eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Cartilage-Hair Hypoplasia

Alan P Knutsen, MD, Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center

Updated: May 19, 2009

Introduction

Background

Cartilage-hair hypoplasia (CHH), which is Online Mendelian Inheritance in Man (OMIM) disease number 250250, is an autosomal recessive inherited disorder that results in short-limb dwarfism associated with T-cell and B-cell immunodeficiency.¹ Cartilage-hair hypoplasia and other short-limb dwarfism phenotypes are associated with metaphyseal or spondyloepiphyseal dysplasia. Cartilage-hair hypoplasia is a variant of short-limb dwarfism in which fine sparse hair is also present.

Hair of a patient with cartilage-hair hypoplasia (left) compared with that of a typical individual. The hair of the patient with cartilage-hair hypoplasia has a smaller diameter because the central core is absent.

Although originally described by McKusik et al in 1964 in Amish children and known as metaphyseal chondrodysplasia McKusick type, cartilage-hair hypoplasia has been described in non-Amish persons throughout the United States, Europe, and Mexico.² The genetic defect in cartilage-hair hypoplasia has been confirmed to be mutations in the RMRP gene.

Pathophysiology

The genetic defect in cartilage-hair hypoplasia has been identified as a mutation in the gene for RNAase RMRP, mapped to 9p12.³ RMRP is a ribonucleoprotein present in the nucleus and mitochondria. RNase RMRP has 2 functions: cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of preribosomal RNA (pre-rRNA). RMRP also plays a role in ribosomal RNA production and may have a role in nuclear DNA replication. RMRP is required for cell growth, consistent with observations that a generalized defect in cell growth is observed in T cells, B cells, and fibroblasts. In 2005, a study reported that different RMRP gene mutations led to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell-cycle regulation.⁴

RMRP has 2 types of mutations. The first are insertions or duplications of 6-30 nucleotides that reside in the region between the TATA box and the transcription initiation site. These mutations interfere with the transcription of the RMRP gene. The second consists of single nucleotide substitutions and other changes that involve at most 2 nucleotides in highly conserved regions of the gene. The latter mutations result in variable expression of the gene, which may explain the variable phenotype seen in cartilage-hair hypoplasia. The most commonly found mutation in patients with cartilage-hair hypoplasia is 70A>G, which causes an alteration in ribosomal processing.

Although the immune defect primarily affects the T-cell system, mutations of RMRP result in more generalized hematopoietic impairments.⁵  In studies from Makitie et al, defective in vitro colony formation in all myeloid lineages was present, including erythroid, granulocyte-macrophage, and megakaryocyte colony formation. This suggests a common cell proliferation defect in cartilage-hair hypoplasia. How the recently identified genetic defects correlate with immunologic defects remains to be determined.

Frequency

United States

Cartilage-hair hypoplasia is a rare defect. It has been described in both Amish and non-Amish populations. In the Amish, the gene frequency was reported to be 1 per 1340 population with a carrier rate of 1 per 19 population.⁶ A recent study examined the temporal trends of primary immunodeficiency diseases.⁷

International

In Finland, the frequency of cartilage-hair hypoplasia was reported to be 1 case per 23,000 live births, with a carrier rate of 1 case per 76 live births.⁸

Mortality/Morbidity

Persons with cartilage-hair hypoplasia may be subject to infections with opportunistic microorganisms, principally life-threatening varicella infections. In one report, approximately 88% of 108 Finnish patients with cartilage-hair hypoplasia had defective cellular immunity and 56% had increased susceptibility to infections.⁹  Individuals with more severe impaired cellular immunity are more susceptible to malignancies, especially leukemia and lymphoma. In their series, the incidence rate of malignancies was 6%. The risk of infections and malignancies correlates with the severity of impaired T-cell immunity.

However, cartilage hair-hypoplasia is a rare cause of severe combined immunodeficiency (SCID).  In a large series of 108 patients with SCID, only one patient with cartilage hair-hypoplasia was identified.¹⁰ Individuals with cartilage hair-hypoplasia and SCID have a greater susceptibility to opportunistic infections, such as Pneumocystis carinii pneumonia and graft versus host disease, and may succumb to overwhelming infections in infancy.

Race

First reported among Amish children, the disorder has also been reported in other groups throughout the United States, Europe, Asia, and Mexico.

Sex

Cartilage-hair hypoplasia is inherited as an autosomal recessive disorder with equal male-to-female frequency.

Age

The predominant clinical feature of cartilage-hair hypoplasia is short-limb dwarfism evident at birth. The onset of dwarfism may be detected in utero, manifesting as shortening and bowing of the femur.

The onset of increased susceptibility to recurrent infections and severity of infections is somewhat more variable in cartilage-hair hypoplasia.

In two studies, increased susceptibility to infections was reported in only 31-56% of individuals with cartilage-hair hypoplasia.^9,8  In addition, infections may be limited to varicella and may occur in early childhood. Thus, immunodeficiency in individuals with cartilage-hair hypoplasia varies, often with limited susceptibility to infections, and many children with cartilage-hair hypoplasia may live healthy lives.

Children with cartilage-hair hypoplasia that causes SCID present in early infancy with susceptibility to overwhelming and opportunistic infections.

Clinical

History

The clinical findings in cartilage hair-hypoplasia (CHH) are outlined below.^9,11,12,13,5  The predominant features include disproportionate short-limbed stature, hair hypoplasia, and immunodeficiency.

The frequency of reported features is as follows:¹

• Short limbed/short stature - 100%
• Hair hypoplasia - 93%
• Immunodeficiency - 56%
  • Propensity to infections - 58%
  • In vitro immunodeficiency - 86%
• Hypoplastic childhood anemia - 79%
• GI dysfunction - 18% (Hirschsprung disease - 9%)
• Defective spermatogenesis - 100%
• Metaphyseal chondrodysplasia - 100%
• Risk of malignancies - 6.9%
  • Non-Hodgkin lymphoma - 90%
  • Basal cell carcinoma - 35%

Disproportionate short-limbed dwarfism is the most prominent feature in cartilage hair-hypoplasia; it is due to metaphyseal dysplasia. The limbs and ribs are most affected, with sparing of the spine and skull. Radiographic studies reveal short and thick tubular bones, with splaying and irregular metaphyseal borders of the growth plates. The costochondral junctions are similarly affected. These radiographic abnormalities develop by age 6-9 months and are diagnostic. In addition, the hair is characteristic in cartilage hair-hypoplasia; it is fair, thin, and sparse, beginning in the newborn period. GI problems occur in approximately 18% of patients with cartilage hair-hypoplasia. Hirschsprung disease is the most common disorder. 

Recently, defective spermatogenesis that affects the number and function of sperm has been identified in all 11 patients with cartilage hair-hypoplasia in one study. Hypoplastic anemia of childhood has been reported in approximately 79% of patients with cartilage hair-hypoplasia and may be life-threatening. It usually resolves by age 2-3 years.

Most individuals with cartilage hair-hypoplasia have limited susceptibility to infections. However, life-threatening varicella infections may occur. Individuals with cartilage hair-hypoplasia occasionally have infections with common pathogens observed in T-cell immunodeficiency, such as Candida species, P carinii, and cytomegalovirus (CMV). Individuals with severe combined T- and B-cell immunodeficiency have more serious infections and are susceptible to graft versus host disease. In some patients with cartilage hair-hypoplasia, a predominant B-cell immunodeficiency with increased susceptibility to bacterial sinopulmonary infections is reported.^14,5 Individuals with cartilage hair-hypoplasia are at increased risk for leukemia and lymphoma. Both Hodgkin lymphoma and non-Hodgkin lymphoma have been reported.

Physical

Abnormal physical findings of cartilage hair-hypoplasia are present at birth.^9,15 Head size is within the normal reference range, hands are short and pudgy, and skin forms redundant folds around the neck and extremities. Hair of the scalp, eyebrows, and eyelashes at birth is light in color, fine, and sparse and lacks a central pigmented core (see Media file 1).

Hair of a patient with cartilage-hair hypoplasia (left) compared with that of a typical individual. The hair of the patient with cartilage-hair hypoplasia has a smaller diameter because the central core is absent.

• Growth - Short-limb dwarfism, average adult height 107-157 cm (40-60 in)
• Skin - Hypopigmentation
• Nails - Dysplasia
• Hair - Fine, sparse, light-colored hair on the scalp, eyebrows, and eyelashes; body hair similarly affected; hair darkens with age
• Teeth - Notched incisor, microdontia, doubling of lower premolar lingual cusps
• Limbs - Short hands, brachydactyly, bowleg
• Joints - Hypermobility, hyperflexibility, possible limitation of motion affecting elbow extension
• Spine - Mild platyspondylia, lumbar lordosis
• Thorax - Flaring of lower rib cage, Harrison grooves
• GI -Malabsorption, celiac syndrome, Hirschsprung disease, anal stenosis, esophageal atresia

Causes

Cartilage-hair hypoplasia is an autosomal recessive inherited disorder. In 2001, mutations of the RMRP gene in the RNA component of the gene for RNase MRP on chromosome band 9p12 were identified as the genetic defect in Finnish patients with cartilage-hair hypoplasia.⁶  RNase MRP has 2 functions: (1) cleavage of RNA in mitochondrial DNA synthesis and (2) nucleolar cleaving of pre-rRNA.

Differential Diagnoses

B-Cell and T-Cell Combined Disorders

Other Problems to Be Considered

Other forms of short-limb dwarfism may also have an associated immunodeficiency, including isolated T-cell defects, isolated B-cell defects, or combined T-cell and B-cell defects. The hair abnormality distinguishes cartilage-hair hypoplasia (CHH) from other forms of short-limb dwarfism.

Although adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency cause skeletal and immune defects, neither is associated with dwarfism.

Workup

Laboratory Studies

• T-cell immunodeficiency: Immunologic dysfunction occurs in approximately 86% of patients with cartilage-hair hypoplasia (CHH).^11,16  T-cell abnormalities include lymphopenia, decreased percentages and numbers of CD3⁺ and CD4⁺ T cells, and normal percentages and numbers of B cells and natural killer (NK) cells. T-cell function is decreased, as indicated by anergy to recall antigens measured by delayed-type hypersensitivity (DTH) responses, decreased lymphoproliferative responses to mitogens (eg, phytohemagglutinin antigen [PHA], concanavalin A [Con A], pokeweed mitogen [PWM]) and to antigens. Serum immunoglobulin levels and antibody responses to immunizations are usually normal, although a few patients with antibody deficiency have been described.
• B-cell immunodeficiency: Approximately 35% of patients have abnormal humoral immunity, consisting of immunoglobulin A (IgA) and/or immunoglobulin G2 (IgG2) or immunoglobulin G4 (IgG4) deficiency.⁵  Although earlier studies reported that antibody responses to protein immunization were normal, data regarding bacterial polysaccharide antigens must be obtained. The T-cell and B-cell immune function should be closely monitored, perhaps on a yearly basis.
• Anemia: Cyclic neutropenia is occasionally associated with cartilage-hair hypoplasia.¹⁷ Megaloblastic anemia unrelated to folate and vitamin B-12 deficiency has been reported. The anemia is related to insulinlike growth factor. Fetal hemoglobulin is increased, correlating with the severity of the anemia. Over time, both the anemia and neutropenia appear to decrease in severity. Routine bone marrow examination is unnecessary. Anemia is observed in more than 80% of patients with cartilage-hair hypoplasia. Although usually mild and self-limited, some patients (9%) have severe anemia, which is permanent in one half of these patients.¹⁸

Imaging Studies

• Radiography reveals bony scalloping, irregular sclerosis, cystic changes of the widened metaphyses, and metaphysial dysplasia in cartilage-hair hypoplasia.^8,19 Ribs display splaying of the ends at the costochondral junctions, reminiscent of vitamin D deficiency and adenosine deaminase deficiency.
• Hirschsprung disease is more common in individuals with cartilage-hair hypoplasia. Appropriate radiographic studies are performed as the clinical symptoms warrant.

Histologic Findings

• Microscopic changes of the bones in cartilage-hair hypoplasia include clusters of hypertrophic and proliferating chondrocytes, as well as loss of normal column and trabecular formations of chondrocytes and osteoblasts. This appears as decreased cartilage.
• Ossification appears normal.

Treatment

Medical Care

The treatment of the immunodeficiency depends on whether an isolated T-cell defect, isolated B-cell defect, or a combined T-cell and B-cell immunodeficiency is present. Some patients with cartilage-hair hypoplasia have only a limited susceptibility to infections, thus need no specific treatment.

Individuals with an isolated T-cell immunodeficiency have an increased susceptibility to infections, and varicella is the most common, severe, life-threatening infection. Acyclovir is recommended in the treatment of varicella infections. In patients exposed to varicella, prophylaxis with varicella-zoster immune globulin (VZIG), acyclovir, or both can be administered. In the United States, VZIG was discontinued by the manufacturer. An investigational product (VariZIG) is currently available via investigational new drug protocol (contact FFF Enterprises at 800-843-7477). However, prophylaxis with acyclovir in other patients with T-cell impairment who are exposed to varicella may not prevent varicella infection.

An attenuated varicella vaccine has been developed as a routine part of childhood immunizations. Some investigators have recommended this vaccine in patients with near-normal T-cell function and normal B-cell function. In this situation, the varicella vaccine may have some protective role in patients with cartilage-hair hypoplasia. However, because it is a live vaccine, it may result in vaccine-related varicella infection. Guidelines for the administration of the vaccine have been established by the Centers for Disease Control and Prevention.²⁰

In patients with cartilage-hair hypoplasia with antibody immunodeficiency and recurrent bacterial infections, antibody replacement therapy in the form of intravenous immunoglobulin (IVIG) or, alternatively, subcutaneous gammaglobulin (SCGG) therapy is indicated.

Patients with a severe T-cell immunodeficiency with or without concomitant B-cell immunodeficiency are given the same treatment as patients with severe combined immunodeficiency (SCID). Thus, T-cell immune reconstitution using bone marrow transplantation (BMT) is performed. BMT corrects the immunodeficiency but not the skeletal abnormalities.²¹  Three patients with cartilage-hair hypoplasia and SCID underwent successful immune reconstitution with BMT.²²  The 3 patients underwent transplantation during infancy and received pretransplant conditioning. One of the 3 patients received a related donor transplant, whereas the other 2 patients received matched unrelated donor transplants. The patients’ immune systems were fully reconstituted. The transplantation did not affect the skeletal dysplasia. Hopefully, BMT can prevent lymphoma.

Treatment of neutropenia with granulocyte colony-stimulating factor (G-CSF) has been successful in patients with cartilage-hair hypoplasia.¹⁴  Neutropenia is a common feature in individuals with cartilage-hair hypoplasia, occurring as frequently as 27% in a group of 79 Finnish children. The typical mechanism is maturation arrest, but autoimmune neutropenia also occurs. The severity of the neutropenia correlates with the severity of the immunodeficiency and, therefore, contributes to the increased frequency and severity of infections in patients with cartilage-hair hypoplasia. Ammann et al reported that a 3-year-old Japanese boy with cartilage-hair hypoplasia and autoimmune anti-FcgRIIIb (NA 1/2) neutropenia was treated with G-CSF, which improved the boy’s peripheral neutrophil numbers and reduced recurrent bacterial infections.¹⁴

Conflicting results have been reported in the use of growth hormone to treat 5 patients with cartilage-hair hypoplasia. In a 3-year-old Japanese boy who was treated with growth hormone for 7 years and underwent a leg-lengthening surgical procedure, the height improved from -4.2 standard deviations (SD) to -2.1 SD.²³  In another report of 4 patients with cartilage-hair hypoplasia, growth hormone was used to treat 4 patients, consisting of 2 pairs of siblings: a pair of 10-year-old twins (one boy, one girl) and a 7-year-old girl and her 4-year-old sister.²⁴ The duration of growth hormone therapy was 5 years, 2 years, 5 years, and 6.5 years, respectively. Slight improvement of growth was reported during the first year of growth hormone treatment, varying from 0.2-0.8 SD, but the growth was not sustained, and no gain in final height was reported.

Surgical Care

Various palliative bone reconstruction procedures have been performed in patients with other short-limb dwarfism disorders. These can also be performed in patients with cartilage-hair hypoplasia. However, the risk of infection in these patients is increased, and extra attention to preventing and treating infections is necessary.

Consultations

Consult an immunologist to evaluate for immune deficiency. In addition, an orthopedic surgeon should be consulted for bone dysplasia. A geneticist should also be consulted.

Diet

No dietary restrictions apply.

Activity

Skeletal dysplasia significantly impairs the normal activity of these patients. Care directed by orthopedists and physical therapists is necessary to monitor and treat these limitations.

Medication

Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies

The overall consensus among clinical immunologists is that intravenous immunoglobulin (IVIG) administered at a dose of 400-600 mg/kg/mo or a dose that maintains trough serum immunoglobulin (Ig)G levels of more than 500 mg/dL is desirable.^25,26 Patients with X-linked agammaglobulinemia and meningoencephalitis require much higher doses (1 g/kg) and, perhaps, intrathecal therapy. The measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level within the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter dosing intervals may be required.

For replacement therapy in patients with primary immune deficiency, all brands of IVIG are probably equivalent, although viral inactivation processes differ (eg, solvent detergent vs pasteurization and liquid vs lyophilized). The choice of brand depends on the hospital or home care formulary and local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion to review for adverse events or other consequences. Recording all adverse effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times annually, is also recommended.

The US Food and Drug Administration (FDA) recommends that, in patients at risk for renal failure (eg, preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, age >65 y, use of nephrotoxic drugs), recommended doses should not be exceeded, and infusion rates and concentrations should be administered at the minimum levels that are practicable.

Initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in initial treatments is high, especially in patients with infections and in those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose may need to be halved (ie, 200-300 mg/kg), with the remaining dose administered the next day to achieve a full dose. Treatment should not be discontinued. After achieving serum IgG levels within reference range, adverse reactions are uncommon, unless patients have active infections.

Adverse affects associated with the new generation of IVIG products have been greatly reduced and include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions include dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG, and the formation of immune complexes are thought to be related to the adverse reactions. Another cause is the formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), hydrocortisone (6 mg/kg/dose, maximum 100 mg), or a combination 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesic and antihistamine administration may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose per kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at an increased risk, monitoring BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

IgE antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency. True anaphylaxis has been reported in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. However, this is rare. In addition, this is not a problem in patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Exercise caution in patients with IgA deficiency (<7 mg/dL) who require IVIG administration because of IgG subclass deficiencies. IVIG preparations with low concentrations of contaminating IgA are advised (see the Table below).

Immune Globulin, Intravenous^27,28,29,30

*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).

Treat infections with appropriate antimicrobial agents. Treat varicella infections with acyclovir. Prophylactic acyclovir is probably not beneficial in the prevention of varicella. Live viral vaccines should be avoided in these patients. The recently developed attenuated varicella vaccine may help reduce varicella infection in patients with cartilage-hair hypoplasia; however, no studies have confirmed this, and patients with cartilage-hair hypoplasia may develop vaccine-related varicella infection.

Antiviral agents

Nucleoside analogs are initially phosphorylated by viral thymidine kinase (TK) to eventually form a nucleoside triphosphate.

Acyclovir (Zovirax)

Synthetic purine nucleoside analogue that inhibits herpes virus replication. Herpes virus TK, but not host cell TK, uses acyclovir as a purine nucleoside, converting it into acyclovir monophosphate, a nucleotide analogue. Guanylate kinase converts the monophosphate form into diphosphate and triphosphate analogues that inhibit viral DNA replication.

Dosing

Adult

200 mg PO q6h for 5 d
10 mg/kg (dose based on ideal body weight) IV infused over 1 h q8h for 7 d in patients with normal renal function

Pediatric

20 mg/kg/d PO q6h for 5 d; not to exceed 800 mg/d
Alternatively, 15-30 mg/kg/d or 750-1500 mg/m²/d IV infused over 1 h q8h for 7 d in patients with normal renal function; dose based on ideal body weight

Interactions

Caution with coadministration of nephrotoxic drugs (eg, cyclosporine); concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose by increasing dosing interval with impaired renal function

Vaccines

Active immunization increases resistance to infection. Vaccines consist of microorganisms or cellular components, which act as antigens. Vaccine administration stimulates the production of antibodies with specific protective properties.

Varicella virus vaccine, live attenuated (Varivax)

Attenuated live varicella virus prepared from the Oka/Merck strain. It is propagated in human diploid cell cultures (MRC-5). Each 0.5-mL dose (when reconstituted) contains 1350 PFU of varicella, sucrose, and gelatin; residual components of MRC-5 DNA and protein; plus trace quantities of neomycin and fetal bovine serum. Indicated for vaccination against varicella in individuals >1 y.

Dosing

Adult

0.5 mL SC initially, follow in 4-8 wk with second 0.5-mL dose

Pediatric

First dose: Minimum age is 12 mo, 0.5 mL SC
Second dose: Typically administered between ages 4-6 y, but may administer before age 4, provided at least 3 mo have elapsed since first dose
>13 years: Administer as in adults

Interactions

Avoid salicylates (aspirin) for 6 wk following vaccination (Reye syndrome has been reported following use of aspirin during natural varicella infection); defer vaccination for >5 mo following administration of blood, plasma, or immune globulin or VZIG because antivaricella antibodies in these preparations may decrease vaccine effect

Contraindications

Documented hypersensitivity; primary or acquired immunodeficiency; patients receiving immunosuppressive therapy may develop a more extensive vaccine-associated rash or disseminated disease; active untreated tuberculosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Because the vaccine is live, recipients may transmit the vaccine virus to close contacts; avoid close contact with susceptible high-risk people (ie, newborns, pregnant women, immunocompromised patients)

Follow-up

Further Outpatient Care

• In children, the greatest mortality rate associated with cartilage-hair hypoplasia (CHH) occurs in young patients with severely impaired T-cell immune function. These patients should probably be evaluated yearly during early childhood. Closely monitor T-cell and B-cell immune function in these patients.
• In adults, the greatest morbidity and mortality is related chronic lung disease secondary to their immunodeficiency. In addition, the risk for malignancy, such as lymphoma, increases with age. Yearly CBC count to monitor for lymphoma is recommended.

Inpatient & Outpatient Medications

• Live viral vaccine should be avoided.
• Some investigators have suggested prophylactic use of acyclovir. However, no long-term studies have studied acyclovir prophylaxis in patients with cartilage-hair hypoplasia. A few studies have used short-term acyclovir prophylaxis in patients who have undergone bone marrow transplantation (BMT), in patients with renal disease receiving corticosteroids, and in healthy patients postexposure to varicella.
• In patients who have undergone BMT, acyclovir prophylaxis administered for 6 months posttransplantation reduced the incidence of varicella infection from 13% to 0%.³¹

Complications

• Numerous orthopedic complications present problems for patients with short-limb dwarfism.
• Susceptibility to infections may be increased because of impaired T-cell and B-cell immunity. 
• Risk of malignancy, especially leukemia and lymphoma, has been reported;
• Risk of GI obstruction in infancy, especially due to Hirschsprung disease, needs to be monitored.

Prognosis

• Mortality rates among young patients with cartilage-hair hypoplasia are greatest in those with severely impaired T-cell immunity. Similarly, development of lymphoma also correlates with the severity of impaired cellular immunity.

Patient Education

• Patients and their families should be educated regarding the problems associated with cartilage-hair hypoplasia. In particular, provide information concerning the immune deficiency, immune system, and immune defect. The family should be taught the risks of infections, how to recognize signs and symptoms of infections, and the importance of prompt treatment of infections. 
• An excellent resource for parents and patients with primary immunodeficiency disorders is the Immune Deficiency Foundation (IDF). This is a foundation for the public started by Marcia Boyle in Baltimore, Maryland, with a medical advisory board consisting of recognized experts in the field of immunodeficiency. Educational material for families can be obtained from the IDF. Many cities throughout the United States have local chapters.  Immune Deficiency Foundation
  40 W. Chesapeake Avenue, Suite 308
  Towson, MD 21204
  Tel: 800-296-4433; Fax: 410-321-9165
  Email: idf@primaryimmune.org
• An additional resource for families with children with primary immunodeficiency disorders is The Jeffrey Modell Foundation.Jeffrey Modell Foundation
  747 3rd Avenue
  New York, NY10017
  Tel: 1-800-JEFF-855

Miscellaneous

Medicolegal Pitfalls

• Failure to confirm diagnosis and to provide appropriate treatment is a pitfall; because cartilage-hair hypoplasia is a congenital primary immunodeficiency that affects the T-cell and B-cell immune system, patients with cartilage-hair hypoplasia are susceptible to life-threatening infections.

Multimedia

Media file 1: Hair of a patient with cartilage-hair hypoplasia (left) compared with that of a typical individual. The hair of the patient with cartilage-hair hypoplasia has a smaller diameter because the central core is absent.

References

1. Abinun M, Kaitila I, Casanova J-L. Immunodeficiencies with associated manifestations of skin, hair, teeth, and skeleton. In: Ochs HS, Smith, CIE, Puck JM. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. 2^nd ed. New York, NY: Oxford University Press, Inc; 2007:513-24.

2. McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Egeland JA. Dwarfism in the Amish. II. Cartilage-hair hypoplasia. Bull Johns Hopkins Hosp. May 1965;116:285-326. [Medline].

3. Hermanns P, Tran A, Munivez E, et al. RMRP mutations in cartilage-hair hypoplasia. Am J Med Genet A. Oct 1 2006;140(19):2121-30. [Medline].

4. Thiel CT, Horn D, Zabel B, et al. Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator. Am J Hum Genet. Nov 2005;77(5):795-806. [Medline].

5. Makitie O, Kaitila I, Savilahti E. Deficiency of humoral immunity in cartilage-hair hypoplasia. J Pediatr. 2000;137:487-492.

6. Ridanpaa M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. Jan 26 2001;104(2):195-203. [Medline].

7. [Best Evidence] Joshi AY, Iyer VN, Hagan JB, St Sauver JL, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin Proc. 2009;84(1):16-22. [Medline].

8. Makitie O, Marttinen E, Kaitila I. Skeletal growth in cartilage-hair hypoplasia. A radiological study of 82 patients. Pediatr Radiol. 1992;22(6):434-9. [Medline].

9. Makitie O, Kaitila I. Cartilage-hair hypoplasia--clinical manifestations in 108 Finnish patients. Eur J Pediatr. Mar 1993;152(3):211-7. [Medline].

10. 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].

11. Makitie O, Kaitila I, Savilahti E. Susceptibility to infections and in vitro immune function in cartilage-hair hypoplasia. Eur J Pediatr. 1998;157:816-820.

12. Makitie O, Pukkala E, Teppo L, Kaitila I. Increased incidence of cancer in patients with cartilage-hair hypoplasia. J Pediatr. Mar 1999;134(3):315-8. [Medline].

13. Makitie O, Kaitila I, Rintala R. Hirschsprung disease associated with severe cartilage-hair hypoplasia. J Pediatr. 2001;138:929-931.

14. Ammann RA, Duppenthaler A, Bux J, Aebi C. Granulocyte colony-stimulating factor-responsive chronic neutropenia in cartilage-hair hypoplasia. J Pediatr Hematol Oncol. Jun 2004;26(6):379-81. [Medline].

15. Makitie O, Kaitila I. Growth in diastrophic dysplasia. J Pediatr. Apr 1997;130(4):641-6. [Medline].

16. Kooijman R, van der Burgt CJ, Weemaes CM, et al. T cell subsets and T cell function in cartilage-hair hypoplasia. Scand J Immunol. Aug 1997;46(2):209-15. [Medline].

17. Lux SE, Johnston RB Jr, August CS, et al. Chronic neutropenia and abnormal cellular immunity in cartilage-hair hypoplasia. N Engl J Med. Jan 29 1970;282(5):231-6. [Medline].

18. Williams MS, Ettinger RS, Hermanns P, et al. The natural history of severe anemia in cartilage-hair hypoplasia. Am J Med Genet A. Sep 15 2005;138(1):35-40. [Medline].

19. Glass RB, Tifft CJ. Radiologic changes in infancy in McKusick cartilage hair hypoplasia. Am J Med Genet. Oct 8 1999;86(4):312-5. [Medline].

20. [Guideline] CDC. Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR Morb Mortal Wkly Rep. Mar 14 2008;57(10):258-60. [Medline].

21. Berthet F, Siegrist CA, Ozsahin H, et al. Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia. Eur J Pediatr. Apr 1996;155(4):286-90. [Medline].

22. Guggenheim R, Somech R, Grunebaum E, Atkinson A, Roifman CM. Bone marrow transplantation for cartilage-hair-hypoplasia. Bone Marrow Transplant. Dec 2006;38(11):751-6. [Medline].

23. Harada D, Yamanaka Y, Ueda K, et al. An effective case of growth hormone treatment on cartilage-hair hypoplasia. Bone. Feb 2005;36(2):317-22. [Medline].

24. Bocca G, Weemaes CM, van der Burgt I, Otten BJ. Growth hormone treatment in cartilage-hair hypoplasia: effects on growth and the immune system. J Pediatr Endocrinol Metab. Jan 2004;17(1):47-54. [Medline].

25. Durandy A, Wahn V, Petteway S, Gelfand EW. Immunoglobulin replacement therapy in primary antibody deficiency diseases – maximizing success. Int Arch Allergy Immunol. 2005;136:217-229.

26. Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122:210-212.

27. Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. Nov 2008;28(4):833-49, ix. [Medline].

28. Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78, viii. [Medline].

29. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].

30. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005;62(11 Pt 2)):78S-84S.

31. Steer CB, Szer J, Sasadeusz J, et al. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant. Mar 2000;25(6):657-64. [Medline].

32. Huang SW, Ammann AJ, Levy RL, Hong R, Bach FH. Treatment of severe combined immunodeficiency by a small number of pretreated nonmatched marrow cells. Transplantation. Jan 1973;15(1):174-6. [Medline].

33. Makitie O, Pukkala E, Kaitila I. Increased mortality in cartilage-hair hypoplasia. Arch Dis Child. Jan 2001;84(1):65-67. [Medline].

34. Makitie O, Sulisalo T, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia. J Med Genet. Jan 1995;32(1):39-43. [Medline].

35. Makitie O, Tapanainen PJ, Dunkel L, Siimes MA. Impaired spermatogenesis: an unrecognized feature of cartilage-hair hypoplasia. Ann Med. 2001;33:201-205.

36. Polmar SH, Pierce GF. Cartilage hair hypoplasia: immunological aspects and their clinical implications. Clin Immunol Immunopathol. Jul 1986;40(1):87-93. [Medline].

37. Sulisalo T, Makitie O, Sistonen P, et al. Uniparental disomy in cartilage-hair hypoplasia. Eur J Hum Genet. Jan-Feb 1997;5(1):35-42. [Medline].

Keywords

cartilage-hair hypoplasia, CHH, short-limb dwarfism, metaphyseal dysplasia, spondyloepiphyseal dysplasia, immunodeficiency, metaphyseal chondrodysplasia McKusick type, T-cell immunodeficiency, isolated B-cell immunodeficiency, varicella infection, severe combined immunodeficiency, SCID, leukemia, lymphoma, graft versus host disease, non-Hodgkin lymphoma, basal cell carcinoma, anal stenosis, esophageal atresia, treatment, diagnosis

Contributor Information and Disclosures

Author

Alan P Knutsen, MD, Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center
Alan P Knutsen, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and Clinical Immunology Society
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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