hydroxocobalamin and Hypertension--Pulmonary

Cobalamin C (cblC) defect is the most common inborn error of vitamin B12 metabolism. Clinical features vary as does the severity of the disease. In most cases, the clinical symptoms of cblC defect tend to appear during infancy or early childhood as a multisystem disease with severe neurologic, ocular, hematologic, renal, and gastrointestinal signs. The neurologic findings are common and include hypotonia, developmental delay, microcephaly, seizures hydrocephalus, and brain MRI abnormalities. We report a case of a young boy with cblC defect, who did not undergo newborn screening, presenting at the age of 2 years with isolated pulmonary hypertension as the leading symptom. This novel way of presentation of cblC defect enlarges the spectrum of inherited diseases that must be considered in the differential diagnosis of pulmonary hypertension.

Topics: Betaine; Brain; Child, Preschool; Diagnosis, Differential; Drug Therapy, Combination; Folic Acid; Genetic Carrier Screening; Humans; Hydroxocobalamin; Hypertension, Pulmonary; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Infant; Infant, Newborn; Injections, Intramuscular; Lung; Magnetic Resonance Imaging; Male; Metabolism, Inborn Errors; Neonatal Screening; Proto-Oncogene Proteins c-cbl; Pulmonary Artery; Tomography, X-Ray Computed; Vitamin B 12 Deficiency

Pulmonary arterial hypertension (PAH) and renal thrombotic microangiopathy (rTMA) are rare diseases in childhood, frequently leading to death and end-stage renal disease, respectively. Their combined occurrence has been reported anecdotally. We investigated the clinical, biochemical, and genetic aspects of 5 children with the rare combination of PAH and rTMA. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, PAH was preceded by rTMA from age 2.5 to 7 years. Three patients presenting at ≤ 3 years of age died of right ventricular failure secondary to progressive PAH. In 2 patients, cobalamin C (cblC) deficiency was diagnosed postmortem. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 patient exhibited progressive pulmonary vasculopathy, and 1 patient is currently in stable condition. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Genetic analysis confirmed mutations in MMACHC in all patients; 4 patients were compound heterozygous, with all having base-pair substitutions (G>A or G>T) at nucleotide 276 in addition to frame-shift mutations. One patient had homozygous nonsense mutations of MMACHC. We established cblC deficiency as the denominator in the rare combination of PAH and rTMA in these children. Early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may beneficially affect the course of this devastating disease.

Topics: Adolescent; Carrier Proteins; Child, Preschool; Diagnosis, Differential; Disease Progression; DNA Mutational Analysis; Early Diagnosis; Fatal Outcome; Female; Follow-Up Studies; Hemolytic-Uremic Syndrome; Humans; Hydroxocobalamin; Hypertension, Pulmonary; Infant; Kidney; Male; Oxidoreductases; Proto-Oncogene Proteins c-cbl; Thrombotic Microangiopathies; Vitamin B 12 Deficiency