Perinatal/Neonatal Case Presentation

A novel FOXF1 mutation associated with alveolar capillary dysplasia and coexisting colobomas and hemihyperplasia


Alveolar capillary dysplasia (ACD) is a rare and lethal cause of hypoxic respiratory failure in the neonate. Here we describe a term neonate with ACD that was found with a previously unreported p.Arg86Pro mutation in the FOXF1 (Forkhead Box-F1) gene and coexisting congenital anomalies, including colobomas of the iris and hemihyperplasia. This unique clinical presentation may indicate a novel, yet unconfirmed disease association for mutations in the FOXF1 gene. Rapid mutation analysis in FOXF1 may provide noninvasive early confirmation of ACD in neonates with respiratory failure and can aid in clinical decision making.


Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a disorder of development that results in abnormality of the air–blood barriers of the lung and impaired gas exchange.1 The decrease in number of functional air–blood barriers results in severe pulmonary hypertension and hypoxemia. Pulmonary hypertension from ACD/MPV is resistant to most medical interventions, with the overwhelming majority of identified cases being lethal.1

In ACD/MPV, the alveolar epithelium has surrounding small blood vessels within the mesenchyme; however, there is a lack of capillaries or a lack of capillary contact with the epithelium.1 Small pulmonary arteries in ACD show increased smooth muscle hypertrophy with abnormal muscular extension into intra-acinar vessels.1 MPV in ACD leads to a type of occlusive blood flow within the lung and arterio-venous shunts that contribute to hypoxemia.2 An estimated 50–80% of identified cases of ACD/MPV have extrapulmonary findings. The majority of these anomalies are genitourinary, gastrointestinal or cardiovascular.1,3 It is likely that there are milder cases of ACD/MPV that are not identified, and as our understanding and awareness of this anomaly expands, a milder phenotype may be identified.4 FOXF1 (Forkhead Box-F1) gene insufficiency is the most commonly identified genetic cause for ACD/MPV and occurs in association with congenital anomalies of the genitourinary, gastrointestinal and cardiovascular systems.5, 6, 7, 8

Case report

We describe the clinical course and diagnosis of a term, Caucasian female newborn infant cared for at our tertiary care Children’s Hospital. Pregnancy was complicated by polyhydramnios and concern for enlarged kidneys was identified around 20 weeks of gestation. Delivery was induced at an outside institution at 39 weeks of gestation for maternal hypertension. Amniotic fluid was stained with meconium. Apgar scores at 1 and 5 min were 8 and 9, respectively. Standard pulse oximetry newborn screening after 24 h of life showed preductal and postductal saturations of 96% on room air. She had an episode of desaturation on day of life one that resolved with oxygen prior to being discharged home from nursery at the outside institution.

At home, the infant was noted to have episodes of perioral cyanosis associated with feedings that would self-resolve. On the day of hospitalization, infant was taken by parents to emergency room at an outside hospital for persistent cyanosis and was subsequently transferred to our Children’s Hospital.

After admission to our intensive care unit on day 6 of life, infant was noted to have mildly dysmorphic facial features not noted in the parents, including a depressed nasal bridge with slightly anteverted nares, posteriorly rotated ears, bilaterally symmetric coloboma iridis as seen in Figure 1 and left sided hemihypertrophy. These features were not documented on examination done after birth at the outside institution.

Figure 1

Coloboma Iris observed in our patient in the left eye—it was symmetric in both eyes in our patient.

Hospital course

Infant developed persistent desaturations 24 h after admission, requiring endotracheal intubation and mechanical ventilation. Echocardiogram revealed severe persistent pulmonary hypertension. She had only transient responses to each escalation in therapies for pulmonary hypertension, including initiation of inhaled nitric oxide at 20 p.p.m. Her oxygenation seemed more responsive to inhaled prostacyclin analog iloprost; however, response to iloprost also waned over time. Persistent desaturations eventually required support with extracorporeal membrane oxygenation on day of life 10. On day of life 13, DNA sequencing for FOXF1 was sent for suspected ACD. Extracorporeal membrane oxygenation support was discontinued on day of life 14 because of clinical stability, as well as for a left middle cerebral artery area infarct. After discontinuation of extracorporeal membrane oxygenation, her oxygenation was initially responsive to intravenous prostacyclin analog, treprostinil; once again the effect was not sustained. On day of life 20, sequencing for FOXF1 gene was reported as abnormal. Automated Sanger sequencing of FOXF1 gene revealed that she had a de novo c.257G>C variant causing a p.R86P change, a novel sequence variant not previously described and not present in the parents. She eventually expired on day of life 29, despite continued support. Postmortem lung biopsy confirmed the diagnosis of ACD/MPV as seen in Figure 2. Full autopsy was not done per family’s request. As variants in STRA6 (stimulated by retinoic acid 6) gene were previously described in association with ACD and blepharophimosis of the eye, STRA6 (NM_022369.3) sequencing was performed on the transcript sequenced in prior reports.9 Sequencing of STRA6 revealed two variants unlikely to be causative of a rare disease on the basis of their frequency in the population, c.1167-10C>G(dbSNP:2277608) and c.1581G>A(rs736118). Both of these variants have an allele frequency listed in dbSNP of >15% (20.5% and 17.5%, respectively), as further explained in the Discussion section.

Figure 2

Representative lung sections from normal lung of a patient who died of hypoxic–ischemic brain injury (top) and postmortem lung biopsy of our patient (bottom). The panel at the top illustrates the normal relationship of pulmonary artery (A) and bronchus (B) and the presence of pulmonary vein (V) along the lobular septum. The small pulmonary artery in the normal lung also shows thin intima and media, and the presence of a large patent lumen. The bottom panel shows the misalignment of pulmonary vein (V) next to the pulmonary artery (A) and bronchus (B) in the same broncho-vascular bundle in our patient, with intimal and medial hyperplasia of the pulmonary arteries to the point of occlusion of the lumen.


Reports of FOXF1-related ACD/MPV have so far not been associated with hemihyperplasia or eye abnormalities like coloboma. Whether these features have been present and not included in case reports or whether these are truly new and unique additions to the ACD/MPV phenotype is not known. They could indicate a coexisting developmental disorder of other organs or reflect a new aspect of the developmental pathway linked to FOXF1 gene mutations. While trying to link ocular anomalies and ACD/MPV, variants in the STRA6 gene were in the differential diagnosis prior to the report of a FOXF1 variant. One previous infant with a STRA6 variant has been reported to have ACD and blepharophimosis.9 Other cases of patients with STRA6 anomalies have been noted to have different congenital eye abnormalities, including colobomas and microphthalmia.9 These reports motivated us to sequence the STRA6 gene in this infant. However, on the basis of allele frequency of the two variants that were observed, we concluded that they are unlikely to be causative for a rare disease like ACD.

FOXF1 gene codes for a protein which is a member of the FOX transcription factor family. These factors bind the promoter regions to regulate the transcription of many different genes involved in an organ development.7 The protein coded by FOXF1 gene is primarily expressed in mesoderm-derived tissues of developing lungs and other intestine-derived organs.7 Homozygous FOXF1−/− mice die in the embryonic period with defects in development of embryonic mesoderm, whereas heterozygous FOXF1−/+ mice develop a lung phenotype similar to ACD.7 These studies demonstrate a dose-sensitive effect of FOXF1 in the regulation of genes involved in an organ development.

The novel, de novo c.257G>C variant observed in FOXF1 gene in our patient has not been previously described. However, a pathogenic c.256C>T variant has been reported, which results in a p.R86W change.7 On the basis of the presence of a sequence variant in the same amino-acid codon of a previously described pathogenic variant and given its de novo status (not present in either parent’s DNA), we conclude that this sequence variant is likely pathogenic and the cause of our patient’s ACD/MPV. The noninvasive confirmation of the patient’s diagnosis by rapid DNA analysis was most helpful in determining the course of medical management and prognosis. The diagnosis was then verified postmortem.

In conclusion, clinical presentation of ACD/MCP can include more complex syndromic phenotypes with additional anomalies we observed in our infant. Rapid confirmation of diagnosis is desirable for clinical decision making and can be achieved noninvasively by DNA analysis for FOXF1 mutations, which appear to be a major cause of ACD/MPV.


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We thank the family of this patient for consenting to this publication and Baylor College of Medicine’s Medical Genetics Laboratories for expediting the clinical confirmation of the genotype for this patient. We also thank the DNA-sequencing laboratory of the HMGC at the Medical College of Wisconsin for providing rapid DNA sequencing on a research basis, which provided concurrent results in <1 week.

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Correspondence to G G Konduri.

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Geddes, G., Dimmock, D., Hehir, D. et al. A novel FOXF1 mutation associated with alveolar capillary dysplasia and coexisting colobomas and hemihyperplasia. J Perinatol 35, 155–157 (2015).

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