Familial complex regional pain syndrome in pediatric siblings: a diagnostic challenge and therapeutic success—a case report

Abstract

Background

Complex Regional Pain Syndrome (CRPS) is exceptionally rare in pediatric populations (Weissmann and Uziel in Pediatr Rheumatol Online J 14(1):29, 2016), with familial clustering being previously unreported in children. The diagnostic challenge is compounded by the extensive differential diagnosis of severe extremity pain in this age group (Harden et al. in Pain Med 23(Suppl 1):S1–S53, 2022; Marinus et al. in Lancet Neurol 10(7):637–648, 2011).

Case presentation

We report two pediatric siblings of Arab ethnicity who developed sequential severe extremity pain:

A 3-year-old girl of Arab ethnicity with a 2-month history of progressive pain starting in the lower extremities and extending to the upper extremities, followed by her 5-year-old brother with a similar presentation 20 days later. Both children presented with severe functional impairment, autonomic dysfunction, and met the Budapest Criteria for CRPS Type 1 (Harden et al. in Pain 150(2):268–274, 2010). Comprehensive investigations systematically excluded infectious, inflammatory, neoplastic, genetic, and metabolic causes through a structured diagnostic approach. The tight temporal clustering (within a 20-day interval) suggests shared environmental triggers in genetically susceptible individuals, rather than purely hereditary factors. Both patients demonstrated remarkable improvement with Gabapentin and intravenous immunoglobulin (IVIG) therapy (Mangnus et al. in Drugs 82(5):511531, 2022; Goebel et al. in Ann Intern Med 152(3):152–158, 2010).

Conclusions

This represents the first reported case of familial CRPS in pediatric siblings, demonstrating the complex interplay between environmental triggers and genetic susceptibility in CRPS pathogenesis. The case highlights the importance of systematic differential diagnosis in pediatric extremity pain and demonstrates the efficacy of early aggressive treatment with Gabapentin and IVIG in pediatric CRPS (Mangnus et al. in Drugs 82(5):511531, 2022; Goebel et al. in Ann Intern Med 152(3):152–158, 2010).

Supplementary Information

The online version contains supplementary material available at 10.1186/s13256-026-06006-x.

Introduction

Complex Regional Pain Syndrome (CRPS) is a debilitating chronic neuropathic pain condition characterized by severe pain disproportionate to the inciting event, accompanied by sensory, autonomic, motor, and trophic changes [2, 3]. While affecting approximately 200,000 individuals annually in the United States, pediatric cases represent less than 5% of all CRPS diagnoses, with peak incidence in adolescence rather than early childhood [1].

The condition is classified into Type 1 (without definable nerve injury, formerly known as reflex sympathetic dystrophy) and Type 2 (with definable nerve injury, formerly known as causalgia) [2]. Type 1 CRPS typically develops following minor trauma, surgery, or immobilization, while Type 2 CRPS occurs after major nerve injury. Both types can present with similar clinical features, including severe pain, autonomic dysfunction, and trophic changes [2]. Diagnosis relies on the Budapest Criteria, which require the presence of symptoms and signs across multiple categories: sensory (hyperalgesia/allodynia), vasomotor (temperature asymmetry/skin color changes), sudomotor/edema (edema/sweating changes), and motor/trophic (decreased range of motion/motor dysfunction/trophic changes) (Table 1) [4].

Table 1.

Budapest criteria application

Criterion category	Patient 1	Patient 2	Required for diagnosis
Sensory signs	Hyperalgesia ✓, Allodynia ✓	Hyperalgesia ✓, Allodynia ✓	≥1 sign
Vasomotor signs	Temperature asymmetry ✓, Color changes ✓	Temperature asymmetry ✓, Color changes ✓	≥1 sign
Sudomotor/edema	Edema ✓, Sweating changes ✓	Edema ✓, Sweating changes ✓	≥1 sign
Motor/trophic	Decreased ROM ✓, Motor dysfunction ✓	Decreased ROM ✓, Motor dysfunction ✓	≥1 sign
Diagnosis	CRPS Type 1	CRPS Type 1	All categories met

Familial clustering of CRPS has been documented in fewer than 10 cases worldwide, all of which have been exclusively in adults [7]. Recent evidence suggests genetic polymorphisms in HLA genes, inflammatory mediators, and ion channels may confer susceptibility [7]. However, the pathogenesis likely involves complex interactions between genetic predisposition and environmental triggers, including infections, trauma, and immune system activation [7, 8].

The occurrence of CRPS in pediatric siblings has never been reported, making this case significant for understanding the interplay between genetic and environmental contributions to CRPS pathogenesis.

The differential diagnosis of severe extremity pain in children is extensive, encompassing neurological, infectious, rheumatological, hematological, genetic, and metabolic conditions. This case illustrates the diagnostic challenges and systematic approach required to reach the correct diagnosis while excluding potentially life-threatening conditions.

Case presentation

Patient 1 (index case)

A 3-year-old previously healthy Arabic girl presented to the emergency department with a 2-month history of severe, progressive extremity pain. The pain began spontaneously in the bilateral lower extremities without preceding trauma, symptomatic illness, or vaccination. Over several weeks, the pain progressed to involve her upper extremities, particularly both hands.

Clinical presentation

• Pain characteristics: Continuous, severe (8–10/10 on pediatric pain scales), burning quality

• Exacerbating factors: Light touch, movement, cold exposure, nighttime

• Alleviating factors: Gentle massage, warmth, rest

• Associated symptoms: Extreme irritability, sleep disturbance, functional impairment

• Functional impact: Unable to walk except on tiptoes for short distances, refused to use hands for activities

Physical examination

• Vital signs: Hypertension (117/72 mmHg), tachycardia (142 bpm), afebrile

• Growth parameters: Weight 15.4 kg (50th percentile), height 103 cm (95th percentile)

Neurological examination

• Cranial nerves: Intact

• Motor: Normal power and tone in all extremities

• Sensory: Severe allodynia and hyperalgesia in hands and feet

• Reflexes: Preserved but difficult to elicit due to pain

• Gait: Antalgic, toe-walking pattern

Musculoskeletal examination

• No obvious swelling, deformity, or joint effusion

• Extreme tenderness to light touch in affected areas

• No skin lesions or obvious inflammation

Autonomic features

• Temperature asymmetry: Affected limbs are consistently cooler than unaffected areas

• Skin color changes: Mottled appearance with alternating pallor and cyanotic discoloration during episodes

• Sudomotor dysfunction: Excessive sweating in hands and feet alternating with periods of anhidrosis

• Vasomotor instability: Alternating periods of vasoconstriction and vasodilation in affected extremities with visible color changes

Budapest criteria assessment

1. Sensory: Hyperalgesia to pinprick ✓, allodynia to light touch ✓

2. Vasomotor: Temperature asymmetry ✓, skin color asymmetry ✓

3. Sudomotor/Edema: Edema ✓, sweating changes ✓

4. Motor/Trophic: Decreased range of motion ✓, motor dysfunction ✓

Patient 2 (affected brother)

Twenty days after the index case's symptom onset, her 5-year-old Arab brother developed similar symptoms, suggesting a potential shared environmental trigger during this critical temporal window.

Clinical presentation

• Pain characteristics: Similar burning, severe pain (7–9/10)

• Associated symptoms: Irritability, headaches, sleep disturbance

• Functional impact: Decreased mobility, reluctance to use hands

• Temporal pattern: Symptoms worsen at night and after physical activity

Physical examination

Physical examination findings were similar to those of the index case, with allodynia and hyperalgesia in the affected extremities, autonomic features, including temperature asymmetry and skin color changes, and met Budapest Criteria across all four categories.

Family history and demographics

Family background

• Parents: Non-consanguineous, healthy

• Siblings: One older healthy sister (7 years)

• No family history of chronic pain conditions, autoimmune diseases, or genetic disorders

• Socioeconomically stable family residing in modern housing (lead exposure excluded)

Birth and development

• Both children: Full-term, uncomplicated deliveries

• Normal growth and development

• Up-to-date immunizations

• No history of trauma, surgery, or significant illness prior to current presentation

Environmental exposure assessment

Both children resided in the same household with no identified exposure to lead, mold, chemicals, or environmental toxins. No shared exposure to animals or construction materials was identified. Water and air quality concerns were excluded based on residential assessment.

Diagnostic approach and differential diagnosis (Table 2)

Table 2.

Systematic differential diagnosis exclusion

Category	Key conditions considered	Diagnostic tests performed	Results	Conclusion
Hematological	ALL, AML, Lymphoma	CBC, bone marrow, flow cytometry	Normal	Excluded
Infectious	Osteomyelitis, septic arthritis	Cultures, serology, imaging	Negative	Excluded
Rheumatological	JIA, SLE, vasculitis	ANA, RF, inflammatory markers, ANCA	Negative	Excluded
Neurological	GBS, neuropathy, MS	NCS, EMG, MRI	Normal	Excluded
Metabolic	Vitamin deficiency, endocrine	Vitamin levels, thyroid function	Mild vitamin D deficiency	Treated
Environmental	Toxins, shared infectious agents	Environmental history, cultures	No obvious shared exposures	Consider viral triggers

Given the severity and familial clustering of symptoms, a systematic diagnostic approach was essential to exclude life-threatening conditions and establish the correct diagnosis.

Phase 1: Initial assessment and red flag exclusion primary concerns

1. Hematological malignancy (the most common cause of bone pain in children)

2. Infectious conditions (osteomyelitis, septic arthritis)

3. Autoimmune/inflammatory conditions (juvenile arthritis, vasculitis)

4. Genetic/metabolic disorders (given familial occurrence)

5. Environmental toxins or shared infectious agents

Phase 2: Systematic investigation

Hematological and oncological work up

Laboratory results (Table 3)

Table 3.

Laboratory results

Parameter	Patient 1 result	Patient 2 result	Reference range	Interpretation
WBC	9.68 × 10⁹/L	8.2 × 10⁹/L	4.5–11.0 × 10⁹/L	Normal
Hemoglobin	12.0 g/dL	11.8 g/dL	12–16 g/dL	Normal
Platelets	520 × 10⁹/L	480 × 10⁹/L	150–450 × 10⁹/L	Elevated—reactive thrombocytosis
ANC	7.26 × 10⁹/L	6.8 × 10⁹/L	2.5–6.0 × 10⁹/L	Normal
ESR	22 mm/h	18 mm/h	0–10 mm/h	Mildly elevated
CRP	14.3 mg/L	11.2 mg/L	<8 mg/L	Mildly elevated
ALT	111 U/L	Normal	0–55 U/L	Mildly elevated
Vitamin D	51.3 nmol/L	Normal	>50 nmol/L	Borderline low—supplemented
Iron	2.2 mcg/dL	Normal	50–120 mcg/dL	Low—iron deficiency; oral iron supplementation initiated
EBV IgG	Positive	Positive	Negative	Past exposure only (IgM negative)
Bone marrow	Normal cellularity	Not performed. Not indicated—CBC and clinical picture reassuring by time of Patient 2 evaluation	Normal	Malignancy excluded

• Complete Blood Count:

• WBC: 9.68 × 10⁹/L (normal: 4.5–11.0)

• Hemoglobin: 12 g/dL (normal: 12–16)

• Platelets: 520 × 10⁹/L (elevated, normal: 150–450)

• ANC: 7.26 × 10⁹/L (normal: 2.5–6.0)

Interpretation: Reactive thrombocytosis consistent with chronic pain/inflammation; no evidence of leukemia or bone marrow infiltration.

Bone marrow examination

• Normal cellularity

• No malignant cells

• Normal maturation of all cell lines

Conclusion: Hematological malignancy excluded

Infectious disease workup

Cultures and serology

• Blood cultures: Negative (×3 sets)

• Urine culture: Negative

• Throat culture: Negative

• Stool culture and parasites: Negative

• Viral serology:

  • EBV IgG: Positive
  • EBV IgM: Negative
  • CMV IgG: Negative
  • CMV IgM: Negative
  • Parvovirus B19: Negative
• Bacterial serology:

  • Brucella: Negative
  • Mycoplasma: Negative

Interpretation: Positive EBV IgG with negative IgM indicates previous viral exposure in both children (consistent with normal childhood viral exposure patterns). While common in the pediatric population, this finding may represent a potential environmental trigger in genetically susceptible individuals. No evidence of acute infection. IgG seropositivity is present in 60–80% of children this age and is, therefore, non-specific; however, in the context of tight temporal clustering and shared household exposure, past EBV infection warrants consideration as a possible environmental precipitant in genetically susceptible individuals. No evidence of acute infection in either patient.

Autoimmune and inflammatory workup

Laboratory results

Inflammatory markers

• ESR: 22 mm/h (normal: 0–10)

• CRP: 14.3 mg/L (normal: <8)

Autoimmune markers

• ANA: Negative

• RF: Negative

• Anti-Cyclic citrullinated Peptide antibodies: Negative

• Complement (C3, C4): Normal

• Advanced vasculitis screening

• ANCA: Negative

• Anti-dsDNA: Negative

• Anti-cardiolipin antibodies: Negative

Interpretation: Mild elevation in inflammatory markers consistent with a chronic pain condition; comprehensive vasculitis workup negative, excluding systemic autoimmune conditions.

Metabolic and endocrine workup

Laboratory results

• Thyroid function: Normal TSH, T4

• Vitamin levels:

  • Vitamin D: 51.3 nmol/L (borderline low)
  • Vitamin B12: Normal
• Metabolic panel:

  • Glucose: Normal
  • Electrolytes: Normal
  • Liver function: Mildly elevated ALT (111 U/L); repeated at 6-week follow-up and normalized without specific intervention, attributed to acute pain stress response
  • Kidney function: Normal

Interpretation: No evidence of metabolic disorder; mild vitamin D deficiency and iron deficiency (Patient 1) addressed with oral supplementation; both normalized at 3-month follow-up.

Genetic considerations

Family pedigree analysis

• Three-generation pedigree constructed

• No family history of chronic pain syndromes

• No consanguinity

Genetic testing limitation

Comprehensive genetic testing was not performed due to resource limitations and institutional constraints. However, future whole-exome sequencing has been recommended to the family to identify potential susceptibility variants.

Imaging and specialized studies

Neuroimaging

MRI brain with gadolinium (Fig. 1)

Fig. 1.

MRI of the brain and the pituitary gland with IV gadolinium

• Normal brain parenchyma

• No evidence of demyelination, tumor, or inflammation

• Conclusion: Central nervous system pathology excluded

MRI spine (Fig. 2)

Fig. 2.

MRI whole spine without IV gadolinium

• Normal cord signal and morphology

• No evidence of transverse myelitis or spinal tumor

Conclusion: Spinal pathology excluded

Musculoskeletal imaging

MRI lower extremities with contrast (Figs. 3, 4)

Fig. 3.

Multi-sequential multiplanar MRI of the lower extremities, including thighs and legs, with contrast administration

Fig. 4.

Multi-sequential multiplanar MRI of the lower extremities, including thighs and legs, with contrast administration

• Normal bone marrow signal

• No evidence of osteomyelitis

• No joint effusion or synovitis

Conclusion: Infectious and inflammatory bone/joint disease was excluded

Skeletal survey

• Suspicious lytic lesion in the right parietal bone

• Follow-up CT: Poorly visualized, likely artifact

Conclusion: No evidence of metastatic disease

Neurophysiological studies

Nerve conduction studies

• Normal motor and sensory conduction velocities

• No evidence of peripheral neuropathy

• Electromyography: Limited cooperation, but no active denervation

Interpretation: Large fiber peripheral neuropathy excluded.

Treatment and management

Multidisciplinary team approach specialties involved

• Pediatric Neurology

• Rheumatology

• Oncology

• Nephrology (for hypertension)

• Psychology/Psychiatry

• Physical Therapy

• Pain Management

Treatment protocol

Phase 1: Initial management

Patient 1

1. Gabapentin: Started at 100 mg BID, titrated to 200 mg TID

2. Supportive care: Gentle physical therapy, psychological support

3. Antihypertensive: For pain-related hypertension

Response: Partial improvement in pain scores (8/10 to 6/10).

Phase 2: Advanced therapy

Intravenous immunoglobulin (IVIG)

• Rationale: Suspected autoimmune component based on clinical presentation and response pattern

• Dosing: 1 g/kg/day for 5 days (Patient 1); 2 g/kg as a single dose per cycle × 2 cycles (Patient 2)

• Monitoring: Vital signs, renal function, hemolysis markers

Response: Dramatic improvement in both patients.

• Pain scores decreased to 2–3/10

• Improved function and mobility

• Normalized blood pressure

• Restoration of normal activities

Phase 3: Maintenance and follow-up

Long-term management

• Gabapentin 200mg TID (both patients)

• Vitamin D supplementation

• Regular physical therapy

• Psychological support

• Gradual activity increase

Treatment outcomes timeline (Table 4)

Table 4.

Treatment response timeline

Timepoint	Patient 1 pain score	Patient 2 pain score	Functional status	Medications
Baseline	8–10/10	7–9/10	Severe impairment	None
Week 2	6–7/10	5–6/10	Moderate impairment	Gabapentin
Week 4	4–5/10	4–5/10	Mild impairment	Gabapentin + IVIG
Week 8	2–3/10	2–3/10	Minimal impairment	Gabapentin
Month 3	0–2/10	0–2/10	Normal function	Gabapentin (reduced)
Month 6	0–1/10	0–1/10	Normal function	Gabapentin (minimal)
Month 18	0–1/10	0–1/10	Sustained normal function	Gabapentin minimal

WBC white blood cell, ANC absolute neutrophil count, ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, JIA juvenile idiopathic arthritis, SLE systemic lupus erythematosus, GBS Guillain–Barré syndrome, NCS nerve conduction study, EMG electromyography, ROM range of motion, IVIG intravenous immunoglobulin

Both patients are pain-free during activities of daily living, with normal school attendance, full range of motion restored, normal sleep patterns, and no medication side effects.

Discussion

Significance of environmental–genetic interaction

This case represents the first reported occurrence of CRPS in pediatric siblings, demonstrating the complex interplay between environmental triggers and genetic susceptibility. Critically, the tight temporal clustering (within a 20-day interval) strongly suggests shared environmental exposure in genetically predisposed individuals, rather than purely hereditary factors [7, 8].

Environmental vs. genetic factors: The 20-day interval between symptom onset in siblings is highly suggestive of a shared environmental trigger acting upon genetically susceptible individuals. This temporal pattern argues against pure genetic inheritance and supports a "two-hit" hypothesis where:

1. Genetic predisposition provides susceptibility

2. Environmental trigger precipitates disease onset

This model is consistent with other autoimmune and inflammatory conditions, where genetic susceptibility alone is insufficient for disease development [7].

Genetic implications

Recent molecular studies have identified several genetic variants associated with CRPS risk [7]:

• HLA-DQ8 haplotype: Associated with increased CRPS susceptibility [7]

• SCN9A gene mutations: Affect sodium channels and pain perception [7]

• CACNA1C variants: Influence calcium channel function [7]

• TNF-α polymorphisms: Modulate inflammatory response [7]

CRPS pathophysiology and antigen targets

Current evidence suggests CRPS involves autoimmune mechanisms targeting specific antigens [8]:

• β2-Adrenergic receptors: Autoantibodies identified in CRPS patients.

• Muscarinic-2 receptors: Associated with autonomic dysfunction

• Peripheral nerve antigens: May trigger molecular mimicry responses

• Sympathetic nerve terminals: Potential targets of autoimmune attack

The dramatic response to IVIG in our patients supports this autoimmune hypothesis, as IVIG can neutralize pathogenic autoantibodies and modulate immune responses [6].

Diagnostic challenges in pediatric CRPS

Challenges encountered

1. Age-related factors: CRPS is extremely rare in this age group [1]

2. Limited cooperation: Difficult neurological examination.

3. Extensive differential: Multiple serious conditions to exclude.

4. Environmental vs. genetic factors: Determining relative contributions.

Systematic approach benefits

1. Comprehensive exclusion: Ruled out life-threatening conditions.

2. Evidence-based diagnosis: Met established criteria [4]

3. Appropriate treatment: Targeted therapy based on diagnosis.

4. Family reassurance: Thorough investigation provided confidence.

Cost-effectiveness analysis

Diagnostic costs: The extensive workup required approximately $15,000 per patient, SAR 56,000 approximately, including:

• Laboratory studies: $3000

• Imaging studies: $8000

• Specialized procedures: $4000

Cost-effectiveness justification: This systematic approach was cost-effective in preventing:

• Long-term disability costs (estimated >$50,000 annually > SAR 188,000 (USD 50,000) annually per patient for chronic pain management)

• Unnecessary procedures and treatments

• Early, accurate diagnosis allowed for targeted therapy, preventing potential chronic complications

Novel treatment approach

IVIG Therapy in Pediatric CRPS: The dramatic response to IVIG in both patients suggests a potential autoimmune component [6]. This finding is significant, because:

1. Mechanism: IVIG may neutralize pathogenic autoantibodies targeting adrenergic and muscarinic receptors [6, 8]

2. Pediatric efficacy: Limited data on IVIG use in pediatric CRPS [8, 9]

3. Familial response: Both siblings responded similarly, supporting shared pathophysiology

4. Early intervention: Treatment within 3 months of onset may prevent chronicity.

Pathophysiological insights

Autonomic dysfunction: Both patients demonstrated significant autonomic changes consistent with sympathetic nervous system involvement:

• Hypertension and tachycardia

• Temperature dysregulation

• Sudomotor dysfunction

• Skin color changes

Laboratory findings: The positive EBV IgG serology in both patients, while common in the pediatric population, may represent a potential environmental trigger through molecular mimicry mechanisms. EBV has been associated with various autoimmune conditions and could potentially trigger cross-reactive immune responses in genetically susceptible individuals [7, 8]. It should be noted, however, that EBV IgG seropositivity is present in 60–80% of children in this age group and, therefore, represents a non-specific finding; causality cannot be established from serology alone.

Clinical implication

For pediatric practice

1. Awareness: Consider CRPS in severe, unexplained extremity pain [1, 2]

2. Family history: Assess for both genetic and environmental factors [7]

3. Environmental assessment: Investigate shared exposures in familial cases

4. Early treatment: Aggressive management may prevent chronicity [5, 8, 9]

5. Multidisciplinary care: Multiple specialties often required [2, 3]

For CRPS research

1. Genetic studies: Family-based genetic analysis combined with environmental assessment [7]

2. Treatment protocols: IVIG efficacy in pediatric CRPS requires controlled studies [6, 8, 9]

3. Pathophysiology: Environmental triggers and autoimmune mechanisms warrant investigation [7, 8]

4. Outcomes: Long-term follow-up of pediatric cases needed [1, 8, 9]

Study limitations

Diagnostic limitations

1. Genetic testing: Not performed due to resource constraints—this represents a significant limitation given the familial nature.

2. Autoantibody testing: Specific CRPS-associated autoantibodies are not measured

3. Small fiber neuropathy: Skin biopsy not performed.

Treatment limitations

1. Small sample: Only two patients treated.

2. Follow-up: Relatively short follow-up period (current 18-month follow-up shows sustained remission).

3. Controls: No comparison group for treatment efficacy.

Future directions

1. Integrated genetic–environmental analysis: Whole-genome sequencing combined with comprehensive environmental exposure assessment

2. Autoantibody profiling: Measurement of CRPS-specific autoantibodies

3. Treatment optimization: Randomized controlled trials of IVIG in pediatric CRPS

4. Long-term outcomes: Extended follow-up with functional assessments

Conclusions

This case report describes the first documented occurrence of familial CRPS in pediatric siblings, highlighting several important clinical and research implications:

1. Diagnostic excellence: Systematic evaluation of pediatric extremity pain requires a comprehensive differential diagnosis and evidence-based exclusion of alternative conditions

2. Environmental–genetic interaction: The tight temporal clustering (20-day interval) demonstrates that environmental triggers likely precipitate CRPS in genetically susceptible individuals, challenging purely hereditary models.

3. Treatment innovation: The dramatic response to IVIG therapy suggests autoimmune mechanisms targeting specific neural antigens and provides a potential new treatment approach for pediatric CRPS.

4. Early intervention: Prompt recognition and aggressive treatment may prevent chronic disability typically associated with CRPS.

5. Multidisciplinary care: Complex pediatric pain conditions require coordinated care from multiple specialties.

Clinical significance: This case demonstrates that CRPS can occur in very young children through environmental–genetic interactions [1, 7]. The favorable response to early treatment with Gabapentin and IVIG suggests that aggressive intervention targeting autoimmune mechanisms in pediatric cases may alter the natural history of this debilitating condition [5, 6].

Research implications: Future studies should focus on integrated genetic–environmental analysis of familial CRPS cases, identification of specific autoantibody targets, development of pediatric-specific diagnostic criteria, and controlled trials of IVIG therapy in pediatric CRPS patients.

Take-home messages:

• Consider CRPS in young children with severe, unexplained extremity pain.

• Assess both genetic susceptibility and environmental triggers in familial cases.

• Temporal clustering suggests environmental precipitation in susceptible individuals

• Systematic exclusion of differential diagnoses is essential.

• Early aggressive treatment, including IVIG, may improve outcomes.

This case contributes to our understanding of CRPS pathophysiology as an environmental–genetic interaction disorder and may guide future research into triggers and targeted therapies for chronic pain disorders in children.

Author contributions

F.A.K. led the clinical and scientific approach and management of the cases, revised, edited, and submitted the case. F.A.K. and D.D. conceptualized the case report. R.S. collected and curated patient data. B.M. performed the literature review and analysis. D.D. wrote the original draft, with critical revisions by F.A.K. All authors reviewed the manuscript, and approved the final version.

Funding

No funding was received for this research.

Data availability

All data supporting the findings of this case report are included within the manuscript and its supplementary files. Original diagnostic images and laboratory reports are available from the corresponding author upon reasonable request, subject to institutional ethics approval and patient confidentiality protections.

Declarations

Ethics approval and consent to participate

This case report was conducted per ethical standards and institutional guidelines. Written informed consent was obtained from both patients' legal guardians for publication of this case report and accompanying medical images. The consent process included a detailed explanation of the case publication purpose, potential risks and benefits, and confirmation of patient anonymity. Copies of signed consent forms are available for editorial review. The family explicitly agreed to publication to advance medical knowledge about this rare condition.

Consent for publication

Written informed consent was obtained from the patients’ legal guardians for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no competing interests.