Clinical characteristics: The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes:
Metaphyseal dysplasia without hypotrichosis (MDWH)
Cartilage-hair hypoplasia (CHH)
Anauxetic dysplasia (AD)
CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
Diagnosis/testing: Diagnosis of the CHH-AD spectrum disorders is based on clinical findings, characteristic radiographic findings, and in some cases, evidence of immune dysfunction, macrocytic anemia, and/or gastrointestinal problems. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in RMRP by molecular genetic testing can confirm the diagnosis and allow for family studies.
Management: Treatment of manifestations:
In the newborn. Hypoplastic anemia may require repeated blood transfusions; congenital megacolon or Hirschsprung disease may require surgical resection.
In childhood. Surgery may be needed to fuse unstable cervical vertebrae and/or to treat progressive kyphoscoliosis that compromises lung function in AD; corrective osteotomies may be required to treat progressive varus deformity associated with ligament laxity in the knees. Pubertal maturation may be delayed and may require hormonal induction.
For those with immunodeficiency. Treatment of underlying infections based on their type, location, and severity; immediate antiviral treatment with intravenous high-dose acyclovir for varicella; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; physiotherapy and acute and long-term medical management for bronchiectasis. Recurrent severe infections and/or the presence of severe combined immunodeficiency (SCID) and/or severely depressed erythropoiesis may warrant bone marrow transplantation.
Malignancies. Treat in the usual manner.
Prevention of secondary complications: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia.
Skeletal dysplasia. Clinical and (if warranted) radiographic monitoring of growth, joints of the lower extremities, and spine annually in childhood and as required in adulthood. Individuals with AD require annual clinical and radiographic monitoring of the spine.
Anemia. For those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, monitor for evidence of relapse.
Immunodeficiency/infection. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella. Annual evaluation after age two years. High-resolution CT examination for those with features suggestive of bronchiectasis.
Malignancies. No specific recommendations exist; regular examination for evidence of lymphomas, basal cell carcinomas, and other associated malignancies is advised.
Endocrinology. Monitor pubertal maturation.
Agents/circumstances to avoid: Administration of live vaccines when signs of abnormal immunologic function or SCID are present.
Evaluation of relatives at risk: Early diagnosis of relatives at risk for the CHH-AD spectrum allows for early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies).
Genetic counseling: The CHH-AD spectrum is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier of a pathogenic variant, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
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