A Young Boy's Recurrent Fevers Reveal Rare Genetic Immune Condition

Table of Contents

• Background: Why This Case Matters
• Case Presentation: The Boy's Symptoms
• Diagnostic Journey: Testing and Findings
• Possible Conditions Considered
• Final Diagnosis and Genetic Cause
• What This Means for Patients
• Limitations of This Case
• Recommendations for Families
• Source Information

Background: Why This Case Matters

This medical case illustrates how recurrent fevers in children can sometimes signal rare genetic conditions rather than common infections. When fevers persist for weeks without clear cause, they may represent what doctors call "fever of unknown origin" - a temperature exceeding 38.3°C (101°F) daily for more than 8 days without diagnosis.

For parents, understanding that persistent symptoms warrant thorough investigation is crucial. This case demonstrates how family medical history can provide vital clues and how advanced genetic testing can reveal inherited immune deficiencies that make children vulnerable to unusual infections.

Case Presentation: The Boy's Symptoms

A 30-month-old boy was admitted to Massachusetts General Hospital for the third time in 4 weeks due to recurrent fever. His symptoms began 4 weeks earlier with fever, dry cough, nasal congestion, and reduced solid food intake. The next day, he developed limping without any trauma.

During his first emergency department visit, he had no fever but appeared tired and walked with a limp favoring his left leg. His initial blood tests showed concerning results:

• White blood cell count: 28,440 per microliter (normal: 4,500-11,000)
• Erythrocyte sedimentation rate: 63 mm per hour (normal: 0-14)
• C-reactive protein: 31.3 mg per liter (normal: 0.0-8.0)

He was admitted but discharged after two days when his fever resolved and blood cultures showed no growth. However, fever returned two days later, leading to a second hospitalization with persistent abnormal blood results.

Diagnostic Journey: Testing and Findings

Doctors performed multiple imaging studies over three hospital admissions:

First admission: Chest X-ray showed peribronchial cuffing and patchy perihilar opacities (lung abnormalities). Hip ultrasound and pelvis X-ray were normal.

Second admission: Abdominal ultrasound revealed multiple hypoechoic (dark) splenic lesions up to 6 mm in diameter. Chest CT scan showed mediastinal lymphadenopathy (enlarged lymph nodes in the chest).

Third admission: The boy presented with fever reaching 40.2°C (104.4°F), rapid heart rate (180 beats/minute), rapid breathing (55 breaths/minute), and low oxygen saturation (88% on room air). Chest CT showed worsening multifocal pulmonary opacities with basilar predominance in both lungs.

Laboratory values progressively worsened over the three admissions:

• White blood cell count increased from 28,440 to 42,390 per microliter
• Hemoglobin decreased from 9.7 to 7.7 g/dL (normal: 10.5-13.5)
• C-reactive protein increased from 31.3 to 107.9 mg/L
• Erythrocyte sedimentation rate increased from 63 to 78 mm/hour
• Lactate dehydrogenase increased to 3443 U/L (normal: 110-295)

Possible Conditions Considered

Doctors considered several possible explanations for the persistent fever and symptoms:

Systemic Juvenile Idiopathic Arthritis (JIA): This inflammatory condition typically affects children 1-5 years old and can cause daily fevers, arthritis, rash, and elevated inflammatory markers. However, the lung findings were not typical for JIA.

Kawasaki's Disease: This vascular inflammatory condition causes fever and lymph node swelling but typically includes characteristic mouth, eye, and skin changes that this patient lacked.

Infections: Given the prolonged course, doctors considered atypical bacterial, mycobacterial, viral, or fungal infections. The patient tested positive for common coronaviruses and rhinovirus/enterovirus, but these were likely coincidental findings.

Inborn Errors of Immunity: The family history revealed that an older brother had been diagnosed with disseminated Mycobacterium avium complex infection at 31 months of age. This suggested a possible genetic immune deficiency that might run in the family.

Final Diagnosis and Genetic Cause

Doctors performed a lymph node biopsy which revealed acid-fast bacilli (a characteristic of mycobacteria). Cultures from multiple sites eventually grew Mycobacterium kansasii, confirming disseminated mycobacterial infection.

Given the family history and unusual infection, genetic testing was performed. The patient's older brother had previously been diagnosed with mendelian susceptibility to mycobacterial disease (MSMD) caused by homozygous pathogenic mutations in the IFNGR2 gene, which encodes subunit 2 of the interferon-γ receptor.

This genetic disorder impairs the immune system's ability to fight certain infections, particularly mycobacteria. Patients with MSMD can develop serious infections from weakly virulent environmental organisms that don't typically cause disease in people with normal immune systems.

The patient was diagnosed with the same condition as his brother - autosomal recessive complete IFNGR2 deficiency. This meant he inherited two defective copies of the gene (one from each parent), resulting in complete absence of functional interferon-γ receptor 2 protein.

What This Means for Patients

This case demonstrates several important points for patients and families:

First, persistent fevers lasting more than 8 days without clear explanation warrant thorough medical evaluation. The pattern of "fever of unknown origin" can signal serious underlying conditions.

Second, family medical history is crucial. The brother's history of unusual infection provided the key clue to diagnosing this genetic condition. Families should always share complete medical histories with healthcare providers.

Third, rare genetic immune deficiencies can present with recurrent or unusual infections. Mendelian susceptibility to mycobacterial disease (MSMD) encompasses a group of disorders that impair interferon-γ immunity, making patients vulnerable to mycobacterial infections.

Fourth, diagnosis requires specialized testing. This case involved multiple imaging studies, biopsies, cultures, and ultimately genetic testing to identify the underlying cause.

Limitations of This Case

While this case provides valuable insights, several limitations should be noted:

This represents a single case study, and findings may not apply to all patients with similar symptoms. The genetic mutation identified is rare, and most children with recurrent fevers do not have this condition.

The diagnosis was facilitated by the known family history, which may not be available in all cases. Without this clue, diagnosis might have been delayed further.

The article doesn't provide long-term follow-up information about treatment response and outcomes for this specific patient.

Recommendations for Families

Based on this case, families should:

1. Track symptoms carefully: Record fever patterns, associated symptoms, and response to medications
2. Share complete family history: Inform doctors about any unusual infections or medical conditions in close relatives
3. Persist with evaluation: When symptoms continue without explanation, seek referral to specialists if needed
4. Consider genetic counseling: Families with history of unusual infections may benefit from genetic evaluation and counseling
5. Ask about immune testing: For recurrent, severe, or unusual infections, inquire about possible immune system evaluation

Source Information

Original Article Title: Case 39-2024: A 30-Month-Old Boy with Recurrent Fever

Authors: Alicia Casey, M.D., Vandana L. Madhavan, M.D., M.P.H., Evan J. Zucker, M.D., and Jocelyn R. Farmer, M.D., Ph.D.

Publication: The New England Journal of Medicine, December 12, 2024;391:2256-65

DOI: 10.1056/NEJMcpc2402490

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine. It preserves all significant medical findings, data points, and clinical details from the original case study while making the information accessible to patients and families.