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

congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

immunodeficiency Immunodeficiency, also known as immunocompromisation, 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 a ...

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 bacterial or fungal infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection ...

infections due to defective production of

specific granules Specific granules are secretory vesicles found exclusively in cells of the immune system called granulocytes. It is sometimes described as applying specifically to neutrophils, and sometimes the term is applied to other types of cells. These gran ...

and

gelatinase Gelatinases are enzymes capable of degrading gelatin. Gelatinases are expressed in several bacteria including ''Pseudomonas aeruginosa'' and ''Serratia marcescens''. In humans, the gelatinases are matrix metalloproteinases MMP2 and MMP9 Matrix ...

granules in patient

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

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 positive ...

'', ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

'' or other

Enterobacteriaceae Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It was first proposed by Rahn in 1936, and now includes over 30 genera and more than 100 species. Its classification above the level of family is still a subject ...

, 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 us ...

''. 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 o ...

abscesses An abscess is a collection of pus that has built up within the tissue of the body. Signs and symptoms of abscesses include redness, pain, warmth, and swelling. The swelling may feel fluid-filled when pressed. The area of redness often extends b ...

and

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...

and chronic lung disease are common. Patients may also develop

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

mastoiditis Mastoiditis is the result of an infection that extends to the air cells of the skull behind the ear. Specifically, it is an inflammation of the mucosal lining of the mastoid antrum and mastoid air cell system inside the mastoid process. The ma ...

otitis media Otitis media is a group of 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 pulling at the ear, ...

, 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 cli ...

. 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 CCAAT/enhancer binding protein (C/EBP), epsilon, also known as CEBPE and CRP1, is a type of ccaat-enhancer-binding protein. CEBPE is its human gene and is pro-apoptotic. The protein encoded by this gene is a bZIP transcription factor which can b ...

gene mutation or a

pathognomonic Pathognomonic (rare 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 doub ...

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

(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 of, ...

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 Zinc finger protein Gfi-1 is a transcriptional repressor that in humans is encoded by the ''GFI1'' gene. It is important normal hematopoiesis. Interactions GFI1 has been shown to interact Advocates for Informed Choice, doing business as, ...

, 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 fina ...

(secondary) and

(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 glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, su ...

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. They hav ...

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 sig ...

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

lysozyme Lysozyme (EC 3.2.1.17, 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 ...

cathepsin Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases ( enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are d ...

, and

elastase In molecular biology, elastase is an enzyme from the class of ''proteases (peptidases)'' that break down proteins. In particular, it is a serine protease. Forms and classification Eight human genes exist for elastase: Some bacteria (includin ...

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 '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

, such as a decreased response to

fMLP ''N''-Formylmethionyl-leucyl-phenylalanine (fMLF, fMLP or ''N''-formyl-met-leu-phe) is an ''N''-formylation, formylated tripeptide and sometimes simply referred to as chemotactic peptide is a potent polymorphonuclear leukocyte (PMN) chemotactic ...

, due to a lack of chemotactic receptors typically found in the specific granules.

Diagnosis

Treatment

Treatment consists mainly of high dose antibiotics for active infections and prophylactic antibiotics for prevention of future infections.

GM-CSF Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

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 of a patient and to produce ...

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