DISEASE CARD

Disease group Ectodermal Dysplasia
DISEASE NAME CARTILAGE-HAIR HYPOPLASIA
Synonymous Metaphyseal Chondrodysplasia, McKusick Type
Estimated prevalence -
OMIM 250250
Inheritance Autosomal Recessive
Gene (s) RMRP (157660)

Definition

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive ectodermal dysplasia disorder. Also known as metaphyseal chondrodysplasia, CHH was first identified in 1965 by McKusick et al. presents with short-limbed dwarfism, sparse hypochromic hair and variable degree of immune dysfunction. Mutations in the gene for RMRP (RNase RMP) have been identified as the molecular basis for this inherited disorder.

Clinical Description

Children born with CHH may be subject to opportunistic infections due to T and/or B-cell immunodeficiency with a reported increased susceptibility to varicella-zoster infection. Several reports of increased susceptibility to malignancies suchas leukaemia and non-Hodgkin's lymphoma have also been documented. Gastrointestinal defects can occur and mayinclude Hirschprung's disease and malabsorption. Varying degrees of anaemia and/or neutropenia may present in childhood which requires careful patient management.

Mortality rate is increased due to infections, malignancy (particularly lymphoma at a median age of 33 years, basal cell carcinoma in sun exposed areas) and pulmonary disease (e.g. recurrent respiratory tract infections, bronchiectasis, asthma, interstitial pneumonitis)

Pathogenesis

In 2001, Ridanpaa et al. reported mutations in the RMRP gene on locus 9p21-p12 as the molecular basis of CHH. RMRP is a ribonucleoprotein required for cell growth and, 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.

Diagnosis

Diagnosis is usually made at birth, though the clinical features of short-limbed dwarfism may also be detected in utero. Skeletal radiology is the most useful diagnostic tool and shows shortened long tubular bones, a curved femur with rounded distal epiphyses, anterior angulation of the sternum and short ribs. Flaring of the ribs at the costochondral junction is also characteristic. Sequencing of genomic DNA for RMRP mutation analysis will help confirm the diagnosis and will aid in genetic counseling.

Treatment

The mainstay of treatment is the careful monitoring and treatment of symptoms and signs of immunodeficiency and opportunistic infection (especially varicella zoster). Prevention by immunization with pneumococcal and annual influenza vaccines can be recommended. Patients should be monitored for lymphopaenia, neutropaenia and anemia - all of which may occur early in infancy. Lymphoma monitoring should also include radiologic evaluation (abdominal ultrasound and other imaging as needed).

Regular screening for further malignancies include dermatologic examination for skin cancer, gynaecologic assessment and cervical cancer screening.

Haematopoietic stem cell transplantation can cure immune dysfunction, but its benefits in mildly symptomatic patients with CHH remain debatable and thus recommended primarily for patients with severe combined immunedeficiency or persistent transfusion-dependent anaemia. Measuring T‐cell receptor excision circles (TREC) count in the newborn screening (usually low or absent in CHH) may become an important prognostic indicator in CHH.

References:

1. Vakkilainen S, Taskinen M, Mäkitie O. Immunodeficiency in cartilage-hair hypoplasia: Pathogenesis, clinical course and management. Scand J Immunol. 2020;92(4):e12913.

2. Scott EM, Chandra S, Li J, Robinette ED, Brown MF, Wenger OK. Abnormal Newborn Screening Follow-up for Severe Combined Immunodeficiency in an Amish Cohort with Cartilage-Hair Hypoplasia. J Clin Immunol. 2020;40(2):321-328.