SUMMARY
1. The nude mouse is a well-known hairless mouse strain that is characterized by an absent thymus and T cell lymphopenia. It is known to be caused by homozygous mutations in the WHN (also known as FOXN1) gene.
2. WHN is a member of the forkhead/winged-helix transcription factor family. It is highly expressed in the thymus and skin and plays a critical role in the differentiation of thymic and skin epithelial cells.
3. Winged-Helix-Nude (WHN) deficiency has been reported in two siblings with a SCID-like phenotype born to consanguineous parents from a small southern Italian community.
4. Cutaneous abnormalities included erythroderma, alopecia (involving the scalp, eyebrows, and eyelashes), and nail dystrophy.
5. Laboratory abnormalities included CD4 lymphopenia and poor in vitro T cell proliferation to PHA or anti-CD3. Specific antibody deficiency with normal immunoglobulin levels was present in one patient.
6. The diagnosis should be suspected in infants with alopecia, combined immunodeficiency and absent thymus. Sequencing of the WHN gene can confirm the diagnosis.
7. In addition to treatment of acute infections, the following immediate management steps (similar to SCID) should be implemented:
-Avoid all live viral vaccines
-Only irradiated, CMV negative blood products should be used (to prevent GVHD and infections)
-Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole
-IVIG replacement therapy
-Start HLA-typing for the patient and any siblings for possible hematopoietic stem cell transplantation (HSCT)
8. Patients with significant combined immunodeficiency are candidates for HSCT.
OVERVIEW
WHN is a member of the forkhead/winged-helix transcription factor family. It is highly expressed in the thymus and skin and plays a critical role in the differentiation of thymic and skin epithelial cells.
Winged-Helix-Nude (WHN) deficiency has been reported in two siblings with a SCID-like phenotype born to consanguineous parents from a small southern Italian community (there appears to be a founder effect with 6.52% of this population carrying the mutation). The first patient developed a clinical picture similar to Omenn syndrome (erythroderma, diarrhea, splenomegaly) with combined immunodeficiency and died at 12 months of age. The second patient also had combined immunodeficiency received an HLA-identical HSCT from a sibling donor who was heterozygous for the WHN mutation.
Cutaneous abnormalities included erythroderma, alopecia (involving the scalp, eyebrows, and eyelashes), and nail dystrophy.
Laboratory abnormalities included CD4 lymphopenia and poor in vitro T cell proliferation to PHA or anti-CD3. Specific antibody deficiency with normal immunoglobulin levels was present in one patient.
EVALUATION
The diagnosis should be suspected in infants with alopecia, combined immunodeficiency and absent thymus.
Step 1: Immune Evaluation
-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-Naïve (CD45RA) and memory (CD45RO) T-cell enumeration by flow cytometry
-T-cell proliferation to Mitogens (PHA)
-IgG, IgA, IgM levels
-Specific Antibody levels (if older than 6 months)
-Chest X-Ray
-The absolute lymphocyte count (ALC) may be decreased due to CD4 lymphopenia.
-Marked CD4 lymphopenia is present while B and NK cell numbers are normal.
-Very low naïve (CD45RA) T cell numbers can be a useful clue for lack of thymic output in WHN deficiency.
-Low T cell proliferation to mitogens is seen. The large blood volume required to perform mitogen proliferation is often an issue with small infants. -Performing the proliferation assay with one stimulus (PHA) is acceptable and requires less blood.
-Immunoglobulin levels may be normal but specific antibody responses are decreased.
-The chest X-ray may reveals absent thymic tissue.
Step 2: Additional Evaluation
-TREC Analysis
-TCR Gene Rearrangement PCR (TCR Spectratyping)
-Maternal Engraftment Study
-TRECs (T cell receptor excision circles) are loops of DNA excised during TCR rearrangement in the thymus. Because TRECs are not replicated with cell division, they are gradually diluted as T cells become activated and expand. Thus, naïve T-cells that are recent thymic emigrants have high TREC numbers. WHN deficiency patients would be expected to have low TREC numbers.
-TCR gene rearrangement is useful for identifying oligoclonally expanded T cells. This can be seen in maternal engraftment as well as Omenn syndrome.
-Maternal T cells can occasionally undergo clonal expansion in patients with severe combined immunodeficiency. Maternal T cells typically are CD45RO+ and proliferate poorly to mitogen stimulation.
Step 3: Genetic Confirmation
-WHN (FOXN1) Gene Sequencing
-Genetic testing for WHN is currently commercially available (Cincinnati Children's)
MANAGEMENT
Pending the completion of an immunologic evaluation for suspected WHN Deficiency, it is critical to initiate certain measures to prevent life-threatening complications for patients. The following precautions should be implemented immediately:
1. Avoid all live viral vaccines (rotavirus, varicella, MMR, BCG)
Severe vaccine strain disease can occur if patients with marked combined immunodeficiency receive
these vaccines.
2. Only irradiated, CMV negative blood products should be used
Leukocytes from non-irradiated blood can cause graft versus host disease and CMV can cause
severe infections.
3. Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole
4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week
4. IVIG replacement therapy
5. High resolution HLA-typing for the patient and any siblings
For possible Hematopoietic Stem Cell Transplantation (HSCT)
Patients with significant combined immunodeficiency are candidates for HSCT. In the single patient who received a matched sibling HSCT, CD4 T cell numbers increased appropriately following the transplant. However, the T cells mainly displayed a memory (CD45RO) phenotype rather than a naïve phenotype (CD45RA) indicating that the immune reconstitution occurred due to expansion of donor T cells.
RESOURCES
Literature Resources
1. Frank 1999
Human WHN Deficiency