AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Cartilage-hair hypoplasia (CHH) is an autosomal recessive inherited disorder that results in short-limb dwarfism and is predominantly associated with immunodeficiency. 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 is an isolated T-cell immunodeficiency, isolated B-cell immunodeficiency, or combined T- and B-cell immunodeficiency.

Although originally described by McKusik et al in 1964 in Amish children and known as metaphyseal chondrodysplasia McKusick type (OMIM no. 250250), cartilage-hair hypoplasia has been described in non-Amish persons throughout the United States, Europe, and Mexico.¹ 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 9p21-p12. 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, Thiel et al showed that different RMRP gene mutations led to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell-cycle regulation.²

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, in 2000, Makitie et al reported a more generalized hematopoietic impairment.³ In their studies, 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, Ridanpaa et al (2001) reported a frequency of 1 per 1340 population with a carrier rate of 1 per 19.⁴

International

In Finland, Makitie et al (1992) reported the frequency of cartilage-hair hypoplasia to be 1 per 23,000 live births, with a carrier rate of 1 per 76.⁵ 

Mortality/Morbidity

Persons with cartilage-hair hypoplasia may be subject to infections with opportunistic microorganisms, principally life-threatening varicella infections. Makitie et al (1993) reported that 88% of 108 Finnish patients with cartilage-hair hypoplasia had defective cellular immunity, and 56% had increased susceptibility to infections.⁶ 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.

Buckley et al (1997) reported one patient with cartilage-hair hypoplasia in a series of 108 patients with severe combined immunodeficiency (SCID).⁷ 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. Cartilage-hair hypoplasia is a rare cause of SCID.

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.

• Immunodeficiency in individuals with cartilage-hair hypoplasia varies, with limited susceptibility to infections. Makitie et al (1992 and 1993) have reported an increased susceptibility to infections of 31-56%.^{5, 6} Thus, many children with cartilage-hair hypoplasia may live healthy lives. Typically, infections are limited to varicella and may occur in early childhood.
• Children with cartilage-hair hypoplasia that causes SCID present in early infancy with susceptibility to overwhelming and opportunistic infections.

CLINICAL

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History

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. Ammann et al (1974) have also reported patients with cartilage-hair hypoplasia who had a predominant B-cell immunodeficiency with increased susceptibility to bacterial sinopulmonary infections.⁸

Individuals with cartilage-hair hypoplasia are at increased risk for leukemia and lymphoma. Both Hodgkin and non-Hodgkin lymphoma have been reported.

Physical

Abnormal physical findings are present at birth. 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 Image 1). 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
  


• 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, Ridanpaa et al identified mutations in the RNA component of the gene for RNase MRP on chromosome band 9p13 as the genetic defect in Finnish patients with cartilage-hair hypoplasia.⁴ RNase MRP has 2 functions, cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA.

DIFFERENTIALS

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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- and B-cell defects. The hair abnormality distinguishes cartilage-hair hypoplasia 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

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Lab Studies

• 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.
• Makitie et al (1998) reported that 57% of 35 Finnish patients with cartilage-hair hypoplasia had decreased T-cell immunity.⁹ Makitie et al (2000) also reported that 35% of their patients had abnormal humoral immunity, consisting of immunoglobulin A (IgA) and/or immunoglobulin G2 (IgG2) or immunoglobulin G4 (IgG4) deficiency.³ Although earlier studies reported that antibody responses to protein immunization were normal, data regarding bacterial polysaccharide antigens must be obtained. The T- and B-cell immune function should be monitored closely, perhaps on a yearly basis.
• Cyclic neutropenia is occasionally associated with cartilage-hair hypoplasia. Megaloblastic anemia unrelated to folate and vitamin B-12 deficiency has been reported. 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.¹⁰

Imaging Studies

• Radiography reveals bony scalloping, irregular sclerosis, cystic changes of the widened metaphyses, and metaphysial dysplasia. 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 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

Section 6 of 11  

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Medical Care

The treatment of the immunodeficiency depends on whether an isolated T-cell defect, isolated B-cell defect, or a combined T- 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. However, prophylaxis with acyclovir in other patients with T-cell impairment who are exposed to varicella may not prevent varicella infection.

Recently, 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.

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.

In patients with a severe T-cell immunodeficiency with or without concomitant B-cell immunodeficiency, treatment as given to patients with SCID is necessary. Thus, T-cell immune reconstitution using bone marrow transplantation (BMT) is performed. BMT corrects the immunodeficiency but not the skeletal abnormalities.¹¹ 

Recently, Guggenheim et al (2006) reported successful immune reconstitution in 3 patients with cartilage-hair hypoplasia and SCID who were treated with BMT.¹² The 3 patients underwent transplantation during infancy and received pretransplant conditioning. One of the 3 patients received a related donor transplant, while the other 2 patients received matched unrelated donor transplants. The patients’ immune systems were fully reconstituted and were alive 6, 12, and 21 years posttransplantation. The transplantation did not affect the skeletal dysplasia. Hopefully, BMT will prevent lymphoma.

Ammann et al (2004) reported the successful use of granulocyte colony-stimulating factor (G-CSF) in the treatment of neutropenia in patients with cartilage-hair hypoplasia.⁸ 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.⁸

Conflicting results have been reported in the use of growth hormone to treat 5 patients with cartilage-hair hypoplasia. Harada et al (2005) reported on a 3-year-old Japanese boy who was treated with growth hormone for 7 years and underwent a leg-lengthening surgical procedure.¹³ The height improved from -4.2 standard deviation (SD) to -2.1 SD. Bocca et al (2004) used growth hormone to treat 4 patients with cartilage-hair hypoplasia, including 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.¹⁴ 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

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Replacement therapy with intravenous immunoglobulin (IVIG) in patients with primary immune deficiencies

The overall consensus among clinical immunologists is that IVIG administered at a dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. 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 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.

Immunoglobulin E (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 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

*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).

Contents of table are adapted from the following sources:

1. Manufacturers' literature.
2. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.
3. Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.

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.

Drug Category: Antiviral agents

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

Drug Category: 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.

FOLLOW-UP

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Further Outpatient Care

• Closely monitor T- and B-cell immune function in these patients. The greatest mortality rate associated with cartilage-hair hypoplasia occurs in young patients with severely impaired T-cell immune function. These patients should probably be evaluated yearly during early childhood.

In/Out Patient Meds

• 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 BMT, in patients with renal disease receiving corticosteroids, and in healthy patients postexposure to varicella. In patients who have undergone BMT, Steer et al (2000) reported that acyclovir prophylaxis administered for 6 months posttransplantation reduced the incidence of varicella infection from 13% to 0%.¹⁵

Complications

• Numerous orthopedic complications present problems for patients with short-limb dwarfism.
• In addition, in patients with cartilage-hair hypoplasia, susceptibility to infections may be increased because of impaired T- and B-cell immunity. Risk of malignancy, especially leukemia and lymphoma, has been reported; monitoring these patients is necessary. These patients must be monitored because of a risk of GI obstruction in infancy, especially Hirschsprung disease.

Prognosis

• Mortality rates among young patients with cartilage-hair hypoplasia are greatest in those with severely impaired of 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, Md, 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.
  
747 3rd Avenue
New York, NY 10017
Tel: 1-800-JEFF-855

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal 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- and B-cell immune system, patients with cartilage-hair hypoplasia are susceptible to life-threatening infections.

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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1. 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].
2. 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].
3. Makitie O, Kaitila I, Savilahti E. Deficiency of humoral immunity in cartilage-hair hypoplasia. J Pediatr. Oct 2000;137(4):487-92. [Medline].
4. 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].
5. 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].
6. Makitie O, Kaitila I. Cartilage-hair hypoplasia--clinical manifestations in 108 Finnish patients. Eur J Pediatr. Mar 1993;152(3):211-7. [Medline].
7. 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].
8. 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].
9. Makitie O, Kaitila I, Savilahti E. Susceptibility to infections and in vitro immune functions in cartilage-hair hypoplasia. Eur J Pediatr. Oct 1998;157(10):816-20. [Medline].
10. 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].
11. 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].
12. 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].
13. 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].
14. 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].
15. 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].
16. 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].
17. 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].
18. 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].
19. 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].
20. 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].
21. Makitie O, Kaitila I. Growth in diastrophic dysplasia. J Pediatr. Apr 1997;130(4):641-6. [Medline].
22. Makitie O, Pukkala E, Kaitila I. Increased mortality in cartilage-hair hypoplasia. Arch Dis Child. Jan 2001;84(1):65-67. [Medline].
23. 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].
24. Makitie O, Sulisalo T, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia. J Med Genet. Jan 1995;32(1):39-43. [Medline].
25. Polmar SH, Pierce GF. Cartilage hair hypoplasia: immunological aspects and their clinical implications. Clin Immunol Immunopathol. Jul 1986;40(1):87-93. [Medline].
26. 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].

Article Last Updated: Jul 11, 2007