Genomic sequencing: ending the diagnostic odyssey for a child with microcephaly and dystonia with a perioperative challenge

Dear Sir, The advancement in genomic technologies has transformed paediatric clinical practice in diagnosing paediatric genetic disorders. We present a case of a 3-year-old girl with neurodevelopmental disorder with an unusual cause of peripheral cyanosis. By using exome sequencing, a rare genetic disorder was diagnosed, and this ended her prolonged diagnostic odyssey. Our patient, born to non-consanguineous parents, has a history of global developmental delay, microcephaly, epilepsy and dystonia with baseline axial hypertonia and upper limb extensor dystonic posturing. She is on long-term nasogastric tube feeding. Magnetic resonance imaging brain showed cerebral atrophy and mild ventriculomegaly [Figure 1a]. Extensive diagnostic work-up performed did not yield any definitive diagnosis. She was noted to be cyanotic during a routine clinic visit. There were no infective symptoms, respiratory distress or choking episode. She was hypoxic (SpO2 91% in room air) with peripheral cyanosis on examination [Figure 1b].Figure 1: (a) MRI brain showed cerebral atrophy and mild ventriculomegaly. (b) Photograph of the patient's blue fingernails indicates peripheral cyanosis. (c) Photograph shows the dark-brown arterial blood sample of the patient.The usual investigations performed for peripheral cyanosis were negative. Arterial blood gases appeared dark brown [Figure 1c] and showed normal pO2, not correlating with her SpO2 reading and degree of cyanosis. Methaemoglobinaemia was confirmed with raised methaemoglobin level (13.2%). Exome sequencing identified biallelic pathogenic deletions of exons 5–9 (maternally inherited) and exon 9 (paternally inherited) in CYB5R3, and low CYB5R3 enzyme activity confirmed a diagnosis of recessive congenital methaemoglobinaemia type II, which explained her neurological symptoms. Methaemoglobinaemia is caused by oxidation of iron in haemoglobin from ferrous to ferric state, forming methaemoglobin that causes functional anaemia.[1] Recessive congenital methaemoglobinaemia type I, caused mostly due to missense variants leading to enzyme instability, is associated with milder symptoms or cyanosis being the only sign.[1,2] Recessive congenital methaemoglobinaemia type II, mostly due to protein-truncating variants, is typically associated with neurological complications with loss of CYB5R3 function in all cell types, causing impairment in fatty acid elongation and damages to neural myelination.[2,3] The main treatment includes methylene blue (MB), ascorbic acid, exchange transfusion and hyperbaric oxygen.[1,4] However, MB was not started in our patient as she was asymptomatic with methaemoglobin level <20%, which was below the treatment threshold. Methylene blue was contraindicated due to concerns of potential interactions with Madopar, which she was taking for dystonia treatment, leading to risk of hypertensive crisis or serotonin syndrome. She was commenced on riboflavin and ascorbic acid and managed conservatively until discharge. Our patient underwent elective laparoscopic gastrostomy button insertion for moderate–severe reflux a few months later. Before surgery, the consensus from the multidisciplinary discussion was to minimise perioperative oxidative stress with preoperative loading of ascorbic acid, meticulous anaesthetic and surgical technique, and close monitoring with percutaneous digital co-oximetry probe (Masimo SpMet, Irvine, CA, USA). The SpMet levels were well correlated with arterial methaemoglobin levels. N-acetylcysteine was another treatment available, with uncertain efficacy.[5] Blue food dye was used in lieu of MB to confirm gastrostomy position. The patient received prophylactic intravenous ascorbic acid, and the SpMet levels dropped from 9%–10% to 5%–6%, in comparison to her baseline methaemoglobin level of 13%. She tolerated the surgery well, was extubated in the intensive care unit and discharged to ward after 24 h. She was the first surgical candidate with congenital methaemoglobinaemia in our hospital and the first reported case of partial dopa-responsive dystonia in congenital methaemoglobinaemia. In summary, this is a rare paediatric condition of type II methaemoglobinaemia diagnosed early using exome sequencing to provide targeted management for the patient, including perioperative preparation and anaesthesia management for her elective surgery. It has shown that genomic medicine would change our practice in the near future for better patient care. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.