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.
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.
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.
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
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
Because of the rarity of the disorder, frequency among races is not known.
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.
Because of the profound level of immunodeficiency, RD is apparent within the newborn period.
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.
Early recognition of lymphopenia and neutropenia is of paramount importance so that protective measures may be undertaken to prevent fatal overwhelming sepsis. In families with a child previously affected with reticular dysgenesis (RD), prenatal diagnosis, elective cesarean delivery, and protective isolation contribute to a better outcome. Other recommendations include the following:
Best results with stem cell transplantation are achieved with a transplant from a histocompatible sibling; however, successful treatment with haploidentical donors and umbilical cord blood stem cells has been reported.
Patients should be treated by a clinical immunologist in a tertiary clinical setting in which specialists in stem cell transplantation, infectious disease, and intensive care are readily available.
During the initial course of treatment, parenteral nutrition is indicated to ensure adequate energy intake and to prevent intestinal colonization of possible harmful bacteria. No dietary restriction is necessary after a successful stem cell transplant.
During the initial course of treatment, place the child in protective isolation. Upon successful stem cell transplantation with immune reconstitution, no restriction in activity is indicated.
The only curative therapy is stem cell transplantation; therefore, the identification of an appropriate donor for stem cell transplantation is of utmost importance. Histocompatible sibling, match-unrelated donor, haploidentical donor, or umbilical cord blood stem cells are potential sources that must be explored. For more information on stem cell transplantation, please see Medscape's Stem Cell Research and Therapy Resource Center.
Haploidentical stem cell transplant was successful in 3 out of 5 patients after an intensive conditioning regimen consisting of busulfan and cyclophosphamide (Bertrand, 2002).7 Other conditioning regimens were not effective in successful engraftment.
Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.
| Drug Name | Trimethoprim and sulfamethoxazole (Bactrim DS, Septra) |
|---|---|
| Description | Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Used for the treatment of and prophylaxis of Pneumocystis carinii pneumonia. |
| Adult Dose | Pneumocystis infection: 15-20 mg/kg/d TMP and 75-100 mg/kg/d SMZ PO divided q6h for 2-3 wk Prophylaxis: 160 mg TMP and 800 mg SMZ PO qd |
| Pediatric Dose | <2 months: Not recommended >2 months: Pneumocystis infection: Administer as in adults Prophylaxis: 150 mg/m2/d TMP and 750 mg/m2/d SMZ PO bid for 3 consecutive d/wk |
| Contraindications | Documented hypersensitivity; megaloblastic anemia due to folate deficiency |
| Interactions | May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus |
| Precautions | Caution in pregnancy and in women who are breastfeeding; discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in individuals with G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation |
Important tool in preventing severe infections, including P carinii.
| Drug Name | Immunoglobulin intravenous (Gammagard S/D, Gamimune N, Sandoglobulin) |
|---|---|
| Description | For treatment of hypogammaglobulinemia. |
| Adult Dose | 400 mg/kg IV q3-4wk to maintain serum IgG >500 mg/dL |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; IgA deficiency, anti-IgE/IgG antibodies |
| Interactions | May interfere with response to vaccines |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Adverse reactions, including fever, chills, malaise, nausea, vomiting, chest pain, back pain, and dyspnea, are associated with IVIG infusion; transient aseptic meningitis is observed |