Combined Pulmonary Arterial Hypertension and Renal TMA in 5 Children With Cobalamin C Deficiency abstract

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. Pediatrics 2013;132:e1–e5 AUTHORS: Martin Kömhoff, MD, PhD,a Marcus T. Roofthooft, MD,b Dineke Westra, MSc,c Thea K. Teertstra, MD,d Attilio Losito, MD,e Nicole C.A.J. van de Kar, MD, PhD,c and Rolf M.F. Berger, MD, PhDb aDepartment of Paediatric Nephrology, bCentre for Congenital Heart Diseases–Paediatric Cardiology, and dDepartment of Paediatric Intensive Care, Beatrix Children’s Hospital, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands; cDepartment of Paediatric Nephrology, Radboud University Nijmegen Medical Centre, University of Nijmegen, Nijmegen, Netherlands; and eNephrology Unit, Santa Maria Della Misericordia Hospital, Perugia, Italy