Related Rhizomelic Chondrodysplasia Punctata

CLINICAL CHARACTERISTICS

-related rhizomelic chondrodysplasia punctata (-RCDP), a peroxisome biogenesis disorder (PBD), has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and most children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) -RCDP is characterized by congenital or childhood cataracts, CDP or, infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, joint contractures, neurobehavioral abnormalities, and milder intellectual disability and growth restriction than classic -RCDP.

DIAGNOSIS/TESTING: The diagnosis of -RCDP is established in a proband with suggestive clinical, radiographic, and laboratory findings and biallelic pathogenic variants in identified on molecular genetic testing.

MANAGEMENT

In those with classic (severe) -RCDP, management is supportive and limited by the severe health issues present at birth and poor outcome. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild -RCDP. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals; consider need for positioning and mobility devices; spinal decompression with or without fusion depending on region of compression and myelopathic signs; cataract extraction may restore and/or preserve vision; community vision services through early intervention or school district; poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; developmental and educational support; standard treatment of seizures by an experienced neurologist; good pulmonary clearance and attention to respiratory function; influenza vaccine, RSV monoclonal antibody, and other interventions to prevent lung disease; management of congenital heart disease per cardiologist; dermatologist management of skin manifestations; management of kidney and urinary tract anomalies per nephrologist and/or urologist; social work and care coordination as needed. Annual measurement of phytanic acid levels in children with non-classic (mild) -RCDP; musculoskeletal assessment, assessment for kyphosis and scoliosis, and neurologic exam with assessment for seizures at each visit; vision assessment every three months until cataracts are detected and then as recommended by ophthalmologist; assessment of growth, nutritional status, safety of oral intake, development, behavior, and respiratory function at each visit; cardiac exam, echocardiogram, and EKG with frequency per treating cardiologist; urine and imaging studies to assess for kidney stones as needed; assessment for skin issues and family needs at each visit.

GENETIC COUNSELING

-RCDP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible.