Kostmann Disease Clinical Presentation

Severe neutropenia is brought to clinical attention after an initial infection, which typically occurs shortly after birth. Symptoms of Kostmann disease include the following:

• Temperature instability in newborn period
• Fever
• Irritability
• Localized site(s) of infection

Signs and symptoms of Kostmann disease include the following:

• Oral ulcers
• Gingivitis, which may lead to early loss of permanent teeth
• Pharyngitis
• Sinusitis, otitis media
• Lymphadenopathy, lymphadenitis
• Bronchitis, pneumonia
• Cellulitis
• Cutaneous abscess, boils
• Omphalitis
• Perianal abscess
• Lung abscess
• Liver abscess
• Peritonitis
• Enteritis with chronic diarrhea and vomiting
• Bacteremia and/or septicemia, most commonly caused by streptococci or staphylococci (Other commonly encountered organisms include Pseudomonas, fungi, and, in rare cases, Clostridium species.)
• Urinary tract infection
• Fractures or bone pain
• Splenomegaly
• Neurological symptoms, including epilepsy and neuropsychological deficits^[2]

Classic Kostmann disease, as originally reported in 1956, is inherited in an autosomal recessive pattern.^[1] Severe congenital neutropenia, in general, consists of a heterogeneous group of blood disorders that may also be inherited in an autosomal dominant fashion or may occur via sporadic mutation.

An abnormal granulocyte colony-stimulating factor (G-CSF)–induced intracellular signal transduction pathway has been suggested as a potential cause of the underlying genetic defect. Neutrophils from patients are shown to have dramatically increased levels of 2 cytosolic protein tyrosine phosphatases that contain src-homology 2 (SH2): SHP-1 and SHP-2. One hypothesis is that overexpression of these proteins, which are involved in cytokine receptor signaling, plays a role in altering intracellular signal transduction processes.

A selective decrease of B-cell lymphoma-2 (Bcl-2) expression in myeloid cells and an increase in apoptosis in bone marrow progenitor cells have been observed. The primary function of Bcl-2, a mitochondria-targeted protein, is the prevention of cytochrome c release from mitochondria. Cytochrome c can activate a cytosolic caspase cascade. Caspases are integral proteolytic enzymes involved in cellular apoptosis. Caspases are activated through one of two pathways: (1) an extrinsic, death receptor–dependent pathway or (2) an intrinsic, mitochondria–dependent pathway. Mitochondrial release of cytochrome c initiates the cytosolic caspase cascade through the second pathway. Thus, decreased Bcl-2 results in enhanced release of cytochrome c, which then perpetuates the caspase cascade leading to more pronounced apoptosis. G-CSF offers clinical protection to patients with Kostmann disease by diminishing this mitochondria-dependent apoptotic death pathway.

G-CSF receptors are expressed on myeloid cells in slightly increased numbers, and the binding affinity for G-CSF to its receptor is normal. This is in contrast to the original theory that the underlying Kostmann defect was related to either decreased G-CSF production or diminished binding of G-CSF to its receptor.

Although neutrophil elastase mutations (ELA2) have been found in a subgroup of patients with Kostmann disease, as in cyclic neutropenia, these mutations are also found in some phenotypically healthy family members. In contrast to the inheritance pattern seen in Kostmann disease (autosomal recessive), these elastase mutations are inherited in an autosomal dominant fashion. Phenotypically, these patients are identical to the patients with classic Kostmann syndrome and may be more predominant in cases of congenital neutropenia.

While G-CSF receptor mutations have not been detected at birth, patients with Kostmann disease who develop leukemia have been found to have acquired G-CSF receptor mutations. Considerable variability between the onset of G-CSF receptor mutation and the development of leukemia has been noted.^[3]

Autosomal recessive inheritance of homozygous hematopoietic cell-specific protein-1 (HS1)-associated protein X-1 (HAX-1) mutations appear to lead to the increased apoptosis of myeloid precursors seen in patients with severe congenital neutropenia.^[4]HAX-1 functions include signal transduction, cytoskeletal control, and regulation of apoptosis.^[2] . HAX-1 is reported to play a role in suppression of apoptosis in lymphocytes and neurons, resulting in prolonged survival of these cells.^[5] Not surprisingly, certain HAX-1 mutations are now shown to be associated with neurological and neuropsychological abnormalities, including neurodevelopmental delay and epilepsy.^{[5, 6]}