Introduction:
Membranoproliferative glomerulonephritis (MPGN) is a glomerulonephritis defined by specific histological findings on kidney biopsy, including thickened glomerular basement membrane and increased mesangial and endocapillary cellularity. We report a case of pregnancy-associated MPGN co-existing with a hypocellular bone marrow syndrome and atypical cardiomyopathy.
Case Presentation:
A 36-year-old female presented at 27weeks’ gestation for antenatal care. Initial pathology revealed macrocytic anaemia (haemoglobin 65 g/L, MCV 106fl), thrombocytopenia (platelets 136x10^9/L) and kidney impairment (creatinine 118umol/L) with haemoproteinuria (protein/creatinine ratio 1300mg/mmol; 105x10^6/L red cells on urine microscopy). Urgent kidney biopsy performed at 27weeks' gestation demonstrated histological findings of MPGN, most consistent with a post-infectious aetiology. Infectious precipitants were investigated but not found. Her kidney disease was managed conservatively. Autoimmune and vasculitic screening was negative and pre-eclampsia screening was unremarkable.
Given significant anaemia of uncertain aetiology, she underwent a bone marrow biopsy at 28weeks’ gestation, showing a hypocellular marrow, mild dyserthropoiesis and non-specific megakaryocytic hyperplasia but without definitive features of myelodysplasia; cytogenetic studies were normal. Differentials included infection, paroxysmal nocturnal haemoglobinuria, Fanconi anaemia and dyskeratosis congenita. The elevated MCV was longstanding, and PNH flow cytometry was normal. Chromosomal fragility studies were inconclusive, possibly suggestive of a mild Fanconi anaemia phenotype or testing artefact during pregnancy. She remained transfusion dependent throughout pregnancy.
At 37weeks' gestation, she underwent an elective caesarean-section, delivering a 2.7kg female neonate, well apart from possible haemorrhagic ovarian and bowel duplication cysts which required neonatal follow-up. Post-partum, she had stable kidney impairment. She became transfusion independent with persisting mild macroctytic anaemia, and she developed a new cardiomyopathy. Given multiple rare presentations in pregnancy, she was referred to genetics. Chromosome microarray identified extensive long continuous chains of homozygosity (LCSH), suggesting consanguinity and an increased risk of recessive genetic disease. Whole exome sequencing identified homozygous pathogenic frameshift variants in HJV, providing a rare diagnosis of haemochromatosis type 2A (MIM# 602390). No pathogenic variants were identified in curated gene lists associated with cardiomyopathy, kidney glomerular disease or Fanconi anaemia.
Discussion:
This case is compelling for two reasons. Firstly, MPGN can be classified as either immune complex/monoclonal immunoglobulin-mediated or complement-mediated, distinguished by immunofluorescence microscopy on kidney biopsy1. This case raises the possibility that pregnancy plays a pathogenetic role in development of immune-mediated kidney disease, including MPGN. Secondly, consanguinity is an important but underappreciated cause of simultaneous presentation of multiple rare diseases. Germline whole exome sequencing may assist in better understanding these presentations and guide clinical care.