PHRINL Syndrome: A Case of Infantile Cataract and Cardiomyopathy

Pontocerebellar Hypoplasia, Hypotonia, and Respiratory Insufficiency Syndrome, Neonatal Lethal (PHRINL Syndrome) is a rare genetic disorder caused by impaired oxidative phosphorylation due to reduced activity of mitochondrial complexes I, IV, and V. The condition results from homozygous or compound heterozygous pathogenic variants in the ATAD3A gene, and is inherited in an autosomal recessive manner. Affected individuals typically present in early infancy with hypotonia, encephalopathy, corneal clouding, cardiomyopathy, and respiratory failure, and often die during infancy.

A 40-day-old female infant was referred for evaluation of a possible inherited metabolic disorder following the death of her brother at 9 months of age. No abnormalities were detected in the metabolic workup. Hypotonia was identified on physical examination at 3 months of age, brain magnetic resonance imaging (MRI) revealed pontocerebellar hypoplasia. Whole-exome sequencing (WES) identified two genetic alterations in the ATAD3A gene, leading to the diagnosis of PHRINL Syndrome. ATAD3A (NM_001170535.3: c.229C>G; p.Leu77Val) c.229C>G heterozygous missense variant was detected, along with a 0.61 kb heterozygous deletion encompassing exons 3-4 of the ATAD3A gene. The patient diagnosed with hypotonia at 3 months of age, developed cataracts at 5 months, and died in the eighth month due to refractory seizures.

In hypotonic infants presenting with cataracts and cardiomyopathy, elevated plasma lactate levels and increased urinary excretion of 3-methylglutaconate and 3-methylglutarate may suggest PHRINL syndrome; however, the diagnosis should not be excluded solely on the basis of normal metabolic test results when characteristic clinical features are present.