Neutrophil-specific granule deficiency ( previously known as lactoferrin deficiency) is a rare

congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...

immunodeficiency Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that aff ...

characterized by an increased risk for

pyogenic Pus is an exudate, typically white-yellow, yellow, or yellow-brown, formed at the site of inflammation during infections, regardless of cause. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collect ...

infections due to defective production of specific granules and gelatinase granules in patient

neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

Symptoms and signs

Atypical infections are the key clinical manifestation of SGD. Within the first few years of life, patients will experience repeated pyogenic infections by species such as ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...

'', ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common Bacterial capsule, encapsulated, Gram-negative bacteria, Gram-negative, Aerobic organism, aerobic–facultative anaerobe, facultatively anaerobic, Bacillus (shape), rod-shaped bacteria, bacterium that can c ...

'' or other

Enterobacteriaceae Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It includes over 30 genera and more than 100 species. Its classification above the level of Family (taxonomy), family is still a subject of debate, but one class ...

, and ''

Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...

''. Cutaneous

ulcers An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing ...

or abscesses and

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

and chronic lung disease are common. Patients may also develop

sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...

, mastoiditis,

otitis media Otitis media is a group of Inflammation, inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pullin ...

, and

lymphadenopathy Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In c ...

. Infants may present with vomiting, diarrhea, and

failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

. Diagnosis can be made based upon CEBPE gene mutation or a

pathognomonic Pathognomonic (synonym ''pathognomic'') is a term, often used in medicine, that means "characteristic for a particular disease". A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt. ...

finding of a blood smear showing lack of specific granules. Neutrophils and eosinophils will contain hyposegmented nuclei (a pseudo- Pelger–Huet anomaly).

Genetics

A majority of patients with SGD have been found to have mutations in the CEBPE (CCAAT/enhancer-binding protein epsilon) gene, a transcription factor primarily active in

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + '' -oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue ...

cells. Almost all patients have been found to be homozygous for the mutation, suggesting the disease is autosomal recessive. One patient, heterozygous for the mutation, was found to be deficient in GFI1, a related gene.

Pathophysiology

The defect in CEBPE appears to block the ability of neutrophils to mature past the promyelocyte stage in bone marrow. Since

specific Specific may refer to: * Specificity (disambiguation) * Specific, a cure or therapy for a specific illness Law * Specific deterrence, focussed on an individual * Specific finding, intermediate verdict used by a jury in determining the final ...

(secondary) and gelatinase (tertiary) granules are only produced past the promyelocyte stage of development, these are deficient in SGD.

Lactoferrin Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular proteins, globular glycoprotein with a molecular mass of about 80 Atomic mass unit, kDa that is widely repre ...

is the major enzyme found in specific granules, and will be largely absent in the

granulocytes Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that ...

of these patients, along with

defensins Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct antimicrobial activity, immune si ...

(despite these also being found in azurophilic (primary) granules). The other major components of azurophilic granules, such as

lysozyme Lysozyme (, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside hydrolase ...

, cathepsin, and

elastase In molecular biology, elastase is an enzyme from the class of proteases (peptidases) that break down proteins, specifically one that can break down elastin. In other words, the name only refers to the substrate specificity (i.e. what proteins i ...

will be normal, however a lack of defensins and lactoferrin drastically weakens the neutrophil innate ability to fight infection. Neutrophils will also display abnormal

chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...

, such as a decreased response to fMLP, due to a lack of chemotactic receptors typically found in the specific granules.

Diagnosis

Diagnosis of SGD can be done using

light microscopy Microscopy is the technical field of using microscopes to view subjects too small to be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of microscopy: optical, el ...

, as

Wright's stain Wright's stain is a hematologic stain that facilitates the differentiation of blood cell types. It is classically a mixture of eosin (red) and methylene blue dyes. It is used primarily to stain peripheral blood smears, urine samples, and bone marr ...

ed neutrophils will not show secondary granules.

Treatment

Treatment consists mainly of high dose antibiotics for active infections and prophylactic antibiotics for prevention of future infections. GM-CSF therapy or

bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...

might be considered for severe cases. Prognosis is difficult to predict, but patients receiving treatment are generally able to survive to adulthood.

Epidemiology

Estimation of the frequency of SGD is difficult, as it is an extremely rare disease with few cases reported in literature. The condition was first reported in 1980, and since only a handful more cases have been published.

References

External links

{{DEFAULTSORT:Neutrophil-specific granule deficiency Congenital defects of phagocyte number, function, or both Enzyme defects Noninfectious immunodeficiency-related cutaneous conditions