Objective To delineate a retrospective diagnosis in a case of severe fixed encephalopathy.
Case description Propositus was a male child, first born to 3rd degree consanguineous South Asian parents. Pregnancy, delivery and clinical examination at birth were normal. During the first months of life, he had generalised hypotonia with spontaneous dystonic leg extension spasm and frequent vomiting. All the developmental milestones were delayed, he never sat alone or never attained speech. From his available photographs head size appeared to be small, and esotropia and adducted thumbs were noted. Magnetic resonance imaging of his brain showed delayed myelination. He also had grade II/III gastro oesophageal reflux evidenced by GER Scintigraphy. Other investigations including routine biochemical and haematological parameters, neurometabolic screening and electrophysiological analysis were within normal limits. He was treated as spastic cerebral palsy from another centre without much improvement to the symptoms. Child expired at the age of 2 years followed by an attack of pneumonia; clinical exome test was performed later from his DNA.
Results Long read sequencing revealed a homozygous, pathogenic novel variation p. Val112ProFSTer8 resulting from the deletion of exons 5–8 of CYB5R3 gene, associated with recessive hereditary methemoglobinemia (RHM) type II, which could explain the clinical profile. This large deletion was validated by polymerase chain reaction and carrier status of parents was established.
Conclusion Type II RHM is a rare condition, with less than 100 cases reported worldwide.
Cyanosis is an invariable presenting feature and important clinical clue to methemoglobinemia. There was no history or documentation of cyanosis in our case. In the absence/failure to elicit the sign in children with severe encephalopathy, possibility of RHM might get overlooked.
Majority of the reported mutations in RHM type II are point mutations with two prior documentations of single exonic deletion. Ours is the first family with the largest deletion of multiple exons of CYB5R3 gene, thus expanding the genotype spectrum.