Writing a Case Report on Vitamin D Dependent Rickets Type 1A with Delayed Diagnosis
Introduction Structure
Your introduction should emphasize that Vitamin D Dependent Rickets Type 1A (VDDR-1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to deficiency of 1α-hydroxylase enzyme and impaired conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D3. 1, 2, 3
Key Points to Include in Introduction:
Epidemiology and Genetics: VDDR-1A represents approximately 20% of hypophosphataemic rickets cases (with X-linked hypophosphataemia being the most common at ~80%). 4 The condition is inherited in an autosomal recessive pattern with mutations in CYP27B1 located on chromosome 12q14. 1, 2, 3
Clinical Presentation: Typical onset occurs between 2-24 months of age with hypocalcemic rickets, failure to thrive, muscle weakness/hypotonia, seizures from hypocalcemia, and skeletal deformities including bowing of legs, widened wrists and ankles, and rachitic rosary. 1, 2, 3, 5
Diagnostic Challenge: The condition is frequently misdiagnosed as nutritional rickets because both present with similar clinical and radiological features. However, VDDR-1A is refractory to standard vitamin D supplementation (cholecalciferol or ergocalciferol) and requires treatment with active vitamin D metabolites (calcitriol or alfacalcidol). 1, 2, 3
Biochemical Profile: Characteristic findings include hypocalcemia, hypophosphatemia, elevated alkaline phosphatase, markedly elevated parathyroid hormone (PTH), normal or elevated 25-hydroxyvitamin D, and low or inappropriately normal 1,25-dihydroxyvitamin D3 levels. 2, 3, 5
Importance of Early Diagnosis: Delayed diagnosis results in irreversible skeletal deformities, as demonstrated by adult cases where patients develop permanent limb deformities and short stature despite eventual treatment. 6 Early genetic diagnosis in infancy allows prevention of these complications. 6
Discussion Structure
Diagnostic Delay and Mismanagement
The critical teaching point of your case is that VDDR-1A should be suspected when a child with apparent rickets fails to respond to standard vitamin D supplementation, particularly when 25-hydroxyvitamin D levels are normal or elevated. 1, 2, 3
Emphasize that nutritional rickets and VDDR-1A can coexist, and diagnosis of VDDR-1A should be considered if serum phosphate levels do not improve after vitamin D supplementation. 4
The biochemical hallmark distinguishing VDDR-1A from nutritional rickets is the combination of elevated PTH with normal/high 25-hydroxyvitamin D but low 1,25-dihydroxyvitamin D3. 2, 3, 5
Note that approximately 40% of infants and toddlers aged 8-24 months have vitamin D insufficiency, making nutritional rickets common and potentially masking the diagnosis of genetic forms. 4
Role of Next-Generation Sequencing
NGS has revolutionized the diagnosis of rare genetic disorders like VDDR-1A by enabling identification of novel mutations and providing definitive diagnosis when clinical and biochemical findings are suggestive but not conclusive. 2, 3, 6
Discuss how molecular genetic analysis should be performed whenever possible before treatment to confirm diagnosis, particularly in cases with negative family history or atypical presentations. 4
Extended molecular genetic analysis is helpful to establish diagnosis in unclear cases of hypophosphataemic rickets and can differentiate between various genetic causes including VDDR-1A, VDDR-1B, VDDR-2A, hereditary hypophosphataemic rickets with hypercalciuria (HHRH), and X-linked hypophosphataemia. 4, 6
Emphasize that novel mutations continue to be identified, expanding our understanding of CYP27B1 gene mutations. 2, 3, 6, 5
Consequences of Delayed Diagnosis
Your 19-year-old patient represents a critical example of how delayed diagnosis leads to irreversible skeletal deformities that persist into adulthood despite eventual appropriate treatment. 6
Adult cases diagnosed late develop permanent limb deformities, disproportionate short stature, and may have complications including nephrocalcinosis from prolonged secondary hyperparathyroidism. 3, 6
Radiographic features in your patient likely include severe leg bowing (genu varum or valgus), metaphyseal irregularities, thickened cortical bone, and possibly pseudofractures or early osteoarthritis. 4
Unlike nutritional rickets where fractures occur in mobile children aged 8-19 months and are typically long bone or rib fractures, VDDR-1A can present with more severe skeletal involvement including multiple fractures and severe hypotonia. 4, 5
Treatment Principles
Once diagnosed, VDDR-1A requires lifelong treatment with active vitamin D metabolites (calcitriol 0.25-2 µg/day or alfacalcidol) plus calcium supplementation (250-500 mg elemental calcium daily). 7, 1, 2, 3, 6
Standard vitamin D2 (ergocalciferol) or D3 (cholecalciferol) supplementation is ineffective because the enzymatic defect prevents conversion to active metabolite. 1, 2, 3
Treatment goals include normalization of serum calcium, phosphorus, alkaline phosphatase, and PTH levels, typically achieved within 2-3 months of initiating therapy. 2, 3, 6, 5
Monitoring should include periodic measurement of serum calcium, phosphorus, alkaline phosphatase, PTH, and urinary calcium to avoid hypercalcemia and hypercalciuria. 7, 3
In your adult patient, treatment will normalize biochemical parameters and may improve bone pain, but skeletal deformities established during growth are irreversible. 6
Differential Diagnosis Considerations
The differential diagnosis of hypophosphataemic rickets includes multiple genetic and acquired conditions that must be distinguished from VDDR-1A. 4
X-linked hypophosphataemia (XLH) is the most common inherited cause (~80% of cases), characterized by elevated FGF23, renal phosphate wasting, hypophosphatemia, but normal calcium and inappropriately normal or low 1,25-dihydroxyvitamin D3. 4
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) presents with hypercalciuria before treatment, distinguishing it from VDDR-1A where urinary calcium is typically low. 4
Renal Fanconi syndrome causes generalized proximal tubular dysfunction with glucosuria, aminoaciduria, and low molecular mass proteinuria in addition to phosphate wasting. 4, 5
Tumor-induced osteomalacia typically presents after the second year of life with symptoms developing later than typical VDDR-1A. 4
Clinical Implications and Recommendations
Early genetic screening should be performed in all children presenting with rickets who have elevated PTH, normal or high 25-hydroxyvitamin D, and low 1,25-dihydroxyvitamin D3, or who fail to respond to standard vitamin D supplementation. 6
Consanguinity increases risk for autosomal recessive conditions like VDDR-1A and should prompt earlier genetic evaluation. 3
Family screening is essential once an index case is identified, as siblings have 25% risk of being affected. 3
Genetic counseling should be provided to families regarding recurrence risk and inheritance patterns. 4
In resource-limited settings where genetic testing may not be readily available, empirical trial of calcitriol with close biochemical monitoring can be diagnostic and therapeutic. 1, 2
Unique Aspects of Your Case
Highlight the 16-year delay from symptom onset (age 3) to definitive diagnosis (age 19), representing an extreme example of diagnostic delay. 6
Discuss how empirical management as "resistant rickets" likely involved higher doses of standard vitamin D without addressing the underlying enzymatic defect. 1, 2
Emphasize that NGS provided definitive diagnosis when clinical suspicion alone was insufficient, enabling appropriate targeted therapy. 2, 3, 6
Note any specific novel mutations identified in your patient and their predicted functional consequences on 1α-hydroxylase activity. 2, 3, 6, 5