PEX7 related nonclassic (mild) rhizomelic chondrodysplasia punctate type 1 patient with global developmental delay without skeletal dysplasia and cataract

Background: Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a rare autosomal recessive disorder of peroxisome biogenesis. RCDP1 is caused by mutations in the PEX7 gene encoding the peroxisomal type 2 targeting signal receptor. The characteristic features of classic RCDP1 are skeletal dysplasias, congenital cataract, short stature and significant developmental delay. Apart from classic RCDP, there are a small number of patients with mild phenotypes including cataracts, variable skeletal findings, developmental delays and sometimes clinical aspects that overlap with adult Refsum disease (ARD). We report the case of a 5-year-old girl with nonclassic RCDP1 who presented with global developmental delay, ataxia, microcephaly, but without skeletal dysplasia and cataract. Two variants were identified in the PEX7 gene using whole exome sequencing.

Case report: A 5-year-old girl visited our clinic with short stature, microcephaly and developmental delay. She started walking independently at 3 years but still had gait imbalance and ataxia. She had speech delay and intellectual disability. On examination, her height, weight and head circumference were below the 3rd percentile. It was diagnosed as a growth hormone deficiency after growth hormone stimulation tests. She had no skeletal abnormalities and no cataract. At 16 months of age, she had acute general weakness and drowsy mental stature after viral infection. At that time, brain magnetic resonance imaging (MRI) and basic metabolic tests were performed due to suspected metabolic disorders, and no abnormal findings were found. We performed whole exome sequencing to identify the cause of the global developmental delay. Two compound heterozygous variants in the PEX7 gene were identified. The c.694C>T (p.Arg232Ter) variant was classified as pathogenic, as previously reported in RCDP1 patients. The c.417+3A>G variant was classified as variant of uncertain significance. Several in silico software programs such as dbscSNV, spliceAI, and MaxEntScan were applied to predict the putative mRNA effect of the PEX7 intron variant(c.417+3A>G) found in the study, and in all of them, this mutation was predicted to affect splicing. Based on her clinical presentations and result of gene test, she was diagnosed with a nonclassic (mild) RCDP1. She is undergoing rehabilitation and is being treated with growth hormone.

Conclusions: RCDP1 has a continuum of phenotypes including classic (severe) RCDP1, nonclassic (mild) RCDP1, and adult Refsum disease (ARD)-like phenotypes. PEX7 related RCDP1 diagnosis may be considered even if the symptoms are milder than classic type.