Poster Presentation - SOMANZ ASM Society of Obstetric Medicine of Australia and New Zealand ASM 2023

FOXF1 mutation: a familial cause of pulmonary haemorrhage and implications for pregnancy (#43)

Annabelle Carter 1 , Sarah Malone 1 , Belinda Liu 2 , Ben Dunne 3
  1. The Royal Women's Hospital, Carlton, NSW, Australia
  2. Respiratory, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  3. Cardiothoracic Surgery, The Royal Melbourne Hospital, Melbourne, Victoria, Australia

Introduction

FOXF1 mutation resulting in alveolar capillary dysplasia (ACD) is a rare congenital lung disorder and can result in neonatal death. We report a case of maternal pulmonary haemorrhage and FOXF1 mutation affecting two pregnancies.

Case Report

A 32-year-old, G1P0 presented with haemoptysis at 33+4 weeks gestation. She had one prior episode of haemoptysis at 18 weeks; otherwise no past medical history. She developed massive pulmonary haemorrhage with severe respiratory failure at 33+6 weeks requiring intubation. She had an emergency Caesarean section for foetal distress.

Imaging and multiple bronchoscopies did not identify a cause for bleeding, which was predominantly left sided. Endobronchial biopsies demonstrated non-specific inflammation. Empiric angioembolisation of left-sided bronchial arteries was performed with no improvement in bleeding. She was empirically treated with antibiotics and corticosteroids. Her bleeding settled spontaneously one week postpartum and she was successfully extubated. She returned to normal respiratory function, with normal CT.

Her baby developed severe pulmonary hypertension, resulting in neonatal death at 2 months. Post-mortem examination diagnosed a maternally inherited FOXF1 mutation resulting in alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV).

She had a subsequent pregnancy of natural conception. Chorionic villous sampling detected FOXF1 variant present, and decision was made for termination of pregnancy at 15 weeks. Up until this gestation she remained physically well.

Due to high risk of recurrence in future pregnancies, decision was made for in-vitro fertilisation with pre-implantation genetic testing. She had successful transfer of an unaffected embryo, and the pregnancy is being monitored with close surveillance and respiratory function testing.

Discussion

We report a case of massive haemoptysis in pregnancy, presumed to be caused by FOXF1 mutation associated with ACD. The working diagnosis was made following post-mortem genetic testing of her child and an absence of other conditions following extensive investigation. Maternal lung parenchymal biopsies haven't been performed due to risk of haemorrhage and limited therapeutic options to prevent bleeding in future pregnancies. Her condition is thought to be unmasked in pregnancy, due to resolution of bleeding after delivery and return to normal respiratory condition post-partum.

FOXF1 gene is expressed in lung tissue1. Mutations can result in ACD/ MPV and often presents as a fatal developmental lung disorder in the neonate2,3. Only 10% of reported mutations are familial; of these, all are maternally inherited, suggesting paternal imprinting1,4,5. FOXF1 gene testing can now provide a diagnosis, allowing for appropriate genetic screening and planning in future pregnancies.

  1. Luk HM, Tang T, Choy KWR, Tong MFT, Wong OK, Lo FMI. Maternal somatic mosaicism of FOXF1 mutation causes recurrent alveolar capillary dysplasia with misalignment of pulmonary veins in siblings. American Journal of Medical Genetics Part A 2016; 170(7): 1942-4.
  2. Stankiewicz P, Sen P, Bhatt SS, et al. Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations. The American Journal of Human Genetics 2009; 84(6): 780-91.
  3. Alsina Casanova M, Monteagudo-Sánchez A, Rodiguez Guerineau L, et al. Maternal mutations of FOXF1 cause alveolar capillary dysplasia despite not being imprinted. Human Mutation 2017; 38(6): 615-20.
  4. Sen P, Yang Y, Navarro C, et al. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum Mutat 2013; 34(6): 801-11.
  5. Deng L, Liu X, Min J, et al. De Novo mutation of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins: A case report. Medicine 2021; 100(14).