AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count with differential
• • Order this study to determine the presence of lymphocytopenia and neutropenia.
  • Hemoglobin values are usually within reference ranges at birth, but the patient may develop anemia secondary to sepsis and chronic illness.
  • Platelet counts are usually within reference ranges.
• Lymphocyte subsets
• • This study shows severely depleted circulating T-cell subsets (eg, CD3, CD4, CD8).
  • B lymphocytes (CD19) may be present.
• Quantitative immunoglobulins: Immunoglobulin G (IgG) levels may be within reference ranges at birth because of transplacental transfusion of maternal immunoglobulins. With time, hypogammaglobulinemia becomes evident.
• Lymphocyte proliferative assays: Lymphocytes show little or no response to mitogens, including phytohemagglutinin, concanavalin A, and pokeweed.

Imaging Studies

• Imaging studies are not useful for diagnosis of reticular dysgenesis (RD) but may be indicated to identify sites of infections.
• Chest radiographs
• • Absence of thymic shadow is indicative of a developmental abnormality of the T lymphocytes.
  • Chest radiographs are also useful to check for evidence of pulmonary infections.

Other Tests

• Audiometry and brainstem-evoked audiometry responses can be used to detect profound bilateral sensorineural deafness.

Procedures

• Bone marrow aspiration: This study demonstrates fairly normal erythroid development, and megakaryocytes are present in adequate numbers. The marrow is characterized by a poor development of the myeloid elements.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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:

• Intravenous gamma-globulin infusion
• Irradiation of all blood transfusion products
• Vigorous antibiotic therapy for infections
• GCSF is usually not effective if myeloid precursors are absent; however, GCSF may be useful if myeloid precursors are present.

Surgical Care

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.

Consultations

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.

Diet

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.

Activity

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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Drug Category: Immunoglobulins

Important tool in preventing severe infections, including P carinii.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Because of the severe level of immunodeficiency, place patients with reticular dysgenesis (RD) in protective isolation in the hospital until a corrective stem cell transplant can be performed.
• Successful stem cell transplantation from a histocompatible sibling is well documented.
• Haploidentical transplantation from a parent is successful in half of the cases attempted.
• The use of umbilical cord blood stem cells was successful in at least 1 case.

Further Outpatient Care

• Following successful stem cell transplantation, carefully monitor the patient for evidence of immune reconstitution.
• Administer intravenous immunoglobulins (IVIG) monthly to protect the patient from infections.
• Continue trimethoprim-sulfamethoxazole for prophylaxis of P carinii until evidence of T-cell function exists (using the lymphocyte proliferation assay).
• Complete reconstitution may take more than a year to achieve.

Deterrence/Prevention

• Offer genetic counseling to the family.
• Attempt prenatal diagnosis with fetal cell sampling.
• Immediately transfer an infant thought to have RD to a protective isolation environment following cesarean delivery.

Complications

• Graft versus host disease (GVHD) can occur with stem cell transplants. The incidence and severity of GVHD may be reduced by T-cell depletion of the donor stem cells, but this may lead to failure of engraftment.
• Overwhelming sepsis can occur during the posttransplant period.

Prognosis

• If a successful stem cell transplant is performed, the patient has a good chance of living a relatively normal life. If the transplant is not available or is not successful, then the prognosis is poor with a high probability of a fatal outcome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize the disease early compromises the patient's chance for survival.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. de Vaal O, Seynhaeve V. Reticular dysgenesia. Lancet. Dec 19 1959;2:1123-5. [Medline].
2. De La Calle-Martin O, Badell I, Garcia A, et al. B cells and monocytes are not developmentally affected in a case of reticular dysgenesis. Clin Exp Immunol. Dec 1997;110(3):392-6. [Medline].
3. Emile JF, Geissmann F, Martin OC, et al. Langerhans cell deficiency in reticular dysgenesis. Blood. Jul 1 2000;96(1):58-62. [Medline].
4. Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. Mar 1997;130(3):378-87. [Medline].
5. Stephan JL, Vlekova V, Le Deist F, et al. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr. Oct 1993;123(4):564-72. [Medline].
6. Ownby DR, Pizzo S, Blackmon L, et al. Severe combined immunodeficiency with leukopenia (reticular dysgenesis) in siblings: immunologic and histopathologic findings. J Pediatr. Sep 1976;89(3):382-7. [Medline].
7. Bertrand Y, Muller SM, Casanova JL, et al. Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients. Bone Marrow Transplant. May 2002;29(9):759-62. [Medline].
8. Bujan W, Ferster A, Sariban E, Friedrich W. Effect of recombinant human granulocyte colony-stimulating factor in reticular dysgenesis. Blood. Sep 1 1993;82(5):1684. [Medline].
9. De Santes KB, Lai SS, Cowan MJ. Haploidentical bone marrow transplants for two patients with reticular dysgenesis. Bone Marrow Transplant. Jun 1996;17(6):1171-3. [Medline].
10. Knutsen AP, Wall DA. Kinetics of T-cell development of umbilical cord blood transplantation in severe T-cell immunodeficiency disorders. J Allergy Clin Immunol. May 1999;103(5 Pt 1):823-32. [Medline].
11. Levinsky RJ, Tiedeman K. Successful bone-marrow transplantation for reticular dysgenesis. Lancet. Mar 26 1983;1(8326 Pt 1):671-2. [Medline].
12. Niehues T, Schwarz K, Schneider M, Schroten H, Schröder E, Stephan V. Severe combined immunodeficiency (SCID) associated neutropenia: a lesson from monozygotic twins. Arch Dis Child. Apr 1996;74(4):340-2. [Medline].
13. Reubsaet LL, Boelens JJ, Rademaker C, Smal J, Wulffraat NM. Successful cord blood transplantation in a premature and dysmature neonate of 1700 g with reticular dysgenesis. Bone Marrow Transplant. Mar 2007;39(5):307-8. [Medline].
14. Roper M, Parmley RT, Crist WM, Kelly DR, Cooper MD. Severe congenital leukopenia (reticular dysgenesis). Immunologic and morphologic characterizations of leukocytes. Am J Dis Child. Aug 1985;139(8):832-5. [Medline].
15. Small TN, Wall DA, Kurtzberg J, Cowan MJ, O'Reilly RJ, Friedrich W. Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness. J Pediatr. Sep 1999;135(3):387-9. [Medline].

Article Last Updated: Nov 21, 2007