Neonatal Chronic Granulomatous Disease With Septic Arthritis and Osteomyelitis: Diagnostic and Therapeutic Challenge With Literature Review

Abstract

This case report underlines the diagnostic and therapeutic dilemmas in a 19-day-old neonate who had presented with features suggestive of chronic granulomatous disease (CGD). The baby had a history of fever, lethargy, and masses on the skin, for which an extensive diagnostic workup was needed to rule out infective etiology given no improvement with initial empiric therapy. Laboratory investigations, including imaging and genetic studies, confirmed the diagnosis of CGD. In addition to the very early manifestation of disease, which is quite rare, our case emphasizes the importance of maintaining a high index of suspicion for immunodeficiency disorders in neonates with severe infections. The report highlights the fact that a high level of suspicion for an underlying immunodeficiency, especially conditions like CGD, must be maintained in neonates with unexplained symptoms, and the diagnosis has to be multidisciplinary in terms of management. Considering its rare inflammatory complications in neonatal CGD, the present case adds important data to the pediatric medical literature. It emphasizes that critical clinical evaluation and detailed diagnostic procedures are mandatory in cases of rare neonatal sepsis and inflammatory disorders.

Introduction

Chronic granulomatous disease (CGD) is an uncommon inherited disorder affecting the phagocytic system. It is characterized by a heightened susceptibility to recurrent and severe bacterial and fungal infections; suppurative lymphadenitis, cutaneous abscesses, pneumonia, and diarrhea constitute the most common problems in children with CGD, often resulting in a significant mortality rate. ¹ Although subject to ethnic variation, the incidence of CGD is estimated to be 1 in approximately 200 000 live births. ²

In familial scenarios, diagnosis may precede observable symptoms, including instances during the prenatal period. However, the predominant age range for CGD diagnoses is between 1 and 3 years, marked by the emergence of clinically symptomatic features, particularly recurrent and severe infections impacting the lungs (79%), lymph nodes (53%), liver (27%), and skin (42%). ³

Chronic granulomatous disease is frequently associated with severe infections caused by common pathogens such as Serratia marcescens (pathognomonic for CGD), especially skin or bone infection, Aspergillus species, Staphylococcus aureus, Burkholderia cepacia complex, and Nocardia species, which contribute significantly to the morbidity seen in affected patients. These infections are often severe and may be challenging to treat due to the underlying defect in phagocyte function. Remarkably, CGD can manifest atypically, presenting challenges for early diagnosis, including manifestations such as gastrointestinal mucormycosis, cardiac empyema, or phlebitis, particularly during the neonatal period. ³ Approximately 70% of CGD cases follow an X-linked inheritance pattern, with the remaining 30% exhibiting an autosomal recessive (AR) inheritance.^4,5

This case report emphasizes the importance of early recognition of CGD in neonates, and maintaining a high index of suspicion for immunodeficiency disorders in neonates with severe infections, highlighting a case of a 19-day-old neonate presenting with severe infections consistent with CGD.

Case Presentation

A 19-day-old full-term neonate presented with fever, lethargy, and multiple skin masses that had developed since he was 12 days old. The neonate was delivered by elective cesarean section at 39 weeks gestation. The mother, a 27-year-old primigravida with 1 previous abortion, received comprehensive antenatal care and was treated for premature rupture of membranes during the second trimester with intravenous ceftriaxone. The father, a 25-year-old smoker with insulin-dependent diabetes mellitus, reported no other significant health issues.

Initially, the neonate was in good health. However, at 3 days old, the neonate was admitted for neonatal jaundice, underwent phototherapy, and was subsequently discharged at 5 days old. By day 7, irritability, decreased oral feeding, and low-grade fever were noted. By day 12, small masses had developed on the neonate’s right wrist, right thigh, left wrist, chest, and right cheek. These symptoms were accompanied by persistent fever and lethargy. Despite consulting various private clinics and receiving oral amoxicillin, there was no improvement. By day 17, the neonate developed swelling in the right lower limb and restricted movement. Consequently, on day 19, the neonate was admitted to the neonatal intensive care unit of the Children Welfare Teaching Hospital (CWTH) in Baghdad.

On examination, the neonate appeared lethargic and unwell, with swelling in the right cheek (Figure 1), but with normal fontanels and no dysmorphic features. Vital signs were as follows: temperature 39°C, heart rate 120/min, and respiratory rate 65/min. The weight was 2500 g, with an occipitofrontal circumference of 34 cm and a length of 48 cm. Examination revealed swelling on the right side of the chest, wrists (Figure 2), and right thigh. Cardiothoracic and abdominal examinations were normal, with no organomegaly.

Figure 1.

Neonate with chronic granulomatous disease (CGD) showing swelling in the right cheek at 19 days old.

Figure 2.

Swelling and inflammation of the right wrist in a neonate with chronic granulomatous disease.

Laboratory results showed a white blood cell count of 24 × 10⁹/L with neutrophilic leukocytosis, hemoglobin of 7.3 g/dL, and a platelet count of 222 × 10⁹/L, indicating normochromic anemia. An elevated erythrocyte sedimentation rate of 120 mm/h, C-reactive protein of 48 mg/L, and a leucoerythroblastic picture were seen. Cerebrospinal fluid analysis revealed glucose levels of 73 mg/dL, protein 182 mg/dL, and 31 lymphocytes, with no bacteria seen on Gram stain and no bacterial growth in culture. Routine blood sugar, renal function tests, liver function tests, and urine analysis were within normal limits.

The x-ray shows changes of osteomyelitis in the right hip joint, with hip dislocation due to fluid collection, and osteomyelitis changes in the right elbow affecting the right humerus (Figure 3). Ultrasound of the right hip joint suggested septic arthritis with osteomyelitis, showing dislocation of the femoral head, irregular bone surface, echogenic joint effusion with debris, and a possible abscess. Superficial masses near wrists and temporomandibular joints contained debris, suggesting hematomas or abscesses. Abdominal and cranial ultrasounds were normal.

Figure 3.

X-ray showing osteomyelitis changes in the right hip joint with dislocation due to fluid collection and osteomyelitis changes in the right elbow affecting the right humerus in a neonate with chronic granulomatous disease.

Blood cultures were obtained, and broad-spectrum antibiotics were initiated, including intravenous vancomycin and ceftazidime. Orthopedic and maxillofacial surgical consultations were sought for abscess drainage. Cultures from the aspirates showed growth of S aureus and Pseudomonas aeruginosa from the hip joint. Antibiotics were adjusted based on culture and sensitivity results to intravenous Garamycin and Tazocin. Although the fever subsided and general activity improved, the swelling and movement limitation in the right hip persisted. Repeat imaging indicated a recurrent joint abscess requiring further surgical intervention.

The cause of repeated abscesses prompted a comprehensive investigation, including the nitroblue tetrazolium test with a result of 1% (normal range 2%-17%) and the dihydrorhodamine test (DHR) with a result of 63 (normal range >73 Neutrophil Oxidative Index (NOI)). A diagnosis of CGD was suspected and further confirmed with whole exome sequencing (WES). The genetic analysis confirmed the diagnosis of the CGD.

Discussion

Chronic granulomatous disease is a rare primary immunodeficiency characterized by recurrent infection and inflammation. A defect in the phagocyte NADPH oxidase complex causes CGD. The DHR assay is a powerful and efficient tool for diagnosing and assessing CGD’s severity. The DHR flow cytometry and genetic sequencing will allow the clinical treatment strategy to include hematopoietic stem cell transplantation. ⁶ In our case, the neonate presented with very early manifestations, developing multiple skin masses by day 12. This makes it a very unusual and rare case of CGD due to the early age at presentation. The early onset of fever and lethargy, starting at 7 days old, is remarkable for CGD, as it usually occurs later in infancy or childhood.^7,8 This reiterates the need for increased vigilance in neonates with unexplained features. The presentation with skin abscesses and osteomyelitis is not uncommon manifestations of CGD but early manifestation of infection in this neonate (<1 month of age) was unusual.

The fact that the infections were severe and poorly responsive to antibiotics despite aggressive therapy underscores the importance of considering an underlying immunodeficiency. In CGD, impaired phagocytic function leads to difficulty clearing infections, resulting in persistent and recurrent infections despite appropriate antibiotic treatment. The diagnosis in this case shows the complexity and the challenges of diagnosing rare immunodeficiencies in neonates. Initial nonspecific symptoms, such as fever and lethargy, later culminated into alarming symptoms, such as masses over the skin and joint swellings, all necessitating a thorough investigative approach.

It is important to also note that, in sharp contrast to the predominant X-linked mutations usually detected in patients with early manifestations of CGD, our patient has an AR mutation.^9,10 This aspect of our case adds to the growing knowledge concerning the genetic spectrum and its clinical phenotypic expression in CGD. It underlines the importance of AR mutations in this disease process. Important takeaways for the clinician from this case include consideration of an underlying immunodeficiency in atypical presentations of neonates with infections, the pivotal role of advanced imaging and genetic testing in the diagnostic process, and that complex cases involving neonates require a multidisciplinary approach. It also stresses that in neonates with atypical presentations, early recognition, complete evaluation, and aggressive management strategies are needed to enrich the pediatric literature about awareness of these rare immunodeficiencies like CGD, whose presentation was neonatal in the setting of sepsis and inflammatory conditions.

Conclusion

This early manifestation of CGD highlights the importance of early and accurate diagnosis. The early manifestation of his symptoms and unusual presentation with septic arthritis and osteomyelitis of his right hip joint, in addition to osteomyelitis of the right elbow joint, represent the clinical complexities seen in CGD. This further demonstrates the varied disease presentation and difficulty in management, stressing the importance of individualized treatment plans. This report adds knowledge to the pool of CGD cases, especially in a neonatal presentation. It further emphasizes that clinical awareness has to be raised to manage such rare and complex cases with a multidisciplinary approach.