Rickets Diagnosis: An Expert Guide for Clinicians

Introduction

Rickets, a condition stemming from impaired mineralization of the epiphyseal plates, remains a significant global health concern, particularly in pediatric populations. While nutritional deficiencies, especially vitamin D, are the predominant cause worldwide, rickets can also arise from genetic disorders, medication side effects, and underlying liver conditions. The clinical spectrum of rickets is broad, ranging from asymptomatic cases to severe manifestations like growth retardation, skeletal deformities, and even life-threatening hypocalcemia. Timely and accurate Rickets Diagnosis is crucial to prevent long-term complications and ensure appropriate management. This article provides an in-depth review of the etiology, pathophysiology, clinical presentation, and diagnostic approaches for rickets, emphasizing the essential role of a multidisciplinary healthcare team in patient care.

Etiology of Rickets

The development of healthy bone mineralization is intricately linked to vitamin D, calcium, and phosphorus homeostasis. Disruptions in these key nutrients can lead to rickets and osteomalacia. Rickets specifically affects children, targeting the epiphyseal plates – the growth zones of bones – and causing mineralization defects. Osteomalacia, in contrast, is the mineralization defect in mature bone, typically seen in adults after epiphyseal plate closure. While both conditions can coexist in children, rickets is exclusively a pediatric concern.

Nutritional Deficiencies:

The most prevalent cause of rickets globally is vitamin D deficiency. Inadequate dietary intake and insufficient sun exposure are primary contributors. Less frequently, deficiencies in calcium or phosphorus can also induce rickets.

Other Causes:

Beyond nutritional factors, rickets can be attributed to:

• Genetic Disorders: Inherited conditions affecting vitamin D metabolism or phosphate regulation.
• Drug-Induced Rickets: Certain medications, such as diphenylhydantoin and rifampicin, can interfere with vitamin D metabolism.
• Liver Diseases: Conditions impairing vitamin D activation.

Classification Based on Biochemical Profile:

Rickets can be categorized based on the underlying biochemical abnormalities:

• Calcipenic Rickets: Characterized by low serum calcium levels, often due to vitamin D deficiency or genetic defects in vitamin D metabolism.
• Phosphopenic Rickets: Caused by low serum phosphate levels, typically resulting from increased renal phosphate loss or impaired intestinal absorption. Dietary phosphate deficiency is rare in healthy individuals but can occur in premature infants. Conditions leading to phosphopenic rickets include:
  • Increased fibroblast growth factor 23 (FGF23) production or decreased degradation, leading to reduced renal phosphate reabsorption and increased excretion.
  • Genetic mutations causing inactivation of sodium-dependent phosphate transporters in the kidneys, resulting in increased urinary phosphate loss.
• Rickets due to Inhibited Mineralization: This category encompasses less common causes where mineralization is directly impaired, independent of calcium or phosphate levels.

Genetic Subtypes of Rickets:

Genetic rickets is broadly classified into:

• Vitamin D-Dependent Rickets (VDDR) (Calcipenic Type): Involves defects in vitamin D metabolism or action.

  • VDDR Type 1A: Deficiency in 1-alpha hydroxylase enzyme (CYP27B1 mutation), preventing the conversion of 25-hydroxyvitamin D to the active form, 1,25-dihydroxyvitamin D.
  • VDDR Type 1B: Deficiency in 25-hydroxylase enzyme (CYP2R1 mutation), impairing the conversion of vitamin D to 25-hydroxyvitamin D.
  • VDDR Type 2A: Vitamin D receptor (VDR) mutations leading to end-organ resistance to 1,25-dihydroxyvitamin D.
  • VDDR Type 2B: Unusual form caused by overexpression of a nuclear protein interfering with vitamin D function.

• Congenital Hypophosphatemic Rickets (Phosphopenic Type): Caused by renal phosphate wasting.

  • FGF-23-Dependent Hypophosphatemic Rickets: Abnormalities in phosphatonin regulation. Subtypes include X-linked dominant, autosomal dominant, and autosomal recessive hypophosphatemic rickets. X-linked dominant hypophosphatemic rickets is the most common form.
  • FGF-23-Independent Hypophosphatemic Rickets: Phosphate transport defects in renal tubules, with normal FGF-23 levels.

Risk Factors for Nutritional Vitamin D Deficiency Rickets:

• Limited Sun Exposure: Insufficient ultraviolet B (UVB) radiation for vitamin D synthesis due to:
  • High latitudes reducing UVB intensity.
  • Clothing covering most skin (cultural, religious, climatic reasons).
  • Indoor lifestyles.
  • Darker skin pigmentation (melanin reduces vitamin D synthesis).
  • Atmospheric pollution blocking UVB rays.
  • Extensive sunscreen use.
• Dietary Factors:
  • Prolonged exclusive breastfeeding without vitamin D supplementation.
  • Excessive juice consumption instead of vitamin D-fortified milk.
  • Inadequate intake of vitamin D-fortified foods.
  • Vegetarian diets (lower vitamin D intake).
• Maternal Vitamin D Deficiency: Pregnant mothers with vitamin D deficiency can predispose their infants to rickets.

Epidemiology of Rickets

While historically reduced in developed countries due to vitamin D supplementation and public health initiatives, rickets prevalence is unfortunately on the rise globally, affecting both developed and developing nations. Developing countries, particularly in Africa, the Middle East, and Asia, experience higher rates, ranging from 10% to 70%. In developed countries, despite fortification programs like vitamin D-fortified milk in the U.S. since the 1930s, incidence rates are increasing in some regions. For example, Minnesota in the U.S. has seen a significant rise in incidence over recent decades.

Incidence Rates in Various Regions (per 100,000):

• Canada: 2.9
• New Zealand: 10.5 (children < 3 years), 2.2 (children 3-15 years)
• Australia: 4.9
• Turkey: 3.8
• United Kingdom: 7.5
• United States (Minnesota): Increased from 0 (1970s) to 24.1 (2000s)

Native Alaskan children in the U.S. face a disproportionately high risk of rickets due to high latitudes and limited sunlight, with hospitalization rates significantly exceeding the national average.

Pathophysiology of Rickets

Rickets fundamentally disrupts endochondral ossification, the process by which cartilage is transformed into bone in growing long bones. This process involves chondrocyte maturation, cartilage matrix production and calcification, and subsequent replacement with bone tissue. Adequate calcium and phosphate are essential for the mineralization of osteoid, the unmineralized bone tissue. Rickets arises from defects in this mineralization process, primarily affecting the growth plate.

Key Steps in Rickets Pathophysiology:

1. Mineral Deficiency (Calcium, Phosphate, or Both): Reduced serum calcium and/or phosphate levels are central to rickets. Vitamin D deficiency, inadequate dietary intake, or renal phosphate wasting can contribute to these deficiencies.
2. Secondary Hyperparathyroidism (in Calcipenic Rickets): Low serum calcium triggers increased parathyroid hormone (PTH) secretion. PTH attempts to restore calcium levels by:
   • Increasing calcium reabsorption in the kidneys.
   • Promoting calcium release from bone.
   • Increasing renal phosphate excretion, further exacerbating hypophosphatemia.
3. Growth Plate Disruption: Hypophosphatemia inhibits chondrocyte apoptosis (programmed cell death) in the growth plate. This leads to an accumulation of hypertrophic chondrocytes and abnormal expansion of the epiphyseal plate.
4. Impaired Mineralization: Reduced calcium and phosphate availability hinders the mineralization of the cartilage matrix and osteoid within the growth plate.
5. Skeletal Deformities: The widened, unmineralized growth plate is weaker and more susceptible to mechanical forces, resulting in characteristic skeletal deformities of rickets. Reduced vascular invasion and altered chondroblast and osteoclast activity further contribute to growth plate abnormalities.

Figure: Rickets. X-ray showing metaphyseal flaring (widening) of the distal femurs and proximal and distal tibial metaphyses in a 2-year-old female with rickets.

History and Physical Examination for Rickets Diagnosis

A comprehensive clinical evaluation is paramount in rickets diagnosis. This involves:

Detailed History:

• Patient Demographics: Age, gestational age at birth. Rickets is most common between 6 months and 2 years of age.
• Sun Exposure History: Duration and frequency of sun exposure, geographic location (latitude), skin pigmentation, clothing habits.
• Dietary History: Breastfeeding history, formula intake (fortified or unfortified), intake of vitamin D-fortified foods, calcium and phosphorus intake, juice and milk consumption.
• Supplement History: Vitamin D and calcium supplementation.
• Developmental and Growth History: Growth charts, developmental milestones, history of fractures.
• Family History: Skeletal abnormalities, short stature, alopecia, dental issues, parental consanguinity (suggestive of genetic rickets).

Thorough Physical Examination:

• General Assessment: Overall well-being, irritability, muscle weakness, delayed motor development.
• Skeletal Examination:
  • Skull: Craniotabes (softening of the skull bones, especially along the sutures). Delayed fontanel closure.
  • Chest: Rachitic rosary (palpable nodules at the costochondral junctions), Harrison’s groove (horizontal depression along the lower rib cage at the diaphragm insertion), pigeon chest deformity.
  • Spine: Scoliosis, kyphosis.
  • Extremities: Widening of wrists and ankles, bowed legs (genu varum), knock knees (genu valgum), metaphyseal swelling and tenderness, fractures.
  • Pelvis: Pelvic deformities may be present in older children.
• Neurological Examination: Assess for hypotonia, muscle weakness, tetany, seizures (signs of hypocalcemia).
• Dental Evaluation: Delayed tooth eruption, enamel hypoplasia, dental caries.

Clinical signs may be subtle, especially in early rickets, and their absence does not rule out the diagnosis.

Diagnostic Evaluation for Rickets

If rickets is suspected based on history and physical findings, further investigations are necessary to confirm the rickets diagnosis. These include biochemical tests and radiological imaging.

Biochemical Investigations:

• Serum Alkaline Phosphatase (ALP): Typically elevated in rickets due to increased osteoblastic activity. Markedly elevated in calcipenic rickets (often > 2000 IU/L), moderately elevated in phosphopenic rickets (400-800 IU/L). ALP is also useful for monitoring treatment response.
• Serum 25-hydroxyvitamin D (25(OH)D): The primary indicator of vitamin D status. Low levels (< 20 ng/mL or 50 nmol/L) are suggestive of vitamin D deficiency. The Global Consensus Recommendations define vitamin D deficiency as 25(OH)D level < 20 ng/mL and insufficiency as 20-29 ng/mL.
• Serum Calcium: May be low, normal, or even elevated depending on the type and stage of rickets. In calcipenic rickets, calcium is often low or normal (due to secondary hyperparathyroidism). Corrected calcium levels should be calculated if albumin is low.
• Serum Phosphate: Typically low in both calcipenic and phosphopenic rickets, although it may be initially normal in calcipenic rickets before decreasing due to PTH-induced renal phosphate wasting.
• Serum Parathyroid Hormone (PTH): Elevated in calcipenic rickets due to secondary hyperparathyroidism. Usually normal in phosphopenic rickets.
• Serum 1,25-dihydroxyvitamin D (1,25(OH)2D): Not routinely used for nutritional rickets diagnosis. Helpful in evaluating genetic forms of vitamin D-dependent rickets. Levels are low in VDDR type 1 and high in VDDR type 2.
• Urine Phosphate: May be measured to assess renal phosphate wasting in genetic hypophosphatemic rickets and other conditions like Fanconi syndrome.
• Urine Calcium: Can be monitored during treatment of hypocalcemic rickets to detect hypercalciuria and prevent nephrocalcinosis.
• Renal Function Tests (BUN, Creatinine): To assess renal status, especially important in differential diagnosis.
• Liver Function Tests (Liver Enzymes): To evaluate liver function and rule out liver disease-induced rickets.

Radiological Investigations:

Radiographs of rapidly growing bone sites are crucial for rickets diagnosis. These typically include:

• Wrists and Knees: Distal radius and ulna, distal femur and proximal tibia are commonly imaged.
• Rib Cage: Chest X-rays can reveal rachitic rosary and widened costochondral junctions.

Characteristic Radiographic Findings in Rickets:

• Early Changes: Widening of the epiphyseal plate due to accumulation of unmineralized osteoid. Loss of the zone of provisional calcification, resulting in a less distinct and widened space between the metaphysis and epiphysis.
• Metaphyseal Changes: Fraying, cupping, and splaying of the metaphysis, giving it an irregular, brush-like appearance.
• Delayed Epiphyseal Ossification: Epiphyseal centers may be delayed in appearance or appear smaller than expected for age.
• Cortical Thinning and Osteopenia: Bone cortex may appear thinner and less dense.
• Deformities and Fractures: Angular deformities and pathological fractures may be seen in advanced cases.

Figure: Radiograph of the left wrist (anteroposterior and lateral views) showing metaphyseal widening and irregularity of the distal radius and ulna indicative of rickets before treatment.

Figure: Radiograph of the left wrist (anteroposterior and lateral views) taken three months after rickets treatment, showing improved density and appearance of the distal metaphysis. Improved mineralization is evident.

Diagnosis Confirmation:

The diagnosis of rickets is confirmed by integrating clinical findings, biochemical abnormalities (elevated ALP, hypocalcemia or hypophosphatemia), and characteristic radiological features. However, it is important to note that normal serum calcium and phosphate levels do not exclude rickets, particularly in early stages.

Treatment and Management of Rickets

The treatment approach for rickets depends on the underlying etiology: nutritional versus genetic.

Nutritional Vitamin D Deficiency Rickets Treatment:

Treatment involves an intensive phase to rapidly replenish vitamin D stores and a maintenance phase for ongoing prevention. Calcium supplementation is also crucial, especially in those with inadequate dietary calcium intake.

Vitamin D Regimens:

• Multiple Daily Doses: Small daily doses of vitamin D2 (ergocalciferol) or D3 (cholecalciferol) are commonly used. Dosage recommendations vary by age and guidelines. For infants under 12 months, typical daily doses range from 1,000 to 2,000 IU during the intensive phase (2-3 months), followed by a maintenance dose of 400 IU daily. Older children and adolescents may require higher intensive phase doses (up to 5,000-6,000 IU daily) based on guidelines.
• Stoss Therapy (Single High-Dose Vitamin D): Involves a single large dose of vitamin D, followed by maintenance therapy. While effective, it may carry a slightly higher risk of hypercalcemia and is less commonly used as the initial treatment approach.

Calcium Supplementation: 500 mg of elemental calcium daily, either through diet or supplements, is generally recommended during the intensive phase, particularly if dietary calcium intake is insufficient.

Monitoring Treatment Response:

• Clinical Improvement: Bone pain typically improves within 2 weeks of treatment initiation. Metaphyseal swelling resolves within 6 months. Skeletal deformities like bowed legs may take up to 2 years to improve, and some residual deformities may require orthopedic correction, especially in adolescents.
• Biochemical Resolution: Serum calcium and phosphate levels usually normalize within 6-10 days. PTH levels normalize within 1-2 months. ALP levels may take 3 months or longer to normalize.
• Radiological Healing: Follow-up radiographs demonstrate progressive healing of rachitic changes, including improved metaphyseal appearance and bone mineralization.

Regular monitoring of serum calcium, phosphate, ALP, and 25(OH)D levels is essential during treatment. Urine calcium-to-creatinine ratio may be monitored to assess for hypercalciuria. Surgical correction may be considered for persistent severe skeletal deformities after biochemical and vitamin D restoration.

Prevention of Nutritional Rickets:

Nutritional rickets is largely preventable through public health measures and parental education. Key strategies include:

• Prenatal Vitamin D Supplementation: Pregnant women should receive at least 600 IU of vitamin D daily.
• Infant Vitamin D Supplementation: Universal vitamin D supplementation of 400 IU daily is recommended for all breastfed infants and formula-fed infants consuming less than 500 mL of fortified formula per day during the first year of life.
• Dietary Education: Educating parents about vitamin D and calcium-rich foods and the importance of vitamin D-fortified foods.
• Safe Sun Exposure: Promoting safe sun exposure practices, while being mindful of skin cancer risks.
• Public Health Programs: Governmental programs promoting vitamin D supplementation and food fortification have been shown to be highly effective in reducing rickets prevalence.

Treatment of Genetic Rickets:

Management of genetic rickets is more complex and depends on the specific genetic defect. Treatment is primarily symptomatic and aims to manage biochemical abnormalities, promote bone health, and minimize skeletal deformities. This often involves specialized care by endocrinologists, nephrologists, and geneticists.

Differential Diagnosis of Rickets

Rickets diagnosis requires differentiation from other conditions that can mimic its clinical or radiological features:

• Renal Osteodystrophy: Bone disease associated with chronic kidney disease, involving complex mechanisms including vitamin D deficiency, phosphate retention, and secondary hyperparathyroidism.
• Conditions with Elevated ALP:
  • Transient hyperphosphatasia: Benign condition with markedly elevated ALP, typically in young children.
  • Cholestatic liver diseases: Characterized by elevated gamma-glutamyl transferase (GGT) along with ALP.
• Conditions with Hypocalcemia:
  • Primary hypoparathyroidism.
• Other Bone Diseases:
  • Osteogenesis imperfecta.
  • Congenital syphilis.
• Non-accidental injury (Child Abuse): Fractures in rickets must be differentiated from non-accidental trauma.
• Normal Physiological Bowing: Bowlegs can be a normal variation in young children, especially toddlers.
• Skeletal Dysplasias: Achondroplasia and other skeletal dysplasias.
• Blount Disease: Tibia vara, a growth disorder affecting the proximal tibia, causing bowing of the legs.

Prognosis of Rickets

The prognosis of rickets varies depending on the underlying cause. Nutritional rickets generally has an excellent prognosis with early rickets diagnosis and prompt treatment. Complete resolution is usually achieved within months of initiating therapy. However, untreated nutritional rickets can lead to significant and potentially irreversible complications. Genetic forms of rickets often require lifelong management to mitigate symptoms and complications, as they are typically not curable.

Complications of Untreated Rickets

Untreated rickets can result in a range of complications:

• Growth Retardation: Impaired linear growth and short stature.
• Skeletal Deformities: Persistent bowed legs, knock knees, scoliosis, pelvic deformities.
• Pathological Fractures: Increased bone fragility and risk of fractures.
• Dental Problems: Delayed tooth eruption, enamel hypoplasia, increased dental caries.
• Neurological Complications: Hypocalcemia-induced seizures. In rare cases, hydrocephalus and increased intracranial pressure have been reported.
• Cardiomyopathy: Severe hypocalcemia can lead to cardiac muscle dysfunction and potentially death.

Deterrence and Patient Education

Patient and parent education is crucial for rickets prevention. Key educational points include:

• Importance of Vitamin D and Calcium: Emphasize dietary sources of vitamin D and calcium, and the role of vitamin D in calcium absorption.
• Vitamin D Supplementation: Recommendations for vitamin D supplementation during pregnancy and infancy.
• Fortified Foods: Encourage consumption of vitamin D-fortified foods like milk, cereals, and juices.
• Safe Sun Exposure: Guidance on safe sun exposure for vitamin D synthesis.
• Nutritional Support Programs: Awareness of governmental nutritional assistance programs like SNAP to address nutritional deficiencies in at-risk populations.

Enhancing Healthcare Team Outcomes

Optimal management of rickets requires a multidisciplinary team approach. This team typically includes:

• Primary Care Physician (Pediatrician): Initial rickets diagnosis, management of nutritional rickets, and coordination of care.
• Pediatric Endocrinologist: Specialized expertise in rickets management, particularly for complex or genetic cases.
• Registered Dietitian: Nutritional assessment and dietary counseling.
• Radiologist: Interpretation of radiographic findings for rickets diagnosis and monitoring.
• Orthopedic Surgeon: Management of skeletal deformities, potentially requiring surgical correction.
• Geneticist: Genetic counseling and management of genetic forms of rickets.
• Pediatric Nephrologist/Metabolic Bone Specialist: Consultation for complex cases, especially genetic or renal-related rickets.
• Pharmacist: Medication management and ensuring appropriate vitamin D and calcium supplementation.
• Other Specialists: Cardiologists, neurologists, physical therapists, and occupational therapists may be involved in managing specific complications.

Effective communication and collaboration among team members are essential to optimize patient outcomes in rickets diagnosis and management.

Figure: Clinical presentation of rickets in a five-year-old child, demonstrating skeletal deformities.

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