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 a CHH-AD spectrum disorder is established in a proband with characteristic clinical and radiographic findings. 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: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia; 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 for progressive varus deformity of the lower extremities; treatment of underlying infections based on their type, location, and severity; immediate high-dose intravenous acyclovir for varicella infection; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; recurrent severe infections, severe combined immunodeficiency (SCID), and/or severely depressed erythropoiesis may warrant hematopoietic stem cell transplantation; physiotherapy and other acute and long-term medical management for bronchiectasis per pulmonologist; red blood cell transfusions for severe anemia with iron chelation as needed; standard treatments for malignancies, congenital megacolon, Hirschsprung disease, and intestinal malabsorption; nutritional evaluation in those with short bowel syndrome; hormonal induction as needed for pubertal maturation; developmental and educational support as needed.
Surveillance: Monitor growth using CHH-specific growth curves; clinical and (if warranted) radiographic examination of joints of the lower extremities and spine annually in childhood and as required in adulthood; annual clinical and radiographic examination of the spine in individuals with AD. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella infection, then monitor annually; laboratory assessment for those with suspected infection; laboratory assessment of immune function with frequency based on initial lab results; assess the frequency of respiratory tract infections at each visit; high-resolution CT examination for those with suspected bronchiectasis and lung MRI to monitor bronchiectasis. For those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, complete blood count every six months. Clinical and laboratory examination for manifestations of malignancy annually in children and as needed in adults; abdominal ultrasound every one to two years in children and as needed in adults. Assess pubertal development annually throughout adolescence; assess for hypogonadism in those with pubertal delay. Developmental and cognitive assessment as needed in those with AD throughout childhood.
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 disorders allows for early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies).
Pregnancy management: Fetal growth is generally unaffected; therefore, planned cæsarean section should be considered in term pregnancies in affected women due to cephalopelvic disproportion.
Genetic counseling: CHH-AD spectrum disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RMRP pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the RMRP pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal and preimplantation genetic testing for CHH-AD spectrum disorders are possible.
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