Clinical characteristics: Rhizomelic chondrodysplasia punctata type 1 (RCDP1), a peroxisome biogenesis disorder (PBD) has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP1 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 the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, CDP or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1.

Diagnosis/testing: The diagnosis of RCDP1 is established in a proband with suggestive clinical, radiographic, and laboratory findings and biallelic pathogenic variants in PEX7 identified on molecular genetic testing.

Management: Treatment of manifestations: Classic (severe) RCDP1: Management is supportive and limited by the multiple handicaps present at birth and poor outcome. Poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; attention to respiratory function and good pulmonary toilet. Cataract extraction may restore some vision. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals. Management of developmental delay/intellectual disability as per standard of care.

Prevention of primary manifestations: Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild RCDP1.

Surveillance: Frequent monitoring of growth, nutritional status, and developmental and educational needs; regular assessments for evidence of aspiration, respiratory insufficiency, seizure control, vision, hearing, contractures, and orthopedic complications.

Genetic counseling: RCDP1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PEX7 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 unaffected carrier, and a 25% chance of inheriting both normal alleles. Molecular genetic carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible once the PEX7 pathogenic variants have been identified in an affected family member.