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].

• Recurrent Bacterial Infection

  bacterial infections (e.g. otitis media, pneumonia, sinusitis, urinary tract infections, abscesses of skin and/or liver) and increased promyelocytes in the bone marrow. [orpha.net]

  Abstract Kostmann syndrome (KS) is an autosomal recessive disorder characterized by a low neutrophil count and recurrent bacterial infections, including periodontal disease. [ncbi.nlm.nih.gov]

  bacterial infections from early infancy. [ajol.info]

  Symptoms of Costman's syndrome Kostmann's syndrome is the debut of the disease in the first months of life or during the newborn period in the form of severe recurrent bacterial infections: stomatitis, chronic gingivitis, repeated pneumonia, including [m.iliveok.com]

  bacterial infections Bacterial infections, recurrent Frequent bacterial infections Increased susceptibility to bacterial infections Recurrent major bacterial infections [ more ] 0002718 Thrombocytosis Increased number of platelets in blood 0001894 Showing [rarediseases.info.nih.gov]

• Rapidly Progressive Glomerulonephritis

  Manabu Sotomatsu, Takashi Kanazawa, Chitose Ogawa, Toshio Watanabe and Akihiro Morikawa, Complication of rapidly progressive glomerulonephritis in severe congenital neutropenia treated with long‐term granulocyte colony‐stimulating factor (filgrastim), [doi.org]

• Pediatric Disease

  Severe Aplastic Anemia the Inborn Error, and the Pediatric Disease Working Parties of the European Society for Blood and Bone Marrow Transplantation (EBMT) and Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE). [ncbi.nlm.nih.gov]

• Recurrent Oral Ulceration

  Recurrent oral ulcerations are common. Bacterial infections often affect the skin, gastrointestinal tract, and respiratory system and can be life-threatening. The most severe form of congenital neutropenia is known as Kostmann Syndrome. [accessanesthesiology.mhmedical.com]

• Psychomotor Retardation

  psychomotor retardation and seizures), which result from mutations of HAX1 isoforms 1 and 5. Management Filgrastim, a granulocyte colony-stimulating factor analog, improves neutrophil counts and immune function. [medical-dictionary.thefreedictionary.com]

• Speech Disorder

  GRIN2A -Related Speech Disorders and Epilepsy Kenneth A Myers and Ingrid E Scheffer. Initial Posting: September 29, 2016. GRIN2B -Related Neurodevelopmental Disorder Konrad Platzer and Johannes R Lemke. Initial Posting: May 31, 2018. [ncbi.nlm.nih.gov]

• Peripheral Neuropathy

  Chediak-Higashi syndrome – Oculocutaneous albinism, progressive peripheral neuropathy, and neutropenia. Shwachman-Diamond syndrome – Triad of neutropenia, metaphyseal dysplasia, and pancreatic insufficiency. [visualdx.com]

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:

• X-rays,
• Dual-energy X-ray absorptiometry (DEXA) scanning. This is done to determine bone density, as patients with KS may have osteoporosis.

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