Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by intra-alveolar surfactant accumulation due to defective macrophage clearance [1]. Although autoimmune PAP is the most common form, secondary PAP (accounting for <10% of cases) is often associated with hematologic malignancies or immunodeficiencies that impair macrophage maturation. We report a case of PAP secondary to MonoMAC syndrome in a patient carrying a previously undescribed germline GATA2 mutation.

A 23-year-old woman presented with progressive exertional dyspnea and cough. Her medical history included idiopathic erythema nodosum, chronic anemia, and a prior tubo-ovarian abscess. Physical examination revealed fine inspiratory crackles and oxygen saturation of 93% on room air. Pulmonary function tests showed a mild restrictive defect (FVC, 70%; FEV1, 76%) and a markedly reduced diffusing capacity (34%). High-resolution computed tomography (HRCT) demonstrated diffuse bilateral ground-glass opacities with a crazy-paving pattern (Fig. 1A).

Fig. 1.

(A) High-resolution chest CT showing bilateral ground-glass opacities with a crazy-paving pattern before HSCT. (B) Complete radiological resolution 2 months after hematopoietic stem cell transplantation.

Bronchoalveolar lavage yielded milky fluid positive for periodic acid-Schiff (PAS) material, and transbronchial biopsy confirmed PAP. Further evaluation included a 6-minute walk test showing significant desaturation to 89%. Extensive testing for surfactant protein mutations and anti-GM-CSF antibodies was negative. However, complete blood count revealed severe monocytopenia and lymphopenia. Peripheral blood immunophenotyping confirmed complete absence of monocytes and reduced B-cell and natural killer cell counts. Genetic sequencing identified a novel heterozygous germline mutation in GATA2: c.1124T>A (p.Leu375His). Bone marrow biopsy showed hypocellularity and trilineage dysplasia, while cytogenetic analysis revealed mosaic trisomy 8. These findings established the diagnosis of low-risk myelodysplastic syndrome (MDS) associated with GATA2 deficiency. The same mutation was also identified in the patient's asymptomatic father.

The patient initially underwent 2 sessions of whole-lung lavage (WLL), which led to clinical improvement and an increase in diffusing capacity to 56%, although radiological improvement was limited. Given the underlying hematologic defect, she was referred for allogeneic hematopoietic stem cell transplantation (HSCT). She received peripheral blood stem cells from a matched unrelated donor following a myeloablative conditioning regimen with busulfan and fludarabine. The post-transplant course was complicated only by mild cutaneous graft-versus-host disease and transient hemorrhagic cystitis. Remarkably, 2 months after HSCT, chest CT showed complete resolution of the parenchymal abnormalities (Fig. 1B).

Secondary PAP remains a therapeutic challenge. Although WLL is the standard treatment for symptomatic relief, it does not correct the underlying macrophage lineage defect in genetic or hematologic disorders [2]. In GATA2 deficiency, HSCT is usually indicated for bone marrow failure or MDS [3]. This case illustrates that HSCT may also be curative for severe pulmonary involvement, provided it is performed before irreversible fibrosis develops [4,5]. Our findings highlight the importance of recognizing PAP as a possible manifestation of MonoMAC syndrome and describe a novel likely pathogenic GATA2 variant.