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SynopsisKostmann syndrome is an autosomal recessively inherited severe congenital neutropenia (SCN) characterized by arrest of neutrophil differentiation, persistently low neutrophil counts (absolute neutrophil count [ANC] < 0.5 x 109/L), and increased susceptibility to bacterial infections starting in the neonatal period.
Kostmann syndrome is due to mutations in the HCLS1-associated protein X-1 (HAX1) gene. Two HAX1 splice isoforms have been identified. Mutations in one HAX1 isoform have been associated with SCN, while mutations in both isoforms are associated with SCN and neurologic symptoms, including developmental delay and epileptic seizures.
SCN is rare, with a prevalence of 3-8.5 cases per million. It is estimated that one-third of patients with SCN carry the HAX1 homozygous mutation. Fewer than 100 cases of Kostmann syndrome have been reported worldwide. These were primarily in consanguineous families in the Middle East (Turkey, Iran), Europe (Sweden, Britain, Italy), and Japan. No cases have been reported in the United States.
The syndrome presents in the neonatal period with high fevers, omphalitis, sinopulmonary infections, gingivitis, otitis, and mastoiditis. Subsequently, infants may develop cellulitis or multiple deep tissue abscesses from staphylococci and streptococci, and periodontitis.
Prior to the advent of antibiotics and granulocyte colony-stimulating factor (G-CSF) therapy, the mortality rate of patients with SCN was > 90% from severe bacterial infections, most before the age of 1. With G-CSF therapy, overall survival is now 90% with most patients reaching adulthood, and only 10% of patient dying from sepsis, myelodysplastic syndrome, or acute myeloid leukemia.
D70.0 – Congenital agranulocytosis
89655007 – Congenital neutropenia
Differential Diagnosis & Pitfalls
- Autosomal dominant SCN – Due to neutrophil elastase (ELANE) gene mutation; also G6PC and GFI13 gene mutations. Clinically similar to Kostmann syndrome.
- Wiskott-Aldrich syndrome – X-linked recessive (WAS) gene.
- Chediak-Higashi syndrome – Oculocutaneous albinism, progressive peripheral neuropathy, and neutropenia.
- Shwachman-Diamond syndrome – Triad of neutropenia, metaphyseal dysplasia, and pancreatic insufficiency.
- WHIM syndrome – Warts, hypogammaglobulinemia, infections, myelokathexis (with retention of mature neutrophils in the bone marrow).
- MonoMAC (GATA2 haploinsufficiency) syndrome – Mild chronic neutropenia and recurrent mycobacterial infections.
- Cyclic neutropenia – Usually less severe.
- Glycogen storage disease type 1b (von Gierke disease) – Some types are associated with neutropenia and infectious complications.
- Barth syndrome – Neutropenia, shortness of breath, and symptoms of heart failure.