Kostmann syndrome is a condition also known as severe congenital neutropenia. It has multiple genetic etiologies, the earliest described being autosomal recessive. Patients present with severe infections early in life.
Kostmann syndrome (KS) is named after Rolf Kostmann, who reported a condition he described as infantile agranulocytosis in 1956 and it was later termed as KS [1]. The ailment that Kostmann described is autosomal recessive. Since then, it has been discovered that KS is a genetically heterogeneous set of disease conditions, and thus the more commonly used term is severe congenital neutropenia (SCN). Modes of inheritance include autosomal dominant, autosomal recessive, X-linked, and a number of cases are sporadic. It is a rare disorder that affects both males and females in equal proportions.
Gene mutations include the gene encoding neutrophil elastase (ELA2) (the most frequent cause of SCN), colony stimulating factor 3 receptor (CSF3R) gene, and the HS1-associated protein X1 (HAX1) gene (responsible for autosomal recessive KS) [2] [3]. The same genes can be affected by different mutations, hence the varying presentation and treatment outcomes [4].
Affected individuals suffer from a wide range of opportunistic infections at a young age, ranging from minor infections to fatal illness. Examples include gingivitis, otitis media, upper respiratory tract infections, liver abscesses, various skin infections, omphalitis, and fever. Many of these infections are bacterial, although other organisms have been identified, such as fungi. The most common bacteria cultured are the Streptococcus and Staphylococcus species.
Congenital neutropenias represent a group of disorders, usually characterized by a low neutrophil count. Other features may be present, to varying degrees, depending on the genetic origin of the illness. SCN often involves failure of neutrophils to reach maturation in the bone marrow as well [5] [6]. The autosomal recessive form of KS is characterized by a more marked neutropenia than the other variants [7]. KS may be present as a part of another disorder, such as Fanconi pancytopenic syndrome or Chediak-Higashi syndrome.
A long-term complication of KS is the higher incidence of myelodysplastic syndrome (MDS) and leukemia (acute myeloid leukemia in particular), among those affected [5] [8]. The prognosis is often poor. Furthermore, the mutation in the HAX1 gene is associated with neurological impairment, manifesting as epilepsy, as well as cognitive and developmental delay [9].
The diagnosis of Kostmann syndrome is made when blood results drawn from successive differential counts, reveal an absolute neutrophil count (ANC) below 500 cells per microliter. Bone marrow analysis showing numerous immature promyelocytes also supports the diagnosis [5] [6] [10]. Furthermore, the bone marrow biopsy may show decreased cellularity and is important in ruling out possible malignancies [11]. Autosomal recessive KS, as described by Kostmann, has a neutrophil count less than 200 cells per microliter [7] [12].
Other features that might be present in the full blood count are anemia, in addition to elevated levels of platelets, monocytes, and eosinophils. The total white cell count remains within the average range, while the immunoglobulin G (IgG) is high. Other chemical parameters are usually normal, and patients respond normally to vaccinations. However, antinuclear antibodies (ANA) may be high if the underlying cause is autoimmune.
Genetic testing may also be conducted, in order to delineate the specific genetic mutation. Imaging modalities are sometimes used, and these include: