Immunodeficiency Search

CARTILAGE HAIR HYPOPLASIA

SUMMARY

1. Cartilage Hair Hypoplasia (CHH) is an autosomal recessive syndrome characterized by short-limb dwarfism, metaphyseal dysplasia, immunodeficiency, fine sparse hair, skin hypopigmentation, gastrointestinal disease (Hirschsprung), and increased risk of malignancy.

2. Patients commonly develop autoimmune manifestations including hemolytic anemia, ITP, juvenile idiopathic arthritis, and autoimmune enteropathy.

3. A wide spectrum of immunodeficiency has been described in CHH. Absolute lymphocyte counts are generally low with T cell lymphopenia and decreased T cell proliferation to mitogens. Hypogammaglobulemia has also been reported in patients. Profound anemia and neutropenia from bone marrow failure has been described.

4. The infections described in CHH patients reflect the combined immunodeficiency found in this syndrome: bacterial sinopulmonary infections, fatal Varicella infections, PJP, CMV pneumonitis, and mucocutaneous candidiasis. Patients with milder forms of disease do not suffer from recurrent infections despite laboratory abnormalities such as lymphopenia.

5. In some patients, a SCID phenotype can occur with severe lymphopenia and marked T cell and B cell dysfunction. These patients have an increased susceptibility to life-threatening opportunistic and invasive infections and are candidates for hematopoietic stem cell transplantation (HSCT). An Omenn syndrome phenotype has also been reported.

6. CHH patients have an increased risk for developing malignancies. These include Non-Hodgkin’s and Hodgkin’s lymphoma, leukemia, squamous cell carcinoma, and basal cell carcinoma.

7. CHH is caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene. RMRP is an RNase present in the nucleus and mitochondria. It functions in the cleavage of RNA during mitochondrial DNA synthesis, cleavage of ribosomal RNA in the nucleus, and cleavage of cyclin B2 mRNA in cell cycle control. Mutations in RMRP affect cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell-cycle regulation.

8. The clinical features of short limb dwarfism, fine sparse hair, and immunodeficiency suggest the diagnosis of CHH. X-ray studies may be helpful to detect skeletal dysplasia. The metaphyseal ends are abnormal and appear as scalloped, irregular surfaces that may contain cystic areas.

9. The definitive diagnosis is made by sequencing of the RMRP gene.

10. Supportive therapies such as immunoglobulin replacement therapy or prophylactic antibiotics should be implemented for patients with immunodeficiency. For patients with a SCID phenotype, HSCT is curative but will not affect the growth and musculoskeletal features of the syndrome. The survival rate for matched sibling or matched unrelated donors is approximately 80%. The success rate is significantly lower for haploidentical transplants.

OVERVIEW

Cartilage Hair Hypoplasia (CHH) is an autosomal recessive syndrome characterized by short-limb dwarfism, metaphyseal dysplasia, immunodeficiency, fine sparse hair, skin hypopigmentation, gastrointestinal disease (Hirschsprung), and increased risk of malignancy. Patients also develop autoimmune manifestations including hemolytic anemia, ITP, juvenile idiopathic arthritis, and autoimmune enteropathy.

A wide spectrum of immunodeficiency has been described in CHH. Absolute lymphocyte counts are generally low with T cell lymphopenia and decreased T cell proliferation to mitogens. Hypogammaglobulemia has also been reported in patients. Profound anemia and neutropenia from bone marrow failure can occur. The infections described in CHH patients reflect the combined immunodeficiency found in this syndrome: bacterial sinopulmonary infections, fatal Varicella infections, PJP, CMV pneumonitis, and mucocutaneous candidiasis. Patients with milder forms of disease do not develop recurrent infections despite the presence of laboratory abnormalities such as lymphopenia.

In some patients, a SCID phenotype can occur with severe lymphopenia and marked T cell and B cell dysfunction. These patients have an increased susceptibility to life-threatening opportunistic and invasive infections and are candidates for HSCT. An Omenn syndrome phenotype has also been reported.

CHH patients have an increased risk for developing malignancies. These include Non-Hodgkin’s and Hodgkin’s lymphoma, leukemia, squamous cell carcinoma, and basal cell carcinoma.

CHH is caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene. RMRP is an RNase present in the nucleus and mitochondria. It functions in the cleavage of RNA during mitochondrial DNA synthesis, cleavage of ribosomal RNA in the nucleus, and cleavage of cyclin B2 mRNA in cell cycle control. Mutations in RMRP affect cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell-cycle regulation..

EVALUATION

The clinical features of short limb dwarfism, fine sparse hair, and combined immunodeficiency suggest the diagnosis of CHH.

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, IgE levels

- Specific Antibody levels (if older than 6 months)

-The absolute lymphocyte count (ALC) should be calculated from the CBC (WBC multiplied by the lymphocyte percentage). Most patients have a decreased ALC.

-Low T-cell numbers and B cell numbers may be present.

-Very low naïve (CD45RA) T-cell numbers can be a useful clue for lack of thymic output. In cases of maternal T-cell engraftment and Omenn’s syndrome, the circulating T-cells have a predominantly memory (CD45RO) phenotype and have poor proliferation in response to mitogens.

-Low T-cell proliferation to mitogens is commonly seen. Markedly decreased mitogen proliferation is seen in patients with a SCID phenotype. 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.

-Hypogammaglobulinemia and low specific antibody response has been described in CHH..

Step 2: Additional Immune Evaluation.

The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations but not necessarily required.

-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. SCID patients typically have very 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’s syndrome.

-Maternal T cells can occasionally undergo clonal expansion in patients with SCID. Maternal T cells typically are CD8+CD45RO+ and proliferate poorly to mitogen stimulation. Assessing for the presence of maternal cells in circulation (maternal engraftment) is useful because it can affect the selection of a stem cell donor and it may necessitate immunosuppression prior to transplantation.

Step 3: Additional Testing for CHH

-Skeletal Survey

-Metaphyseal dysplasia most commonly affects the lower extremities. Metaphyseal ends appear as scalloped, irregular surfaces that may contain cystic areas.

Step 4: Gene sequencing

-RMRP Gene Sequencing

-RMRP gene sequencing is commercially available through Gene Dx.

MANAGEMENT

Supportive therapies for immunodeficiency include monthly IVIG and prophylactic antibiotics.

For patients with a SCID phenotype, 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 SCID patients 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. HLA-typing for the patient and any siblings

-For possible HSCT

-The survival rate for matched sibling or matched unrelated donors is approximately 80%. The success rate is significantly lower for haploidentical

transplants.

RESOURCES