Purpose

This case report is the first to describe the treatment approach and clinical outcomes in a newly identified FILS syndrome patient.

Introduction

Facial dysmorphism, Immunodeficiency, Livedo, and Short stature (FILS) syndrome is a rare autosomal recessive disorder caused by POLE1 mutations affecting polymerase epsilon (Polε). Reported in 16 patients from three kindreds, FILS is a combined immunodeficiency syndrome typically presenting with normal T, B, and NK cell counts, though some exhibit lymphopenia, low memory B cells, and impaired vaccine responses. Recurrent bacterial respiratory infections are the most common clinical manifestation.

Case Presentation

A 3-year-old boy of Arabic descent, born to consanguineous parents, presented with dysmorphic features and skeletal abnormalities. By 13 months, he developed chronic diarrhea, failure to thrive, recurrent infections, and breakthrough varicella post-vaccination accompanied by a persistent nodular rash. Whole-exome sequencing at 14 months identified a homozygous POLE1 splice variant (c.4444 + 3A > G).

At 24 months, he was hospitalized with septic shock, mucositis, hepatitis, and pneumonia. Despite normal B, T, and NK cell counts, he exhibited reduced memory B and T cells with impaired vaccine responses. Treatment with antibiotics, Granulocyte colony-stimulating factor, and intravenous immunoglobulin (IVIG) resolved hepatitis and pancytopenia, and prophylactic therapy was initiated. Despite ongoing management, he continued to experience recurrent respiratory infections and developed bronchiectasis. Monthly IVIG administration was introduced, resulting in encouraging clinical improvement over six months.

Discussion

This case describes a patient with FILS syndrome presenting with severe immune dysfunction and reduced memory B and T cells. Monthly IVIG therapy resulted in clinical improvement. However, given the combined immunodeficiency nature of FILS syndrome and the association of POLE1 mutations with mismatch repair deficiencies, careful evaluation of hematopoietic stem cell transplantation (HSCT) and its conditioning regimens is crucial.

Conclusion

IVIG therapy appears to be a safe and effective short-to-medium-term FILS syndrome treatment. HSCT remains a potential curative approach, though risks related to POLE1-associated DNA repair defects must be carefully managed.