# CIM Case: X-Linked Hypophosphataemic Rickets ## Clinical Scenario **Patient:** 14-month-old male **Presentation:** Bowed legs, delayed walking, stunted growth, family history of "bone problems" in mother and maternal grandmother **Relevant history:** Full-term delivery, normal birth, delayed motor milestones (not yet walking independently), no dietary deficiency suspected (breast-fed with adequate weaning), mother is short stature (150cm) with bow legs **Examination findings:** - Height: 3rd percentile (below expected for mid-parental height) - Weight: 25th percentile - Bilateral genu varum with intercondylar distance 4cm - Widened wrists (metaphyseal flaring) - Frontal bossing - Dental: Delayed eruption (no teeth at 14 months) - No muscle weakness (unlike nutritional rickets) - No hypotonia - Normal neurological examination - Mother has similar leg bowing and required childhood osteotomies --- ## Investigations Provided ### Laboratory Results | Test | Result | Normal Range | Interpretation | |------|--------|--------------|----------------| | Serum Calcium | 2.35 mmol/L | 2.10-2.55 | Normal | | Serum Phosphate | 0.65 mmol/L | 1.25-1.90 | **LOW** | | Alkaline Phosphatase | 850 U/L | 150-400 | **HIGH** | | PTH | 35 pg/mL | 15-65 | Normal | | 25-OH Vitamin D | 75 nmol/L | 50-250 | Normal | | 1,25-(OH)2 Vitamin D | 55 pmol/L | 45-185 | Normal (inappropriately normal) | | Creatinine | 28 μmol/L | 20-40 | Normal | ### Urine Studies | Test | Result | Normal | Interpretation | |------|--------|--------|----------------| | Urinary Calcium | 3.8 mmol/day | <4.0 | Normal to slightly elevated | | TmP/GFR | 0.5 mmol/L | 1.0-1.5 | **LOW - Renal phosphate wasting** | | Fractional Excretion PO4 | 28% | <15% | **HIGH - Phosphaturia** | ### Imaging **Image 1: AP Radiographs of Knees and Wrists** **Radiological features:** - Bilateral genu varum (tibial bowing) - Metaphyseal widening and cupping at distal femur and proximal tibia - Fraying of metaphyseal margins - No periosteal reaction - Wrist: Widening of distal radial and ulnar physes - Rachitic rosary not prominent (unlike nutritional rickets) - No fractures or Looser zones **Image 2: Standing Full-Length Lower Limb Alignment** **Findings:** - Mechanical axis deviation: 25mm lateral (bilateral) - Anatomical tibiofemoral angle: 20° varus - Metaphyseal-diaphyseal angle: 15° - No angular deformity at ankle --- ## Questions & Model Answers **Diagnosis: X-Linked Hypophosphataemic Rickets (XLH)** The laboratory pattern is diagnostic: | Finding | XLH | Nutritional Rickets | |---------|-----|---------------------| | **Calcium** | Normal | Low or low-normal | | **Phosphate** | LOW | Low | | **ALP** | High | Very high | | **PTH** | Normal | ELEVATED | | **25-OH Vit D** | Normal | LOW | | **Urinary phosphate** | HIGH (wasting) | Normal/Low | **Key Diagnostic Features of XLH:** | Feature | Significance | |---------|-------------| | **Isolated hypophosphataemia** | Renal phosphate wasting, not dietary | | **Normal calcium** | Not secondary hyperparathyroidism | | **Normal PTH** | Not driven by calcium deficiency | | **Normal 25-OH Vit D** | Adequate vitamin D stores | | **High urinary phosphate** | TmP/GFR low = renal tubular defect | **Pathophysiology:** - PHEX gene mutation (X-linked dominant) - Results in elevated FGF23 (fibroblast growth factor 23) - FGF23 inhibits renal phosphate reabsorption - FGF23 also inhibits 1-alpha hydroxylase - Results in "inappropriately normal" 1,25(OH)2 Vitamin D **Clinical Differentiators:** | Feature | XLH | Nutritional | |---------|-----|-------------| | **Family history** | Usually positive | Usually negative | | **Muscle weakness** | Absent | Present (profound) | | **Hypotonia** | Absent | Present | | **Response to Vitamin D alone** | None | Complete | | **Geographic/Social factors** | Any | Dark skin, covered dress, limited sun | > **Consultant Tip:** The key diagnostic triad is: isolated hypophosphataemia + normal calcium + normal PTH + renal phosphate wasting. This excludes nutritional rickets where PTH is elevated. **Genetics of XLH:** **Inheritance Pattern:** | Aspect | Detail | |--------|--------| | **Gene** | PHEX (Phosphate-regulating gene with Homology to Endopeptidases on X chromosome) | | **Location** | Xp22.1 | | **Inheritance** | X-linked DOMINANT | | **Female carriers** | Affected (variable expressivity) | | **Male transmission** | All daughters affected, no sons affected | **Inheritance Pattern Implications:** | Parent | Offspring | |--------|-----------| | Affected mother | 50% daughters affected, 50% sons affected | | Affected father | 100% daughters affected, 0% sons affected | **This Patient:** Mother and maternal grandmother affected - classic X-linked dominant pattern. **Pathophysiology - The FGF23 Axis:** | Step | Mechanism | |------|-----------| | 1. | PHEX gene mutation | | 2. | Loss of FGF23 degradation (PHEX normally cleaves FGF23) | | 3. | Elevated circulating FGF23 | | 4. | FGF23 acts on proximal renal tubule | | 5. | Downregulation of NaPi-IIa and NaPi-IIc transporters | | 6. | Renal phosphate wasting (phosphaturia) | | 7. | Hypophosphataemia | | 8. | FGF23 also inhibits 1-alpha hydroxylase | | 9. | Reduced 1,25(OH)2 Vitamin D production | | 10. | Impaired intestinal phosphate absorption | **Why Rickets Develops:** | Deficiency | Effect on Bone | |------------|----------------| | **Low phosphate** | Cannot mineralize osteoid | | **Reduced calcitriol** | Impaired osteoblast function | | **Growth plate** | Hypertrophic zone expands (chondrocyte apoptosis fails) | | **Result** | Widened, frayed metaphyses = rickets | **Other Causes of Phosphate Wasting:** | Condition | Gene | FGF23 Level | |-----------|------|-------------| | XLH | PHEX | Elevated | | ADHR (Autosomal Dominant) | FGF23 | Elevated (mutant resistant to cleavage) | | ARHR (Autosomal Recessive) | DMP1, ENPP1 | Elevated | | Tumour-induced osteomalacia | Tumour secretes FGF23 | Very elevated | > **Consultant Tip:** PHEX does not transport phosphate - it degrades FGF23. The name is confusing but understanding this is key to explaining the pathophysiology. **Medical Treatment of XLH:** **Conventional Therapy:** | Medication | Dose | Rationale | |------------|------|-----------| | **Oral phosphate** | 20-40 mg/kg/day in 4-5 divided doses | Replace phosphate loss | | **Calcitriol** | 20-30 ng/kg/day in 2 divided doses | Enhance intestinal absorption | **Why Both Are Needed:** | Treatment | Alone | Combined | |-----------|-------|----------| | **Phosphate only** | Causes secondary hyperparathyroidism (PTH rises) | PTH remains controlled | | **Calcitriol only** | Causes hypercalcaemia, no phosphate provision | Synergistic mineralisation | **Treatment Goals:** | Parameter | Target | |-----------|--------| | **Serum phosphate** | Low-normal range (not complete normalisation) | | **ALP** | Normalise over 6-12 months | | **PTH** | Normal (avoid secondary hyperparathyroidism) | | **Urine calcium** | <4 mg/kg/day (avoid hypercalciuria) | | **Clinical** | Improved growth velocity, reduced deformity progression | **Monitoring Schedule:** | Interval | Tests | |----------|-------| | Every 3 months | Calcium, phosphate, ALP, PTH, creatinine | | Every 3 months | Spot urine calcium:creatinine ratio | | Every 6 months | Renal ultrasound (nephrocalcinosis) | | Every 12 months | Spine X-ray if on long-term therapy | **Complications of Treatment:** | Complication | Cause | Prevention | |--------------|-------|------------| | **Nephrocalcinosis** | Hypercalciuria from calcitriol | Monitor urine calcium | | **Secondary hyperparathyroidism** | Phosphate alone stimulates PTH | Always give calcitriol | | **Tertiary hyperparathyroidism** | Long-standing PTH elevation | May need parathyroidectomy | | **GI upset** | Oral phosphate | Divide doses, take with food | **Newer Therapy - Burosumab:** | Aspect | Detail | |--------|--------| | **Mechanism** | Anti-FGF23 monoclonal antibody | | **Administration** | Subcutaneous every 2 weeks | | **Advantage** | Targets the underlying pathophysiology | | **Evidence** | Improved growth, rickets healing, phosphate levels | | **Indication** | Growing children with XLH, now first-line in many centres | | **Limitation** | Cost, requires specialist initiation | > **Consultant Tip:** Oral phosphate causes diarrhoea and must be given 4-5 times daily which affects compliance. Burosumab is a game-changer but discuss conventional therapy first in exams. **Indications for Surgical Correction:** | Indication | Detail | |------------|--------| | **Severe mechanical axis deviation** | >15-20mm from knee centre | | **Failed medical management** | Progressive deformity despite treatment | | **Functional impairment** | Gait abnormality, pain | | **Skeletal maturity** | Definitive correction when growth complete | **Timing Considerations:** | Age | Approach | |-----|----------| | **<4-5 years** | Medical management, observe | | **4-8 years** | Guided growth (if mild-moderate) | | **8-12 years** | May need osteotomy if severe | | **Skeletal maturity** | Definitive osteotomy if persistent | **This Patient (14 months):** - Too young for surgical intervention - Start medical management (phosphate + calcitriol) - Serial clinical and radiographic monitoring - Anticipate some spontaneous improvement with treatment - Reassess at age 3-4 years **Surgical Options:** | Technique | Indication | Advantages | Disadvantages | |-----------|------------|------------|---------------| | **Guided growth (8-plates)** | Skeletally immature, mild-moderate deformity | Minimally invasive, reversible | Slow, requires growth remaining | | **Osteotomy (closing wedge)** | Any age, moderate-severe | Immediate correction | More invasive, hardware | | **Osteotomy (opening wedge)** | May need bone graft | Avoids limb shortening | Graft site morbidity | | **Ilizarov/Taylor Spatial Frame** | Complex multiplanar deformity | Precise correction, can lengthen | External fixator issues | **Pre-Operative Requirements:** | Requirement | Rationale | |-------------|-----------| | **Metabolic control** | ALP normalising, rickets healing | | **Adequate phosphate** | Bone healing requires phosphate | | **Normal PTH** | Avoid secondary hyperparathyroidism | | **Active rickets controlled** | Operating on active rickets has high recurrence | **Expected Outcomes:** | Outcome | Expectation | |---------|-------------| | **Correction** | Good if rickets healed | | **Recurrence** | 20-30% if medical treatment lapses | | **Delayed union** | Higher risk than normal population | | **Further surgery** | Often needed as child grows | > **Consultant Tip:** Never operate on active rickets - heal the rickets first with 6-12 months of medical treatment, confirm with normalising ALP, then correct residual deformity. **Differential Diagnosis of Rickets:** **Classification of Rickets:** | Category | Examples | |----------|----------| | **Calcipenic** | Vitamin D deficiency, Vitamin D-dependent rickets | | **Phosphopenic** | XLH, tumour-induced osteomalacia | | **Mixed** | Renal osteodystrophy | **Laboratory Differentiation:** | Condition | Ca | PO4 | ALP | PTH | 25-OH D | 1,25-OH D | |-----------|-----|-----|-----|-----|---------|-----------| | **Nutritional Rickets** | Low/N | Low | High | HIGH | LOW | Variable | | **XLH** | Normal | Low | High | Normal | Normal | Normal/Low | | **VDDR Type I** | Low | Low | High | High | Normal | LOW | | **VDDR Type II** | Low | Low | High | High | Normal | HIGH | | **Renal osteodystrophy** | Low | High | High | HIGH | Normal | Low | **Clinical Differentiation:** | Feature | Nutritional | XLH | VDDR | |---------|-------------|-----|------| | **Muscle weakness** | Present | Absent | Present | | **Hypotonia** | Present | Absent | Present | | **Tetany/seizures** | May occur | Never | May occur | | **Alopecia** | Never | Never | VDDR II only | | **Family history** | Usually none | X-linked | AR | | **Response to Vit D** | Complete | None | Type I responds | **Vitamin D-Dependent Rickets:** | Type | Gene | Mechanism | Treatment | |------|------|-----------|-----------| | **Type I (VDDR I)** | CYP27B1 | Cannot make 1,25(OH)2 D | Calcitriol (lifelong) | | **Type II (VDDR II)** | VDR | Receptor resistance | High-dose calcitriol, IV calcium | **Key Features of VDDR II:** - Alopecia totalis (pathognomonic) - Resistance to vitamin D treatment - May need IV calcium infusions **Acquired Causes to Consider:** | Cause | Clinical Clue | |-------|---------------| | **Tumour-induced osteomalacia** | Adult onset, very high FGF23 | | **Fanconi syndrome** | Aminoaciduria, glycosuria, proximal RTA | | **Drugs** | Ifosfamide, tenofovir | > **Consultant Tip:** Ask about muscle weakness - its absence essentially rules out calcipenic rickets and points toward XLH where phosphate is the problem, not calcium. **Long-Term Prognosis:** **With Adequate Treatment:** | Outcome | Expectation | |---------|-------------| | **Height** | Improved but usually remains below average (final height ~155-160cm for males) | | **Rickets** | Heals radiographically | | **Deformity** | May improve, may need surgery | | **Function** | Usually good | | **Life expectancy** | Normal | **Factors Affecting Outcome:** | Factor | Better Prognosis | Worse Prognosis | |--------|------------------|-----------------| | **Diagnosis timing** | Early (<2 years) | Late | | **Treatment compliance** | Good | Poor | | **Access to specialists** | Yes | Limited | | **Severity** | Mild phenotype | Severe | **Complications to Anticipate:** | System | Complication | Management | |--------|--------------|------------| | **Musculoskeletal** | Persistent lower limb deformity | Osteotomy | | **Musculoskeletal** | Short stature | Growth hormone controversial | | **Dental** | Abscesses from defective dentin | Prophylactic dental care | | **Hearing** | Sensorineural hearing loss (adult) | Audiometry screening | | **Spinal** | Spinal stenosis, enthesopathy | May need decompression | | **Renal** | Nephrocalcinosis from treatment | Regular USS monitoring | **Dental Issues (Important):** | Problem | Cause | |---------|-------| | **Periapical abscesses** | Defective dentin allows bacterial invasion | | **Pulp exposure** | Through defective enamel | | **Recurrent infections** | Despite normal-appearing teeth | | **Management** | Aggressive dental prophylaxis, early sealants | **Adult Manifestations:** | Complication | Mechanism | |--------------|-----------| | **Enthesopathy** | Calcification of tendons/ligaments | | **Spinal stenosis** | Ossification of ligamentum flavum | | **Pseudofractures** | Looser zones in femur, tibia | | **Osteomalacia** | If treatment lapsed | **Follow-up Protocol:** | Age | Focus | |-----|-------| | **Childhood** | Growth, rickets control, deformity | | **Adolescence** | Transition planning, compliance | | **Adult** | Dental, hearing, spinal surveillance | **Transition to Adult Care:** | Aspect | Consideration | |--------|---------------| | **Specialist** | Metabolic bone/endocrine physician | | **Treatment** | Continue or modify based on symptoms | | **Pregnancy** | Genetic counselling, increased phosphate needs | | **Offspring** | 50% risk if female, 100% daughters affected if male | > **Consultant Tip:** Dental complications are often forgotten - these children need early dental referral and aggressive preventive care. Abscesses occur in teeth that look normal. --- ## Key Teaching Points ### Pattern Recognition **This pattern suggests X-Linked Hypophosphataemic Rickets:** - Isolated hypophosphataemia with normal calcium - Normal PTH (not secondary hyperparathyroidism) - Normal vitamin D levels - Renal phosphate wasting (high TmP/GFR) - Family history of short stature/bowing (especially maternal line) - Absence of muscle weakness ### Critical Management Points 1. **Differentiate from nutritional rickets** - XLH has normal calcium, normal PTH, no muscle weakness 2. **Treatment requires BOTH phosphate AND calcitriol** - phosphate alone causes secondary hyperparathyroidism 3. **Burosumab (anti-FGF23)** is now available and may be first-line 4. **Nephrocalcinosis** is a treatment complication requiring monitoring 5. **Surgery should wait** until rickets healed and metabolically controlled 6. **Dental surveillance** is essential - abscesses occur in normal-looking teeth --- ## Common Examiner Follow-ups **Q: "What would you do if this child develops tertiary hyperparathyroidism?"** This occurs when long-standing secondary hyperparathyroidism becomes autonomous: - PTH remains elevated despite normalised calcium - Causes hypercalcaemia - May develop parathyroid adenoma - Requires parathyroidectomy - Prevention: careful monitoring and calcitriol dose adjustment --- **Q: "The mother asks about having another child - what do you tell her?"** Genetic counselling: - XLH is X-linked dominant - If the mother is affected: - 50% of sons will be affected - 50% of daughters will be affected - Prenatal diagnosis is possible with known PHEX mutation - Severity can vary even within families - Early treatment improves outcomes --- **Q: "At age 4, the deformity is worsening despite treatment. What now?"** Reassess: 1. Confirm compliance with medications 2. Check serum phosphate, ALP, PTH 3. Renal ultrasound for nephrocalcinosis 4. Consider burosumab if on conventional therapy 5. If metabolically controlled but still progressing: - Consider guided growth (8-plates) if mild - Osteotomy if severe - Ensure at least 6 months of optimised medical treatment first --- ## Related Topics - Nutritional Rickets - Vitamin D-Dependent Rickets - Renal Osteodystrophy - Paediatric Lower Limb Deformity - Genu Varum/Valgum - Blount's Disease - Metabolic Bone Disease