A 16q deletion involving FOXF1 enhancer is associated to pulmonary capillary hemangiomatosis

Abstract

Background: Pulmonary capillary hemangiomatosis (PCH) is an uncommon pulmonary disorder, with variable clinical features depending on which lung structure is affected, and it is usually linked to pulmonary arterial hypertension. Congenital PCH has been very rarely described and, so far, the only causative gene identified is EIF2AK4, which encodes for a translation initiation factor. However, not all PCH cases might carry a mutation in this gene.

Case presentation: We report the clinical and cytogenetic characterization of a patient (male, newborn, first child of healthy non-consanguineous parents) died after three days of life with severe neonatal pulmonary hypertension, due to diffuse capillary hemangiomatosis diagnosed post mortem. Conventional karyotyping, Microarray-Based Comparative Genomic Hydridization (CGHa) and quantitative PCR were performed. CGHa revealed a heterozygous chromosome 16q23.3q24.1 interstitial deletion, spanning about 2.6 Mb and involving a FOXF1 gene enhancer. Quantitative PCR showed that the proband's deletion was de novo. Microsatellite analysis demonstrate that the deletion occurred in the maternal chromosome 16.

Conclusion: FOXF1 loss of function mutation have been so far identified in alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), a lung disease different from PCH. Our data suggest the hypothesis that disruption of the FOXF1 gene enhancer could be a genetic determinant of PCH. Moreover, our findings support the idea that FOXF1 is a paternally imprinted gene.

Fig. 1

Microscopic evaluation of lung tissues. Panel a, histologic image (Hematoxilin-Eosin, 20X) of lung autoptic sample showing widespread proliferation of septal capillaries with extensive alveolar hemorrhage, without a proliferation in septal, or lung bronchovascular bundles. Panel b, CD31 endothelial immunostaining (20X) demonstrates marked septal capillaries dilatation and proliferation

Fig. 2

CGHa analysis. Panel a, CGH signals of patient’s chromosome 16. The deleted region is highlighted by a brown area. Panel b, chromosome 16 region containing the deletion. The deleted region is shown in red. Positions of FOX genes are shown in black. Positions of microsatellites LINC01081 and LINC01082 utilized for analysis are shown in green. Location of genes utilized for quantitative PCR are shown in blue. Base-pairs are numbered according to hg19

Fig. 3

Deletions associated with PCH and ACD/MPV. The map of the FOXF1 region is represented at the top: the FOXF1 gene and the long non-coding RNAs LINC01081 and LINC01082 are shown. The gray bar below indicates the deletion found in our PCH patients, while black bars indicate deletions in patients with ACD/MPV so far found

Fig. 4

Microsatellite analysis. Top, electropherograms of L17941 (left) and L29692 (right). Bottom, pedigree of the family with alleles of L17941 and L29692 present in each subject. Numbers correspond to the base-pair length of each allele