Cartilage-Hair Hypoplasia 

Updated: Aug 06, 2019
Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD 

Overview

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.

The immunodeficiency in cartilage-hair hypoplasia may be an isolated T-cell immunodeficiency, isolated B-cell immunodeficiency, or combined T-cell and B-cell immunodeficiency.

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.[3]

Pathophysiology

The genetic defect in cartilage-hair hypoplasia has been identified as a mutation in the gene for RNAase RMRP, mapped to 9p12.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13] RMRP is a ribonucleoprotein present in the nucleus and mitochondria. RNAase RMRP has multiple functions: cleavage of the upstream 5.8S rRNA junction site necessary for ribosome assembly and associated with bone dysplasia; mRNA cleavage of cyclin B2 mRNA necessary for cell cycle progression, associated with susceptibility to cancer, immune deficiency, anemia, and hair hypoplasia; processing of mitochondrial RNA in the yeast RMRP ortholog; and interaction of RMRP and hTERT leads to an RNA-dependent RNA polymerase activity leading to siRNA altering gene expression. 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.[5]

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.[14] These mutations interfere with the transcription of the RMRP gene and are considered null mutations. Kavadas et al reported that mutations in the promoter region are associated with immune defects.[15] The second consists of single nucleotide substitutions and other changes that involve at most 2 nucleotides in highly conserved regions of the gene.These are considered leaky mutations and result in variable expression of the gene, which may explain the variable phenotype seen in cartilage-hair hypoplasia. These 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 occurs in 30-50% of patients with cartilage-hair hypoplasia and causes an alteration in ribosomal processing.[10] RMRP mutations that reduce ribosomal RNA cleavage are associated with bone dysplasia; whereas, mutations that affect mRNA cleavage are associatedwith hair hypoplasia, immunodeficiency, and dermatologic abnormalities.[8]   Recently, it was observed that RMRP associates with the human telomerase catalytic subunit (hTERT).[16] The 3’ end of RMRP is essential for RNA dependent RNA polymerase acitivity of the RMRP-hTERT complex. 

Although the immune defect primarily affects the T-cell system, mutations of RMRP result in more generalized hematopoietic impairments.[17] 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.

Epidemiology

Frequency

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.[18]

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.[19]

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.[20] 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.[21] 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.

Demographics

First reported among Amish children, the disorder has also been reported in other groups throughout the United States, Europe, Asia, and Mexico. Cartilage-hair hypoplasia occurs most often in the Old Order Amish population, where it affects about 1 in 1,300 newborns. In people of Finnish descent, its incidence is approximately 1 in 20,000. Outside of these populations, the condition is rare, and its specific incidence is not known. It has been reported in individuals of European and Japanese descent.[22]

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

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.[20, 19] 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.

 

Presentation

History

The clinical findings in cartilage hair-hypoplasia (CHH) are outlined below.[17, 20, 23, 24, 25, 26] The predominant features include disproportionate short-limbed stature, hair hypoplasia, and immunodeficiency.

The frequencies of reported features are as follows:[1]

  • Short limbed/short stature - 100%
  • Hair hypoplasia - 93%
  • Immunodeficiency in 86% of patients
    • T cell immunodeficiency, 58% in vitro immunodeficiency
    • B cell immunodeficiency, especially specific pneumococcal antibody deficiency
  • Recurrent infections - 56% of patients
    • Varicella most common severe infection
    • Bronchiectasis
  • 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.The hair of the scalp, eyebrows and eyelashes  is characteristic in CHH; it is fair, thin, sparse, and white or yellow in color, beginning in the newborn period. In addition, the hair is thinner due to decreased central pigment core core.  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.

Hair of a patient with cartilage-hair hypoplasia ( 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 pigmented core is absent.

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, Pneumocystis carinii, and cytomegalovirus (CMV). In these patients with cartilage hair-hypoplasia, the immunodeficiency may resemble severe combined immunodeficiency (SCID) or Omenn syndrome (OS).[14] OS is characterized as SCID associated with generalized erythroderma, lymphadenopathy, hepatosplenomegaly, and eosinophilia. 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.[17, 27] Toivianen-Salo et al reported that cartilage hair-hypoplasia patients are also at risk of developing bronchiectasis.[28] Autoimmune cytopenia, such as hemolytic anemia and autoimmune neutropenia, and hypothyroidism have also been reported. Moshous et al reported epithelial cell granulomatous lesions in the skin and internal organs of 4 patients with cartilage hair-hypoplasia.

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.[20, 29] Head size is within the normal reference range, hands are short and pudgy, and skin forms redundant folds around the neck and extremities.

Physical findings include the following:

  • 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. Hair of the scalp, eyebrows, and eyelashes at birth is light in color, fine, and sparse and lacks a central pigmented core.

  • 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. RMRP mutations have also been identified in three additional syndromes: metaphyseal dysplasia without hypotrichosis (OMIM 250460), kyphomelic dysplasia (OMIM 211350), and anauxetic dysplasia (OMIM 607095).[11, 30, 31]

 

DDx

 

Workup

Laboratory Studies

T-cell immunodeficiency

Immunologic dysfunction occurs in approximately 86% of patients with cartilage hair-hypoplasia.[23, 32] Notarangelo et al[14] and Ip et al[12]  reported on the heterogeneity of the immunodeficiency. The immunodeficiency predominantly affects T-cell immunity.

Lymphopenia and decreased CD3+, CD4+, and CD8+ T cells present in early infancy. There may be a selective decrease of CD8+ T cells. Skewing of TCRab repertoire may be present.

T cell lymphoproliferative responses to mitogens such as phytohemagglutinin ([PHA], concanavalin A [Con A], and pokeweed mitogen [PWM] and to antigens such as Candidaalbicans and tetanus toxoid may be decreased.

Delayed-type hypersensitivity (DTH) responses to recall antigens are absent, anergic. de la Fuente et al[33] reported decreased CD4+ CD45RA+ CD31+ –naïve T cells in patients with cartilage hair-hypoplasia. In addition, T-cell receptor rearrangement circles (TRECs) were reduced in cartilage hair-hypoplasia patients, indicating decreased thymopoiesis.

T cells from cartilage hair-hypoplasia patients also demonstrated defects in cell cycle control with reduced cell divisions and increased apoptosis.

Previous studies demonstrated decreased stimulated T-cell interleukin 2 and interferon-γ synthesis and defective CD25 expression. There also appears to be increased T cell apoptosis associated with increased expression of Fas, FAS ligand (FasL), proapoptotic Bax molecules, whereas expression of antiapoptotic bcl-2 and inhibitory of apoptosisi (IAP) molecules are reduced.

B-cell immunodeficiency

Serum immunoglobulin levels and antibody responses to immunizations are usually normal, although a few patients with antibody deficiency have been described. Approximately 35% of patients have abnormal humoral immunity, consisting of immunoglobulin A (IgA) and/or immunoglobulin G2 (IgG2) or immunoglobulin G4 (IgG4) deficiency.[17]   Although earlier studies reported that antibody responses to protein immunization were normal, data regarding bacterial polysaccharide antigens must be obtained. Occasionally, hypogammaglobulinemia consistent with common variable immunodeficiency has been described. CD27+ IgD-switched B cells are normal.[33] The T- and B-cell immune function should be closely monitored, perhaps yearly.

Anemia

Cyclic neutropenia is occasionally associated with cartilage-hair hypoplasia.[34] 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.[35, 36]

Imaging Studies

Radiography reveals bony scalloping, irregular sclerosis, cystic changes of the widened metaphyses, and metaphysial dysplasia in cartilage-hair hypoplasia.[19, 29, 36] 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.

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.[37, 38] BMT can prevent lymphoma. Bordon et al reported on the outcome of 16 patients with cartilage hair-hypoplasia who received BMT.[39] Thirteen patients were transplanted in early childhood (~2.5 y) and 3 patients were transplanted at adolescent age. Ten patients, 62.5%, were long-term survivors; T-cell numbers and function were normal. Kavadas et al reported an additional 4 patients with cartilage hair-hypoplasia who had severe T-cell immunodeficiency successfully transplanted with matched unrelated donor stem cells during infancy.[15]

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.

The measles mumps rubella (MMR) vaccine may be given in the second year of life in patients with cartilage-hair hypoplasia without severe combined immunodeficiency. Rotavirus vaccine, a live-viral vaccine given in the first year of life, should be avoided.

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.[40]

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 (SCIG), therapy is indicated

Treatment of neutropenia with granulocyte colony-stimulating factor (G-CSF) has been successful in patients with cartilage-hair hypoplasia.[27] 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.[27]

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.[41] 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.[42] 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.

Obara-Moszynska et al reported the use of recombinant human growth hormone in an 8-year-old girl with cartilage hair-hypoplasia.[43] . Recombinant growth hormone rhGH therapy was used for 4 years and 7 months and had a significant effect on height from -4.00 to -2.98 height SD score.[43]

Surgical Care

Various palliative bone reconstruction procedures have been performed in patients with other short-limb dwarfism disorders. Medical and surgical correction for scoliosis may be necessary. Arthroscopy and/or joint replacement surgery may be beneficial. 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. Genu varum, with or without knee pain, is the most common reason a patient with CHH will seek orthopaedic consultation.[44] 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

Medication Summary

IVIG replacement therapy

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.[45, 46] 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).

Table 1. Immunoglobulin, Intravenous [47, 48, 49, 50] (Open Table in a new window)

Brand (Manufacturer)

Manufacturing Process

pH

Additives (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])

Parenteral Form and Final Concentrations

IgA Content (mcg/mL)

Carimune NF

(CSL Behring)

Kistler-Nitschmann fractionation; pH 4, nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3%, 6%, 9%, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25M glycine

Ready-for-use liquid 10%

37

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Does not contain carbohydrate stabilizers (eg, sucrose, maltose), contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation

4.8-5.1

Contains sorbitol (40 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation; pH 4 incubation, trace pepsin, nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl

Lyophilized powder 3%, 6%, 9%, 12%

720

Privigen Liquid 10%

(CSL Behring)

Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration

4.6-5

L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)

Ready-for-use liquid 10%

< 25

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

Class Summary

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.

Valacyclovir (Valtrex)

Valacyclovir is metabolized to acyclovir and L-valine with better oral absorption than acyclovir.

Vaccines

Class Summary

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.

 

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%.[51]

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, NY 10017

Tel: 1-800-JEFF-855