg/m ² at days 1 to 3), cisplatin (20 mg/m ² at days 1 to 5), and IFO (1.5 g/m ² at days 1 to 5) with mesna prophylaxis for six cycles. IFO is known to cause nephrotoxicity. The pathophysiology of IFO toxicity is unclear. It has been reported that chloroacetaldehyde, which is a metabolite of IFO, is responsible for tubular injury in recent studies. Chloroacetaldehyde decreases the antioxidant glutathione (GSH) and adenosine triphosphate (ATP) levels and inhibits the activity of NA ⁺ /K ⁺ -ATPase pump. The spectrum of tubular dysfunction varies from partial reabsorption defects in amino acids, glucose, sodium, potassium, bicarbonate, and phosphorus to generalized proximal tubulopathy. The common presentation is generalized aminoaciduria with 28%, also 17% present with both phosphaturia and aminoaciduria.

The correct answer is C

Comment: Normal serum phosphorus is between 3 and 4.5 mg/dL. Potential causes can include malnutrition and starvation or the use of aluminum hydroxide-based/magnesium-based antacids. Renal insufficiency, hypoparathyroidism, and TLS are causative factors for hyperphosphatemia. The patient was started on total parenteral nutrition (TPN).

The correct answers are A, B, C, and D

Comment: Severely malnourished patients can suffer from shifts in fluids and electrolytes during TPN administration. These shifts can be fatal. During severe malnutrition, the body adjusts its metabolism from carbohydrates to fat and protein for energy. The carbohydrates in the TPN can cause an increase in insulin secretion and cellular uptake in magnesium, potassium, and phosphate.

The correct answers are A, B, C, and D

Comment: Clinical manifestations of hypophosphatemia include decreased cardiac contractility, decreased cardiac output, slowed peripheral pulses, shallow respirations, weakness, decreased deep tendon reflexes, decreased bone density, rhabdomyolysis, irritability, confusion, kidney stones, and immune suppression. Increased clotting will not occur as hypophosphatemia decreases platelet aggregation and increases bleeding.

The correct answers are A and C

Comment: Phosphorus also has an inverse relationship with calcium and potassium. If the phosphorus is low, the calcium and potassium will be high. Sodium and phosphorus do not have any correlation.

Hypophosphatemia is defined as a serum phosphate level of less than 2.5 mg/dL (0.8 mmol/L). Hypophosphatemia is caused by inadequate intake, decreased intestinal absorption, excessive urinary excretion, or a shift of phosphate from the extracellular to the intracellular compartments. Renal phosphate wasting can result from genetic or acquired renal disorders. Acquired renal phosphate wasting syndromes can result from vitamin D deficiency hyperparathyroidism, oncogenic osteomalacia, and FS. Genetic disorders of renal hypophosphatemic disorders generally manifest in infancy and are usually transmitted as X-linked hypophosphatemic rickets. Symptoms of hypophosphatemia are nonspecific, and most patients are asymptomatic. Severe hypophosphatemia may cause skeletal muscle weakness, myocardial dysfunction, rhabdomyolysis, and altered mental status. The diagnostic approach to hypophosphatemia should begin with the measurement of fractional phosphate excretion; if it is greater than 15% in the presence of hypophosphatemia, the diagnosis of renal phosphorus wasting is confirmed. Renal phosphorus wasting can be divided into three types based upon serum calcium levels: primary hyperparathyroidism (high serum calcium level), secondary hyperparathyroidism (low serum calcium level), and primary renal phosphate wasting (normal serum calcium level). Phosphate supplementations are indicated in patients who are symptomatic or who have a renal tubular defect leading to chronic phosphate wasting. Oral phosphate supplements in combination with calcitriol are the mainstay of treatment. Parenteral phosphate supplementation is generally reserved for patients with life-threatening hypophosphatemia (serum phosphate < 2.0 mg/dL). Intravenous phosphate (0.16 mmol/kg) is administered at a rate of 1 mmol/h to 3 mmol/h until a level of 2 mg/dL is reached.

The correct answer is A

Comment: In this case, the patient presented with hypophosphatemia beginning at an early age and investigations revealed evidence for hypophosphatemic ricket. After an initial diagnosis of hypophosphatemic ricket during early childhood based on the association between bone deformities and hypophosphatemia, the patient received long-term treatment with phosphate supplementation and active vitamin D sterol (alfa-calcidol) and as a young adult, the presents with the two main long-term complications secondary to therapies often observed in hypophosphatemic ricket: secondary hyperparathyroidism and nephrocalcinosis.

Hypophosphatemic ricket correspond to a heterogeneous genetic pathology, affecting 1/20,000 children, resulting from mutations in FGF23 or their regulators to induce hypophosphatemia, rickets, dental abnormalities (pulp chambers, dental hypoplasia, dentin abnormalities, and dental abscesses) and bone deformations. Patients present with hypophosphatemia, normal serum calcium, decreased TPR, normal 25 (OH) vitamin D and PTH, and increased alkaline phosphatase levels.

Untreated severe hypophosphatemia can induce hemolysis, rhabdomyolysis, respiratory failure, cardiac dysfunction, and neurological impairment, thus requiring a rapid correction to avoid severe complications.

The recent description of the key role of the FGF23 in the “bone–kidney–parathyroid” axis had led to a better understanding of genetic conditions associated with hypophosphatemia and of the pathophysiology of both phosphate disorders. In hypophosphatemic ricket patients, a careful use of phosphate supplements and active vitamin D sterols should be considered to prevent nephrocalcinosis, secondary hyperparathyroidism, and soft tissue calcifications.

The correct answer is A

Comment: Hypophosphatemia is defined as a serum phosphate level of less than 2.5 mg/dL (0.8 mmol/L) in adults. The normal level for serum phosphate in neonates and children is considerably higher, up to 7 mg/dL for infants.

Phosphate is critical for a remarkably wide array of cellular processes. It is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that comprise DNA and RNA. Phosphate bonds of ATP carry the energy required for all cellular functions. It also functions as a buffer in bone, serum, and urine.

Diet, hormones, and physical factors such as pH regulate serum phosphate concentration. Importantly, because phosphate enters and exits cells under several influences, the serum concentration of phosphate may not reflect true phosphate stores. Often, persons with alcoholism who have severely deficient phosphate stores may present for medical treatment with a normal serum phosphate concentration. Only after refeeding will serum phosphate levels decline, often abruptly plummeting to dangerously low levels.

Phosphate is plentiful in the diet. A normal diet provides approximately 1000 to 2000 mg of phosphate, two-thirds of which is absorbed, predominantly in the proximal small intestine. The absorption of phosphate can be increased by increasing vitamin D intake and by ingesting a very low phosphate diet. Under these conditions, the intestine increases expression of sodium-coupled phosphate transporters to enhance phosphate uptake.

Regulation of intestinal phosphate transport overall is poorly understood. Although studies had suggested that the majority of small intestine phosphate uptake is accomplished through sodium-independent, unregulated pathways, subsequent investigations have suggested that regulated, sodium-dependent mechanisms may play a greater role in overall intestinal phosphate handling than was previously appreciated. Furthermore, intestinal cells may have a role in renal phosphate handling through elaboration of circulating phosphaturic substances in response to sensing a phosphate load. Recent studies have confirmed that the ability of intestinal phosphate transport to influence renal phosphate transport is PTH-dependent; however, the signal to the parathyroid gland remains unknown.

Absorption of phosphate can be blocked by commonly used over-the-counter aluminum, calcium, and magnesium-containing antacids. Mild-to-moderate use of such phosphate binders generally poses no threat to phosphate homeostasis because dietary ingestion greatly exceeds body needs. However, very heavy use of these antacids can cause significant phosphate deficits. Stool losses of phosphate are minor (i.e., 100 to 300 mg/day from sloughed intestinal cells and gastrointestinal secretions). However, these losses can be increased dramatically in persons with diseases that cause severe diarrhea or intestinal malabsorption.

Bone loses approximately 300 mg of phosphate per day, but that is generally balanced by an uptake of 300 mg. Bone metabolism of phosphate is influenced by factors that determine bone formation and destruction, that is, PTH, vitamin D, sex hormones, acid–base balance, and generalized inflammation.

The kidneys to maintain phosphate balance excrete the excess ingested phosphate. The major site of renal regulation of phosphate excretion is the early proximal renal tubule with some contribution by the distal convoluted tubule. In the proximal tubule, phosphate reabsorption by type 2 sodium phosphate cotransporters is regulated by dietary phosphate, PTH, and vitamin D. High dietary phosphate intake and elevated PTH levels decrease proximal renal tubule phosphate absorption, thus enhancing renal excretion.

Conversely, low dietary phosphate intake, low PTH levels, and high vitamin D levels enhance renal proximal tubule phosphate absorption. To some extent, phosphate regulates its own regulators. High phosphate concentrations in the blood down-regulate the expression of some phosphate transporters, decrease vitamin D production, and increase PTH secretion by the parathyroid gland.

Distal tubule phosphate handling is less well understood. PTH increases phosphate absorption in the distal tubule, but the mechanisms by which this occurs are unknown. Renal phosphate excretion can also be increased by the administration of loop diuretics.

PTH and vitamin D were previously the only recognized regulators of phosphate metabolism. However, several novel regulators of mineral homeostasis have been identified through studies of serum factors associated with phosphate wasting syndromes such as oncogenic osteomalacia and the hereditary forms of hypophosphatemic rickets, have been discovered.

Medical care for hypophosphatemia is highly dependent on three factors: cause, severity, and duration. Phosphate distribution varies among patients, so no formulas reliably determine the magnitude of the phosphate deficit. The average patient requires 1000 to 2000 mg (32 to 64 mmol) of phosphate per day for 7 to 10 days to replenish the body stores.

Oral phosphate supplements, although not curative, are useful for the treatment of the genetic disorders of phosphate wasting and can often normalize phosphate levels and decrease bone pain. Parenteral phosphate supplementation is generally reserved for patients who have life-threatening hypophosphatemia or nonfunctional gastrointestinal syndromes.