P2.258: Severe Congenital Neutropenia in a Neonate with an Autosomal Dominant CLPB (Caseinolytic Peptidase B) Deficiency Treated with Allogenic Bone Marrow Transplant.

Introduction: Severe congenital neutropenia is a rare hematological disorder characterized by impaired neutrophil maturation, leading to recurrent, life-threatening infections. We report a neonate with severe congenital neutropenia who was found to have a heterozygous pathogenic CLPB mutation, requiring bone marrow transplantation after failed G-CSF (granulocyte colony-stimulating factor) treatment.

Case Description: We present a male infant born to non-consanguineous parents at 39 weeks via C-section due to category 2 fetal tracing. The pregnancy was complicated by morbid obesity, gestational diabetes, preeclampsia, and transaminitis. The baby was admitted to the NICU with respiratory distress, and had APGAR scores of 5 at 1 minute and 8 at 5 minutes. Initial blood gas results showed metabolic acidosis (pH of 7.3, HCO3 13.2), which responded to a normal saline bolus. The WBC count was 6.26, ANC 0, and CRP was 56. The baby was treated with ampicillin and gentamicin for presumed neonatal sepsis. Blood cultures and CSF studies were negative, and the CRP level trended down, but severe neutropenia persisted. The newborn screen and T-cell subset testing were normal. After two weeks, the baby was discharged on daily amoxicillin prophylaxis. Genetic testing revealed a de novo CLPB mutation (c.1681C>T, p.Arg561Trp), and both parents tested negative for the mutation. G-CSF was administered in incremental doses over six months but remained ineffective. The baby underwent allogenic bone marrow transplantation and is currently receiving immunosuppressive treatment. He is developing well, with no signs of cataracts, seizures, or cardiac anomalies.

Discussion: Severe congenital neutropenia is a rare cause of bone marrow failure, with a prevalence of 5 cases per 1 million individuals. The most commonly characterized genotypes are ELANE- and HAX1-related neutropenias. To date, and to the best of our knowledge, only six individuals have been reported with autosomal dominant CLPB deficiency, carrying the following pathogenic variants: c.1211A>C (p.Lys404Thr), c.1280C>T (p.Pro427Leu), c.1678G>A (p.Gly560Arg), and c.1681C>T (p.Arg561Trp) [1]. CLPB encodes an adenosine triphosphatase involved in protein folding and mitochondrial function. These variants disrupt the refoldase and, to a lesser extent, ATPase activity of CLPB in a dominant-negative manner [1,2]. The mechanisms by which CLPB mutations impair granulocytic differentiation remain unclear. Patients may present with severe recurrent infections and low ANC, often associated with mild to severe syndromic features [3]. Some patients exhibit 3-methylglutaconic aciduria, neurological involvement (such as brain atrophy, myelination deficits, and epilepsy), developmental delays, and cataracts [2,4].

Conclusion: CLPB mutation is a rare cause of severe congenital neutropenia. We report an infant who presented with severe congenital neutropenia and was diagnosed with autosomal dominant CLPB deficiency (c.1681C>T, p.Arg561Trp). The infant showed a poor response to G-CSF treatment and required allogenic bone marrow transplantation.