Rhizomelic chondrodysplasia punctata (ORPHA:177)
A rare, primary bone dysplasia characterized by rhizomelic limb shortening, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata) and coronal cleft vertebrae associated with profound postnatal growth deficiency, early-onset cataracts, severe intellectual disability and seizures.
Epidemiology
Rhizomelic chondrodysplasia punctata (RCDP) prevalence is estimated to be lower than 1/100,000. The disorder is pan ethnic.
Clinical description
Presentation is at birth with severe joint contractures; cataracts may be present or appear in the first few months of life. Respiratory distress and feeding difficulties are commonly observed after birth. Whilst birth parameters (weight, length, and head circumference) are in the lower range from normal, profound postnatal growth retardation ensues. Rhizomelic limb shortening is typically greater in the humerus than the femur. Other skeletal abnormalities include punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata) and coronal cleft vertebrae. Intellectual disability is severe, and the majority of children develop seizures.
Etiology
The disease is caused by defective plasmalogen biosynthesis and impaired peroxisome function. The majority of patients have variants in the PEX7 gene (6q21-q22.2, RDCP type 1) encoding the peroxisomal targeting signal 2 receptor which plays an important role in peroxisomal protein import. Biallelic variants in the GNPAT gene (1q42) encoding dihydroxyacetone phosphate acyltransferase cause RDCP type 2, variants in the AGPS gene (2q31) encoding peroxisomal alkyldihydroxyacetonephosphate synthase cause RDCP type 3, and variants in the PEX5 gene (12p13.31) encoding the peroxisomal targeting signal 1 receptor cause RDCP type 5.
Diagnostic methods
Diagnosis is suspected on clinical and radiologic findings and confirmed by either biochemical or molecular testing. Sub-typing requires molecular testing.
Differential diagnosis
The principle differential diagnosis is Zellweger syndrome. It also includes Warfarin embryopathy, fatty acyl-CoA reductase 1 deficiency, and Chondrodysplasia punctata, tibia-metacarpal type.
Antenatal diagnosis
Prenatal diagnosis is feasible for at risk pregnancies where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disease is transmitted in an autosomal recessive manner. Genetic counseling should be proposed to at risk couples (where both parents are unaffected carriers of the disease) informing them that the risk of having and affected child is 25% for each pregnancy.
Management and treatment
Management is supportive. Cataract extraction may restore some vision. Physical therapy is recommended to improve contractures; orthopedic procedures may improve function in some individuals. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with milder forms of RCDP. Gastrostomy tube may be considered for poor weight gain, feeding intolerance, aspiration, and gastroesophageal reflux. Anti-seizure medications may be considered for seizures particularly where seizures are progressive, continuous and apparently painful, or significantly interfering with a child's interaction with the environment.
Prognosis
RCDP has a severe prognosis with death generally occurring during the first decade of life, mainly due to respiratory complications; a proportion may die in the neonatal period. Greater than 90% of individuals with RCDP survive the first year of life, and about 75% live to school age. Those with less severe plasmalogen deficiency, had improved survivability compared with those with very low classical plasmalogen levels.

                            Last update: 
                            October 2020


                            - Expert reviewer(s): 
                            Dr Karen HEATH