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Hypophosphatemic Disorders, Pediatric

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Hypophosphatemic Disorders, Pediatric

Basics

Description

Hypophosphatemia is defined by serum phosphorus values below the age-appropriate normal range.

Acute hypophosphatemia is a common laboratory finding in the hospital, especially in the intensive care unit (ICU) setting.

Genetic forms are less common than acquired forms and occur due to mutations in:

Confirm laboratory diagnosis before treating (unless unstable).

  • Normal phosphorus concentrations in infants and children are significantly higher than in adults.
  • Hypophosphatemia can be missed if an adult normal range is used for pediatric patients.

Epidemiology

Etiology

  • Chronic hypophosphatemia is a common etiology of rickets. It can result from multiple causes, including:Vitamin D deficiencyMost common form of ricketsX-linked hypophosphatemic (XLH) ricketsMost common inherited cause of rickets (prevalence ā‰ˆ1 in 20,000)Other genetic forms of rickets are less common.
  • Isolated dietary phosphate deficiency is rare; dietary phosphate deficiency usually involves generalized malnutrition.
  • Vitamin D deficiencyMost common form of rickets
  • X-linked hypophosphatemic (XLH) ricketsMost common inherited cause of rickets (prevalence ā‰ˆ1 in 20,000)Other genetic forms of rickets are less common.
  • Most common form of rickets
  • Most common inherited cause of rickets (prevalence ā‰ˆ1 in 20,000)
  • Other genetic forms of rickets are less common.
  • PHEX (XLH rickets)
  • FGF23 (autosomal dominant hypophosphatemic rickets [ADHR])
  • DMP1 (autosomal recessive hypophosphatemic rickets [ARHR])
  • ENPP1 (ARHR, generalized arterial calcification of infancy [GACI])
  • FAM20C (autosomal recessive hypophosphatemia, Raine syndrome)
  • SCL34A3 (NPT2c, hereditary hypophosphatemic rickets with hypercalciuria [HHRH])
  • CYP27B1 (1Ī±-hydroxylase deficiency)
  • VDR (vitamin D receptor)
  • GNAS (McCune-Albright syndrome, activating mutations of GsĪ±, sometimes associated with hypophosphatemia)
  • Others

Risk Factors

  • NutritionalVitamin D deficiencyMalnutrition/refeeding syndromeChronic diarrhea
  • Medications affecting phosphate absorptionAntacidsSevelamerLanthanum carbonateExcess calcium salts
  • GeneticsPrimary renal phosphate wasting disorders (see "Differential Diagnosis")Vitamin D metabolism disordersRenal Fanconi syndrome
  • Other:Medications affecting renal phosphate transportTreatment of diabetic ketoacidosisAcute respiratory alkalosisPost renal transplantHungry bone syndrome after parathyroidectomy for hyperparathyroidismAlso causes hypocalcemia
  • Vitamin D deficiency
  • Malnutrition/refeeding syndrome
  • Chronic diarrhea
  • Antacids
  • Sevelamer
  • Lanthanum carbonate
  • Excess calcium salts
  • Primary renal phosphate wasting disorders (see "Differential Diagnosis")
  • Vitamin D metabolism disorders
  • Renal Fanconi syndrome
  • Medications affecting renal phosphate transport
  • Treatment of diabetic ketoacidosis
  • Acute respiratory alkalosis
  • Post renal transplant
  • Hungry bone syndrome after parathyroidectomy for hyperparathyroidismAlso causes hypocalcemia
  • Also causes hypocalcemia

Pathophysiology

  • Decreased nutritional intake or malabsorption
  • Redistribution of extracellular phosphate into the intracellular compartment
  • Increased renal phosphate loss (due to medications, hormonal effects, or primary renal tubulopathy)

Diagnosis

History

  • Family history of hypophosphatemia or rickets
  • Medications
  • Known disease affecting phosphate metabolism (see "Differential Diagnosis")
  • Nutritional historyVitamin D intake, phosphate sourcesAnorexia or other malnutritionParenteral or enteral nutrition formulation
  • Duration of symptoms (acute vs. chronic)
  • Dental abnormalitiesAbscessed teeth associated with XLH
  • Gastrointestinal symptomsChronic diarrhea
  • Cardiovascular, respiratory, or neurologic symptoms (may accompany acute hypophosphatemia, usually in hospital setting)
  • Myalgia or weakness
  • Bowed legs, short stature
  • Bone pain or stress fractures/pseudofractures
  • Precocious puberty, caf © au lait macules, fibrous dysplasia-due to McCune-Albright syndrome
  • Vitamin D intake, phosphate sources
  • Anorexia or other malnutrition
  • Parenteral or enteral nutrition formulation
  • Abscessed teeth associated with XLH
  • Chronic diarrhea

Physical Exam

  • Height, rate of growth
  • Rachitic featuresFrontal bossingDelayed closure of fontanelleRachitic rosaryHarrison sulcus (groove corresponding to the rib insertion site of the diaphragm)Widened wrists or anklesValgus, varus, or windswept deformity of the legs
  • Dental abscess
  • Muscle weakness
  • Caf © au lait macules (McCune-Albright syndrome)
  • Frontal bossing
  • Delayed closure of fontanelle
  • Rachitic rosary
  • Harrison sulcus (groove corresponding to the rib insertion site of the diaphragm)
  • Widened wrists or ankles
  • Valgus, varus, or windswept deformity of the legs

Diagnostic Tests & Interpretation

  • Serum phosphorus concentration-below age-appropriate normal range (ideally fasting)
  • Normal ranges by age0-1 month 4.8-8.2 mg/dL1-4 month 4.8-8.1 mg/dL4 months-1 year 4.8-6.8 mg/dL1-5 years 3.6-6.5 mg/dL5-10 years 3.4-5.5 mg/dL10-20 years 2.6-5.2 mg/dL>20 years 2.5-4.9 mg/dL
  • Serum calciumNormal in most primary renal phosphate wasting disordersElevated in primary hyperparathyroidismLow or low normal in vitamin D deficiency rickets
  • Parathyroid hormone concentrationCan be elevated if chronic hypophosphatemia is due to vitamin D deficiency or to XLH (pre- or posttreatment). Elevations in parathyroid hormone (PTH) concurrent with hypercalcemia indicate primary hyperparathyroidism.
  • Alkaline phosphataseElevated in rickets and many patients with hyperparathyroidism
  • Serum creatinine
  • 25-hydroxyvitamin DLow in vitamin D deficiency rickets
  • 1,25-dihydroxyvitamin DLow in 1Ī±-hydroxylase deficiencyElevated in vitamin D receptor mutations and nutritional phosphate deficiencyLow or inappropriately normal in fibroblast growth factor 23 (FGF23)-mediated causes of hypophosphatemia
  • Urine phosphorus and creatinine for assessment of tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR or TP/GFR)Should be obtained at same time as serum phosphorus and creatinineTP/GFR = serum phosphorus - (urine phosphorus — serum creatinine/urine creatinine)Normal or high in vitamin D-mediated hypophosphatemia and nutritional deficiencyLow in renal phosphate wasting disorders
  • FGF23 (a phosphaturic hormone)-may be helpful in renal phosphate wasting disordersElevated in many forms of inherited rickets (XLH, ADHR, ARHR)Elevated in most patients with tumor-induced osteomalacia (TIO) due to FGF23-secreting tumorsLow in nutritional phosphate deficiency or malabsorption or Fanconi syndrome or HHRH
  • 0-1 month 4.8-8.2 mg/dL
  • 1-4 month 4.8-8.1 mg/dL
  • 4 months-1 year 4.8-6.8 mg/dL
  • 1-5 years 3.6-6.5 mg/dL
  • 5-10 years 3.4-5.5 mg/dL
  • 10-20 years 2.6-5.2 mg/dL
  • >20 years 2.5-4.9 mg/dL
  • Normal in most primary renal phosphate wasting disorders
  • Elevated in primary hyperparathyroidism
  • Low or low normal in vitamin D deficiency rickets
  • Can be elevated if chronic hypophosphatemia is due to vitamin D deficiency or to XLH (pre- or posttreatment). Elevations in parathyroid hormone (PTH) concurrent with hypercalcemia indicate primary hyperparathyroidism.
  • Elevated in rickets and many patients with hyperparathyroidism
  • Low in vitamin D deficiency rickets
  • Low in 1Ī±-hydroxylase deficiency
  • Elevated in vitamin D receptor mutations and nutritional phosphate deficiency
  • Low or inappropriately normal in fibroblast growth factor 23 (FGF23)-mediated causes of hypophosphatemia
  • Should be obtained at same time as serum phosphorus and creatinine
  • TP/GFR = serum phosphorus - (urine phosphorus — serum creatinine/urine creatinine)
  • Normal or high in vitamin D-mediated hypophosphatemia and nutritional deficiency
  • Low in renal phosphate wasting disorders
  • Elevated in many forms of inherited rickets (XLH, ADHR, ARHR)
  • Elevated in most patients with tumor-induced osteomalacia (TIO) due to FGF23-secreting tumors
  • Low in nutritional phosphate deficiency or malabsorption or Fanconi syndrome or HHRH
  • Radiographs to evaluate for signs of ricketsKnees and wrists
  • Skeletal survey in patients suspected of fibrous dysplasia of boneBone scan is also very sensitive in evaluating for fibrous dysplasia.
  • Rare: other imaging to identify TIO-these rare tumors can be very difficult to localizePET/CT scan, MRI, CT, octreotide scan, whole body sestamibi scan
  • Knees and wrists
  • Bone scan is also very sensitive in evaluating for fibrous dysplasia.
  • PET/CT scan, MRI, CT, octreotide scan, whole body sestamibi scan
  • Genetic studies, when appropriate

Differential Diagnosis

  • Nutritional- or absorption-relatedLow phosphorus intakePremature infantsChronic diarrheaShort bowel syndromeVitamin D deficiencyNutritional, lack of sun exposure1Ī±-hydroxylase deficiencyVitamin D receptor mutationMedicationsAntacidsSevelamerLanthanum carbonateExcess calcium salts
  • Redistribution of phosphate into the intracellular compartmentInsulin therapy for diabetic ketoacidosisAcute respiratory alkalosisRefeeding syndromeHungry bone syndrome (after parathyroidectomy for primary hyperparathyroidism)
  • Increased renal phosphate lossMedications (glucocorticoids, diuretics)Primary hyperparathyroidismFGF23-dependent (FGF23 excess)XLH ricketsADHR (may present after childhood with new-onset hypophosphatemia; consider ADHR if considering TIO)ARHRTIO (primarily diagnosed in adults, but cases reported in children)Fibrous dysplasia of bonePostrenal transplant phosphate wastingFGF23-independentRenal Fanconi syndromeFamilialMedication-inducedAssociated with other disorders (cystinosis, multiple myeloma, and others)HHRH (rare-mutations impairing NPT2c)
  • Low phosphorus intake
  • Premature infants
  • Chronic diarrhea
  • Short bowel syndrome
  • Vitamin D deficiencyNutritional, lack of sun exposure1Ī±-hydroxylase deficiencyVitamin D receptor mutation
  • MedicationsAntacidsSevelamerLanthanum carbonateExcess calcium salts
  • Nutritional, lack of sun exposure
  • 1Ī±-hydroxylase deficiency
  • Vitamin D receptor mutation
  • Antacids
  • Sevelamer
  • Lanthanum carbonate
  • Excess calcium salts
  • Insulin therapy for diabetic ketoacidosis
  • Acute respiratory alkalosis
  • Refeeding syndrome
  • Hungry bone syndrome (after parathyroidectomy for primary hyperparathyroidism)
  • Medications (glucocorticoids, diuretics)
  • Primary hyperparathyroidism
  • FGF23-dependent (FGF23 excess)XLH ricketsADHR (may present after childhood with new-onset hypophosphatemia; consider ADHR if considering TIO)ARHRTIO (primarily diagnosed in adults, but cases reported in children)Fibrous dysplasia of bonePostrenal transplant phosphate wasting
  • FGF23-independentRenal Fanconi syndromeFamilialMedication-inducedAssociated with other disorders (cystinosis, multiple myeloma, and others)HHRH (rare-mutations impairing NPT2c)
  • XLH rickets
  • ADHR (may present after childhood with new-onset hypophosphatemia; consider ADHR if considering TIO)
  • ARHR
  • TIO (primarily diagnosed in adults, but cases reported in children)
  • Fibrous dysplasia of bone
  • Postrenal transplant phosphate wasting
  • Renal Fanconi syndromeFamilialMedication-inducedAssociated with other disorders (cystinosis, multiple myeloma, and others)
  • HHRH (rare-mutations impairing NPT2c)
  • Familial
  • Medication-induced
  • Associated with other disorders (cystinosis, multiple myeloma, and others)

Treatment

Medication

  • AcuteOral phosphate supplementation preferred routeIntravenous phosphate should be used with caution:High doses require central venous catheter.Can cause severe hypocalcemia: Monitor calcium.Telemetry recommended due to possible arrhythmiasReplete vitamin D if needed (this will not acutely increase serum phosphorus levels)
  • ChronicIf dietary deficiency or malabsorption: oral phosphate and vitamin D repletionIf renal phosphate wasting due to an FGF23-mediated causePhosphate 20-40 mg/kg/day divided in 3-5 dosesStart therapy with low doses and then increase gradually to reduce risk of diarrhea.Calcitriol 20-30 ng/kg/day in 2 divided doses (may require higher doses)Non-FGF23-mediated renal phosphate wasting with elevated 1,25-dihydroxyvitamin D (HHRH)Phosphate 20-40 mg/kg/day divided in 3-5 doses
  • Oral phosphate supplementation preferred route
  • Intravenous phosphate should be used with caution:High doses require central venous catheter.Can cause severe hypocalcemia: Monitor calcium.Telemetry recommended due to possible arrhythmias
  • Replete vitamin D if needed (this will not acutely increase serum phosphorus levels)
  • High doses require central venous catheter.
  • Can cause severe hypocalcemia: Monitor calcium.
  • Telemetry recommended due to possible arrhythmias
  • If dietary deficiency or malabsorption: oral phosphate and vitamin D repletion
  • If renal phosphate wasting due to an FGF23-mediated causePhosphate 20-40 mg/kg/day divided in 3-5 dosesStart therapy with low doses and then increase gradually to reduce risk of diarrhea.Calcitriol 20-30 ng/kg/day in 2 divided doses (may require higher doses)
  • Non-FGF23-mediated renal phosphate wasting with elevated 1,25-dihydroxyvitamin D (HHRH)Phosphate 20-40 mg/kg/day divided in 3-5 doses
  • Phosphate 20-40 mg/kg/day divided in 3-5 dosesStart therapy with low doses and then increase gradually to reduce risk of diarrhea.
  • Calcitriol 20-30 ng/kg/day in 2 divided doses (may require higher doses)
  • Start therapy with low doses and then increase gradually to reduce risk of diarrhea.
  • Phosphate 20-40 mg/kg/day divided in 3-5 doses

Additional Treatment

  • Chronic hypophosphatemic disorders resulting in skeletal deformity (especially inherited causes) may require surgical intervention to correct valgus or varus deformities of the lower extremities.Adequate medical therapy should be initiated first, as it may reduce the need for surgical interventions.
  • Routine dental careDental abscess common in some genetic forms of hypophosphatemia
  • For the rare cases of TIO, complete surgical removal of the offending tumor is curative.
  • Adequate medical therapy should be initiated first, as it may reduce the need for surgical interventions.
  • Dental abscess common in some genetic forms of hypophosphatemia
  • Routine dental care at least twice per year (especially for patients with inherited rickets)
  • Audiology evaluation in patient with inherited hypophosphatemic ricketsIncreased risk of hearing loss
  • Increased risk of hearing loss

Ongoing Care

Follow-up Recommendations

  • For chronic hypophosphatemiaFrequent laboratory monitoring is mandatory if long-term phosphate and calcitriol therapy is needed (every 3-4 months)CalciumPhosphorusCreatinineAlkaline phosphataseParathyroid hormoneUrine calcium, creatinine, and phosphorusThe goal is NOT to normalize serum phosphate in chronic renal phosphate wasting disorders, as this may lead to secondary or tertiary hyperparathyroidism and/or nephrocalcinosis.Periodic radiographic studiesAnnual renal ultrasound to evaluate for nephrocalcinosisPeriodic x-ray of knees/wrists to evaluate response to treatmentImprovement in rachitic changesImprovement in varus/valgus deformities
  • Frequent laboratory monitoring is mandatory if long-term phosphate and calcitriol therapy is needed (every 3-4 months)CalciumPhosphorusCreatinineAlkaline phosphataseParathyroid hormoneUrine calcium, creatinine, and phosphorus
  • The goal is NOT to normalize serum phosphate in chronic renal phosphate wasting disorders, as this may lead to secondary or tertiary hyperparathyroidism and/or nephrocalcinosis.
  • Periodic radiographic studiesAnnual renal ultrasound to evaluate for nephrocalcinosisPeriodic x-ray of knees/wrists to evaluate response to treatmentImprovement in rachitic changesImprovement in varus/valgus deformities
  • Calcium
  • Phosphorus
  • Creatinine
  • Alkaline phosphatase
  • Parathyroid hormone
  • Urine calcium, creatinine, and phosphorus
  • Annual renal ultrasound to evaluate for nephrocalcinosis
  • Periodic x-ray of knees/wrists to evaluate response to treatmentImprovement in rachitic changesImprovement in varus/valgus deformities
  • Improvement in rachitic changes
  • Improvement in varus/valgus deformities

Prognosis

  • Hypophosphatemia due to nutritional deficiencyHypophosphatemia resolves with adequate replacement of nutritional deficiencies or discontinuation of phosphate-binding agents.
  • Acute hypophosphatemia (typically seen in the hospital setting) can be life-threatening and requires careful monitoring and treatment.Hypophosphatemia resolves when the underlying condition is treated.
  • Chronic renal phosphate wasting disorders have a variable response to treatment. Some have radiographic healing of rickets, correction of varus/valgus deformity, and normalization of alkaline phosphatase, whereas others have an incomplete response to therapy.
  • Short stature is a common result of chronic hypophosphatemia.
  • Hypophosphatemia resolves with removal of the offending tumor in patients with TIO, but long-term monitoring for recurrence is necessary, as hypophosphatemia may recur years later.
  • Hypophosphatemia resolves with adequate replacement of nutritional deficiencies or discontinuation of phosphate-binding agents.
  • Hypophosphatemia resolves when the underlying condition is treated.

Additional Reading

  • Carpenter TO, Imel EA, Holm IA, et al. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388. [View Abstract]
  • Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab. 2012;97(3):696-706. [View Abstract]

Codes

ICD09

  • 275.3 Disorders of phosphorus metabolism
  • 270.0 Disturbances of amino-acid transport

ICD10

  • E83.39 Other disorders of phosphorus metabolism
  • E72.09 Other disorders of amino-acid transport
  • E83.31 Familial hypophosphatemia

SNOMED

  • 4996001 Hypophosphatemia (disorder)
  • 82236004 Familial x-linked hypophosphatemic vitamin D refractory rickets (disorder)

FAQ

  • Q: What is the most important complication of intravenous phosphate administration?
  • A: Severe life-threatening hypocalcemia. Infusions of phosphate should be slow and monitored with telemetry.
  • Q: Should I measure FGF23 concentrations?
  • A: Generally, a diagnosis can be made without FGF23 measurement. FGF23 measurement is only useful if the TP/GFR is low.
  • Q: What are dietary phosphate sources?
  • A: Phosphate sources are ubiquitous; examples include processed meats, dairy, legumes, nuts, whole grains, citrus, and colas. Phosphates are used as a preservative in processed foods.