Cartilage Hair Hypoplasia

Cartilage hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia with short limbed short stature, fine sparse hair and a variable immunodeficiency. It is caused by variants in RMRP, which encodes the RNA of the mitochondrial RNA processing complex.

Pathophysiology. Defective ribonucleoprotein function disturbs cartilage growth, hair follicle growth and lymphocyte proliferation. Immune disease ranges from none to combined immunodeficiency.

A founder variant (n.70A>G) is common in Finland and among the Old Order Amish, with a carrier frequency of about 1 in 76 in Finland. In other populations it is rare.

Anaemia, Hirschsprung disease, and risks of lymphoma and basal cell carcinoma complicate the disorder.

• Short stature with short limbs, bowed legs, joint hypermobility (especially fingers) and limited elbow extension
• Fine, sparse, light coloured hair
• Recurrent respiratory infection, with severe varicella and complications from live vaccines in some
• Combined immunodeficiency in a minority; Omenn like features rarely
• Macrocytic hypoplastic anaemia and neutropenia
• Hirschsprung disease and malabsorption
• Bronchiectasis in those with antibody failure
• Lymphoma and basal cell carcinoma in adulthood

• Skeletal survey: metaphyseal flaring and irregularity, short tubular bones, scoliosis.
• Genetic testing of RMRP (founder variant n.70A>G and other variants).
• Lymphocyte subsets: low T cells (especially naive CD4 cells), reduced proliferation to mitogens.
• Immunoglobulins and specific antibody responses.
• Full blood count with differential and reticulocytes; mean cell volume.
• Rectal biopsy or contrast study for suspected Hirschsprung disease.
• Hair examination for hypoplasia.

Differential diagnosis.

• Other metaphyseal chondrodysplasias (Schmid type, Jansen type)
• Shwachman-Diamond syndrome
• Diamond-Blackfan anaemia
• Short limb skeletal dysplasias
• Combined immunodeficiency with other causes
• Achondroplasia

• Immunological assessment before any live vaccine: check CD4 count and T cell function. Give no live vaccine (BCG, oral polio, measles-mumps-rubella, varicella) if T cell numbers are low or function is poor.
• Immunoglobulin replacement for antibody failure with infection: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Pneumocystis prophylaxis with T cell lymphopenia: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly).
• Antiviral treatment: varicella or zoster with aciclovir 10 mg/kg intravenously every 8 hours (adjust to renal function); recurrent herpes prophylaxis aciclovir 400 mg orally twice daily in adults.
• Anaemia: transfuse irradiated, leukodepleted red cells when needed; consider a corticosteroid course (prednisolone 1 mg/kg daily, maximum 60 mg, then taper) for hypoplastic anaemia; iron chelation if transfusion dependent.
• Neutropenia: filgrastim 1 to 5 microgram/kg subcutaneously daily or on alternate days, titrated to keep neutrophils at 1.0 x 109/L or more.
• Hirschsprung disease: surgical resection.
• Haematopoietic stem cell transplantation for severe combined immunodeficiency like disease; it does not correct skeletal disease.
• Skeletal care: orthopaedic review for bowing and scoliosis, avoiding spinal injury in hypermobile children.
• Cancer surveillance: yearly skin examination, and prompt biopsy of new nodes or masses.

Special groups.

• Children with growth failure: growth hormone does not correct the skeletal dysplasia.
• Pregnancy: risk of a small pelvis, so obstetric planning.

Monitoring. Growth and height every 6 months. Full blood count every 3 to 6 months. Lymphocyte subsets and trough IgG every 6 months. Skin and lymph node examination yearly.

Referral and escalation. Refer to paediatric immunology and genetics. Urgent for severe varicella, sepsis, intestinal obstruction, or severe anaemia.