Omenn Syndrome - Causes, Symptoms, and Management

Introduction:

Omenn syndrome is a rare, autosomal recessive inherited condition that affects the body’s immune system. This syndrome is one of the severe combined immunodeficiency (SCID). Severe combined immunodeficiency is a group of disorders where the person has the least or no ability to resist the invasion of bacteria, viruses, or other microorganisms. They are highly susceptible to repeated infections that may even be life-threatening. The organisms that cause these infections are mostly opportunistic; that is, they do not cause any harm to a healthy individual, and only the immune-compromised are affected. Infants with Omenn syndrome are likely to develop pneumonia and diarrhea. Along with immunodeficiency, they also develop auto-immunity, where the body begins to destroy its immune system. This article gives a brief of Omenn syndrome, its clinical manifestations, diagnosis, and treatment.

Why Is It Named Omenn Syndrome?

In 1965, it was Mr.Gilbert S Omenn who described this condition in an American-Irish family and hence the name, Omenn syndrome. He noticed recurrent infections, skin eruptions, eosinophilia, lymphadenopathy, and respiratory and gastrointestinal symptoms. These children also experienced failure to thrive.

How Is Omenn Syndrome Otherwise Called?

• Familial reticuloendotheliosis.

• Histiocytic medullary reticulosis.

What Is Autosomal Recessive Inheritance?

As we know that Omenn syndrome is an autosomal recessive condition, you might not be familiar with the medical term autosomal recessive condition. So here is the answer to your query. In autosomal recessive conditions, each of the parents will carry one normal, healthy gene and one mutated gene. These parents are not affected by the disease, but they are carriers of the disease; they do not even show any signs and symptoms. But, they can pass on the disease to their children. As the children get the condition from their parents, it is referred to as an inherited condition. These parents will have three possibilities:

1. 25 percent of chances for an unaffected child with two normal genes

2. 50 percent of chances for an unaffected child with one normal gene and one mutated gene. They are also carriers of the disease.

3. 25 percent of chances for an affected child with two mutated genes.

What Is the Incidence of This Condition?

• It is a rare syndrome affecting one in 75000-100000 newborns.

• It has no gender predilection and can affect males and females.

• It is presented soon after birth.

• It is highly fatal if left untreated. They do not survive beyond 1-2 years of age without treatment.

What Causes Omenn Syndrome?

Omenn syndrome is a genetic disorder that means there is a defect in the function of several genes. Several genetic mutations result in Omenn syndrome. The ADA, RAG-1, RAG-2, CHD7, DCLRE1C, IL2RG, LIG4, RMRP, and IL7R. However, the predominant ones are the RAG-1 and RAG-2.

• The main function of the RAG-1 and RAG-2 is to instruct the body in making proteins for the t -cells and B-cells.

• These special proteins present on the surface of the B and T lymphocytes help to recognize foreign bodies and help to fight infections.

• These RAG-1 and RAG-2 also increase the proteins present on the surface of the b-cells and t-cells, thus enhancing their defense mechanisms.

• Any defect or mutation of these two genes results in reduced protein formation, thereby reducing the ability of the T and B cells to recognize foreign bodies and fight against infection.

• This results in recurrent infections leading to life-threatening conditions.

• There is a marked reduction of the lymphatic system, causing the reduction of B lymphocytes. The T lymphocytes are normally seen, and some abnormal T cells attack the body’s tissues and immune system resulting in auto-immunity.

What Are the Clinical Manifestations of Omenn Syndrome?

The auto-immune reaction results in the following features:

• They have short stature and short limbs due to metaphyseal chondrodysplasia (abnormality in the development of bones and cartilage).

• Erythroderma (the skin appears very red).

• Alopecia (hair loss).

• Dry skin and desquamation are seen soon after birth.

• Chronic diarrhea.

• Pneumonitis is caused by pneumocystis jirovecii or by the virus Cytomegalovirus or Parainfluenza virus.

• Hepatosplenomegaly (enlarged spleen and liver).

• Lymphadenopathy (enlargement of the lymph nodes and thymus where the lymphocytes are produced in response to an infection).

How to Diagnose the Condition in Your Child?

Most of these cases are diagnosed soon after birth. However, a few investigations may be essential to confirm the diagnoses.

• Blood Investigations: The complete blood picture shows,

  • Increased eosinophil count.

  • There is a depletion of the lymphocytes in the thymus and lymphoid tissue.

  • There is a reduction in immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (Ig M).

  • The B lymphocytes are absent, and the T-lymphocytes may be increased or normal with impaired function. These elevated T-cells are typically seen in the skin and gut.

  • Hypocalcemia.

• Evaluation of the Thymus: On examination of the thymus, it shows dysplastic (containing abnormal cells and growth) changes with few thymocytes, complete loss of corticomedullary architecture, and absence of Hassall’s corpuscles.

• Skin Biopsies: The hematoxylin and eosin staining of the tissue shows:

1. Acanthosis (increase in the thickness of the prickle cell layer- an epidermal layer of the skin) and parakeratosis (presence of nucleated keratinocytes in the stratum corneum.)
2. Inflammatory cells are seen in the epidermis and more in the dermal layer, and less frequent in the junction of the dermis and epidermis.

• Immuno-Histochemistry: It shows the infiltration of mononuclear cells, eosinophils, and macrophages.

What Is the Management of Omenn Syndrome?

Omenn syndrome is highly fatal if it is not treated and the patient survives only until the age of two years. The treatment aims to restore the proper functioning of the immune system. It includes the following:

1. Patients with Omenn syndrome are treated with immunosuppressive drugs such as Prednisone and Cyclosporine A. This proved to be effective as it suppressed the expansion of the T cells and their infiltration into the tissues. This resulted in drastic skin improvements within one to three weeks after the therapy.

2. The abnormal and the activated T-cells are suppressed using pharmacological agents. This enhances the engraftments of the bone marrow cells from human leukocyte antigens (HLA) identical donors.

3. Another approach is transplantation surgery from matched unrelated donors. These patients should be first treated with myeloablative regimens such as Busulfan and Cyclophosphamide (the agents that kill the cells in the bone marrow where both the healthy and abnormal cells are killed). This improves the prognosis of the patient.

4. Haploidentical bone marrow transplant (BMT) also cures Omenn syndrome. It is a type of allogeneic transplant where healthy blood-forming cells are taken from half-matched donors to replace the unhealthy and defective ones. Immunosuppressive therapy should be started before the surgery.

5. A good prognosis is also seen in cases of cord blood stem cell transplant surgery.

Conclusion:

Although Omenn syndrome is a very rare and fatal condition, medical sciences and advancements have paved the way for the survival of the affected individuals. Early diagnosis and treatment improve the survival rate to about 80 %. As this condition is a genetic disorder, there are no known ways to prevent the disease. However, few studies and research have concluded that increased incidence is seen in consanguineous marriages. So avoiding these types of marriages might reduce the risk of Omenn syndrome in your baby. And the patients do respond well to the treatment with the best outcomes, so unnecessary fear can be avoided in parents.