An elusive diagnosis of congenital methemoglobinemia type II
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Congenital methemoglobinemia is an autosomal recessive condition caused by deficiency of cytochrome b5 reductase (CYB5R3). Homozygous missense mutations in CYB5R3 result in congenital methemoglobinemia type I, which is characterized by mild intermittent cyanosis. Deletions, splice site, and nonsense variants lead to congenital methemoglobinemia type II, a life-limiting condition marked by severe progressive neurological deterioration.
Case Presentation
We report a medically complex male patient with a history of global developmental delay, microcephaly, seizure disorder, cortical visual impairment, axial and appendicular hypotonia, osteopenia with multiple fractures, restrictive lung disease, and feeding intolerance with G-tube dependence. His younger sister displayed a similar phenotype. He was born at 41 weeks gestation to consanguineous parents. Brain MRI at 17 months of age showed frontotemporal cortical-subcortical atrophy, mildly delayed myelination, thin corpus callosum, and mega cisterna magna. Extensive biochemical workup, including electrolytes, liver function tests, lactate, pyruvate, acylcarnitine profile, plasma amino acids, and urine oligosaccharides was unremarkable. A chromosomal microarray demonstrated several large regions of homozygosity encompassing approximately 13% of the genome but was nondiagnostic. Whole exome sequencing revealed homozygous variants in RPE65 (c.394G>A [p.A132T]) and UCHL1 (c.436G>A [p.V146M]), neither of which were thought to account for his symptoms. At 4 years old, the patient was admitted for status epilepticus in the context of aspiration pneumonia. During hospitalization, he developed cyanosis and a brown appearance of his blood.
Diagnostic Workup
Oxygen saturation was poor, yet PaO2 was high. Oxygen dissociation p50 was low, indicating increased oxygen affinity of hemoglobin. Methemoglobin was elevated to 20.2%. Cytochrome b5 reductase enzyme level was 1.1 U/g Hb (reference range: 6.6-13.3 U/g Hb). He was given a clinical diagnosis of congenital methemoglobinemia type II and further genetic testing was pursued. Surprisingly, whole exome sequencing reanalysis failed to identify any CYB5R3 variants.
Treatment and Management
Despite no confirmed genetic diagnosis, the patient was acutely treated with methylene blue and his methemoglobin levels and oxygen saturation subsequently improved. Methemoglobin levels were routinely monitored and remained stably elevated (2-14%). In discussion with Hematology, the decision was made to administer methylene blue only if methemoglobin levels exceeded 20%, if he had clinically significant hypoxemia, or if he developed worsening lactic acidosis. He was ultimately discharged on daily ascorbic acid.
Outcome and Follow-Up
Over the next several years, the patient continued to decline, eventually developing intractable seizures and requiring tracheostomy with mechanical ventilation. At 13 years old, the patient passed away from cardiorespiratory complications. Given the similar symptoms in his younger sister and his parents’ desire to have more children, the case was submitted to the Rare Genomes Project at the Broad Institute. Whole genome sequencing did not reveal any findings, so they proceeded to structural variant analysis. The patient and his sister were found to be homozygous for a 10.1 kb deletion spanning the 5' UTR, first coding exon, and part of intron 1 of the CYB5R3 gene (c.-1307_22-3779 del [p.?]).
Discussion
This case highlights the challenges of diagnosing congenital methemoglobinemia type II. The neurologic features are severe but relatively nonspecific, and there is significant overlap with several other genetic and metabolic conditions. While cyanosis is a distinct finding, our case and others have noted that it may be subtle and only visible during intercurrent illness. In our case, genetic diagnosis was particularly difficult, as whole exome sequencing and genome sequencing were initially unable to detect the large deletion involving non-coding regions.
Conclusion
In this case of congenital methemoglobinemia, we recognize the limitations of genetic testing and emphasize the importance of combining comprehensive physical examination, biochemical testing, and targeted genetic approaches to diagnose complex cases.
Congenital methemoglobinemia is an autosomal recessive condition caused by deficiency of cytochrome b5 reductase (CYB5R3). Homozygous missense mutations in CYB5R3 result in congenital methemoglobinemia type I, which is characterized by mild intermittent cyanosis. Deletions, splice site, and nonsense variants lead to congenital methemoglobinemia type II, a life-limiting condition marked by severe progressive neurological deterioration.
Case Presentation
We report a medically complex male patient with a history of global developmental delay, microcephaly, seizure disorder, cortical visual impairment, axial and appendicular hypotonia, osteopenia with multiple fractures, restrictive lung disease, and feeding intolerance with G-tube dependence. His younger sister displayed a similar phenotype. He was born at 41 weeks gestation to consanguineous parents. Brain MRI at 17 months of age showed frontotemporal cortical-subcortical atrophy, mildly delayed myelination, thin corpus callosum, and mega cisterna magna. Extensive biochemical workup, including electrolytes, liver function tests, lactate, pyruvate, acylcarnitine profile, plasma amino acids, and urine oligosaccharides was unremarkable. A chromosomal microarray demonstrated several large regions of homozygosity encompassing approximately 13% of the genome but was nondiagnostic. Whole exome sequencing revealed homozygous variants in RPE65 (c.394G>A [p.A132T]) and UCHL1 (c.436G>A [p.V146M]), neither of which were thought to account for his symptoms. At 4 years old, the patient was admitted for status epilepticus in the context of aspiration pneumonia. During hospitalization, he developed cyanosis and a brown appearance of his blood.
Diagnostic Workup
Oxygen saturation was poor, yet PaO2 was high. Oxygen dissociation p50 was low, indicating increased oxygen affinity of hemoglobin. Methemoglobin was elevated to 20.2%. Cytochrome b5 reductase enzyme level was 1.1 U/g Hb (reference range: 6.6-13.3 U/g Hb). He was given a clinical diagnosis of congenital methemoglobinemia type II and further genetic testing was pursued. Surprisingly, whole exome sequencing reanalysis failed to identify any CYB5R3 variants.
Treatment and Management
Despite no confirmed genetic diagnosis, the patient was acutely treated with methylene blue and his methemoglobin levels and oxygen saturation subsequently improved. Methemoglobin levels were routinely monitored and remained stably elevated (2-14%). In discussion with Hematology, the decision was made to administer methylene blue only if methemoglobin levels exceeded 20%, if he had clinically significant hypoxemia, or if he developed worsening lactic acidosis. He was ultimately discharged on daily ascorbic acid.
Outcome and Follow-Up
Over the next several years, the patient continued to decline, eventually developing intractable seizures and requiring tracheostomy with mechanical ventilation. At 13 years old, the patient passed away from cardiorespiratory complications. Given the similar symptoms in his younger sister and his parents’ desire to have more children, the case was submitted to the Rare Genomes Project at the Broad Institute. Whole genome sequencing did not reveal any findings, so they proceeded to structural variant analysis. The patient and his sister were found to be homozygous for a 10.1 kb deletion spanning the 5' UTR, first coding exon, and part of intron 1 of the CYB5R3 gene (c.-1307_22-3779 del [p.?]).
Discussion
This case highlights the challenges of diagnosing congenital methemoglobinemia type II. The neurologic features are severe but relatively nonspecific, and there is significant overlap with several other genetic and metabolic conditions. While cyanosis is a distinct finding, our case and others have noted that it may be subtle and only visible during intercurrent illness. In our case, genetic diagnosis was particularly difficult, as whole exome sequencing and genome sequencing were initially unable to detect the large deletion involving non-coding regions.
Conclusion
In this case of congenital methemoglobinemia, we recognize the limitations of genetic testing and emphasize the importance of combining comprehensive physical examination, biochemical testing, and targeted genetic approaches to diagnose complex cases.