Reticular Dysgenesis ?>

Reticular Dysgenesis

Reticular Dysgenesis


Introduction
Background

Reticular dysgenesis (RD) is a rare form of severe immunodeficiency that is usually fatal unless a successful stem cell transplant is performed. RD is characterized by combined immunodeficiency and neutropenia. In 1959, de Vaal and Seynhaeve first described this disorder as RD.1 To date, fewer than 30 cases have been described.
Pathophysiology

The genetic basis for RD is not known. Both males and females are affected. Consanguinity has been noted in several families, suggesting an autosomal inheritance.

The pathology of the lymphoid tissues is similar to that observed in severe combined immunodeficiency (SCID). The thymus is small and dysplastic, containing mainly epithelioid cells but without Hassall corpuscles or thymocytes. Lymph nodes, tonsils, and Peyer patches are absent or small with markedly reduced numbers of lymphocytes. The spleen may be normal in size, but the number of lymphocytes is markedly reduced, and periarterial cuffing is absent. Erythrophagocytosis is observed in the spleen, bone marrow, and liver.

The bone marrow may contain normal numbers of erythroid precursors and megakaryocytes; however, cells of the myeloid series are usually not observed.

The circulating T lymphocytes are nonfunctional and do not respond to mitogenic stimulation. In a study by De La Calle-Martin et al, CD5+ B lymphocytes were present and persisted after a stem cell transplant, resulting in mixed chimerism.2 These B cells were functional with normal immunoglobulin production.

Langerhans cells are absent in patients with RD. In contrast, macrophages and monocytes are present. Emile et al found that 2 of the 4 patients had detectable Langerhans cells of host origin after stem cell transplantation.3

These findings suggest that the genetic defect responsible for RD may participate in the expansion of progenitors of the T lymphocytes and neutrophils but not of the B lymphocytes or monocytes. Other extrinsic factors may be responsible for the Langerhans cell defect.

Frequency
United States

RD is an extremely rare disorder and is often classified as a variant of SCID. Only 1 case of RD was included in a series of 108 patients with SCID reported from Duke University.4 Six cases of RD were included in another series of 125 patients with SCID. The frequency of SCID is estimated at 1 case per 100,000 people, and the incidence of patients with RD is estimated at less than 1 case per 3-5 million people.
International

Little is known about the frequency of RD in various ethnic groups. Only 1 case of RD was included from a French study of 117 patients with SCID, suggesting that the worldwide frequency of RD is similar to that observed in the United States.5
Mortality/Morbidity

Because of the severity of the immunodeficiency, patients with RD die early in life unless they receive a stem cell transplant. In a study by Ownby et al, the newborn brother of a child with RD was immediately placed in a sterile incubator following cesarean delivery; despite this precaution, he died of sepsis.6
Race

Because of the rarity of the disorder, frequency among races is not known.
Sex

RD has been described in both sexes. Because of the small number of reported cases, a difference in frequency among the sexes is not known. In a case study by Small and colleagues, only 2 of the first 10 reported patients were females, but a more recent study revealed that 5 of 8 were females.
Age

Because of the profound level of immunodeficiency, RD is apparent within the newborn period.
Clinical
History

The disorder usually manifests early in the neonatal period, with signs of sepsis as the first day of life and death within the first few days or weeks. This presentation is mainly caused by severe leukopenia.

The patient may present with the following conditions:
Upper respiratory tract infection
Oral candidiasis
Omphalitis
Perianal lesions
Abscesses
Abdominal distension
Diarrhea
Patients fail to thrive and are usually small and chronically ill.
In some cases, the following infective organisms are identified:
Escherichia coli
Pseudomonas
Klebsiella
Staphylococcus
Candida
Cytomegalovirus (CMV)
Bilateral sensorineural deafness was found in 7 of 8 patients with reticular dysgenesis (RD). This finding was observed before the use of ototoxic antibiotics.
Physical
The child is usually chronically ill and fails to thrive.
The patient may be anemic with recurrent infections.
Associated signs of infection may arise, including fever, skin abscess, respiratory distress, and diarrhea.
Immunodeficiency
Despite recurrent infections, no significant lymphoid and tonsillar tissues can be found.
The spleen may be normal in size.
Hepatomegaly is reported.
Causes
Familial studies suggest that RD is an autosomal inherited disorder, although the exact nature of the gene defect is not known.
The defect affects the development of specific hematopoietic cell lines, including T lymphocytes and neutrophils.
The lack of certain extrinsic growth factor(s) has been hypothesized as the cause for the disorder. These putative growth factors are not granulocyte colony-stimulating factor (GCSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) because these factors cannot correct the neutropenia.

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