Alveolar capillary dysplasia with misalignment of the pulmonary veins and hypoplastic left heart sequence caused by an in frame deletion within FOXF1

Abstract

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rare, autosomal dominant disorder of interstitial lung development, leading to pulmonary hypertension, and death in infancy. Associated features include malformations of the heart, gastrointestinal tract, and genitourinary system. ACDMPV is caused by heterozygous variants in the FOXF1 gene or microdeletions involving FOXF1. We present a male infant with ACDMPV, hypoplastic left heart sequence (HLHS), duodenal atresia, and imperforate anus due to a de novo, in frame deletion in FOXF1: c.209_214del (p.Thr70_Leu71del). Previous reports have suggested that microdeletions involving FOXF1 are associated with ACDMPV with congenital heart defects, including HLHS, gastrointestinal atresias, and other anomalies; whereas likely pathogenic variants within FOXF1 have not been reported with ACDMPV and HLHS. This is the first patient reported with ACDMPV, HLHS, imperforate anus, and duodenal atresia associated with a likely pathogenic variant in the FOXF1 gene.

Two cases of different genetic variants of alveolar capillary dysplasia associated with left-sided obstructive CHDs

“…5 An early recognition of this disease will provide guidance for therapeutic decisions and appropriate counseling for the affected families, identifying those that will have an increased risk of subsequent children that may inherit the condition. 6 Histopathological analysis remains the diagnostic gold standard, although there are atypical cases with differences in their histological features, as with case 1, in which the biopsy had atypical features that have not been previously reported in association with alveolar capillary dysplasia. 3,5 Hence, it is important to consider complementing with chromosomal microarray or whole-genome sequencing to identify individuals with FOXF1 gene mutations.…”

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry

“…The proper identification of some of these genes could allow us to use specific treatments that potentially improve prognosis (as in the case of Cobalamin C deficiency), result in a redirection of care ( NFU mitochondrial disease), or even in the consideration of an early Potts shunt or lung transplantation (in cases of FOXF1 variants). Mitochondrial diseases, inborn errors of metabolism, neurodevelopmental disorders, and glycogen storage diseases (GSD), such as those caused by NFU1 , Cobalamin C (CblC) disease, MECP2 variants, or GBE1 , respectively, should be covered by the genetic techniques used in childhood-onset cases of PAH [ 28 , 29 , 30 , 31 , 32 ]. Of relevance, although PH has been described in multiple cases of GSD type 1 or type 2 [ 33 , 34 ], as far as we know we describe here for the first time the association of PH in a newborn with a genetic variant in GBE1 , diagnostic of a GSD type 4.…”

Genotype–phenotype correlation in two Polish neonates with alveolar capillary dysplasia

“…In contrast, phenotypic differences have been observed for co-existing extra-pulmonary anomalies. Interestingly, hypoplastic left heart syndrome (HLHS) and single umbilical artery have been reported in ACD newborns with CNV deletions involving FOXF1, FOXC2, FOXL1, and FENDRR [3]; only one infant with ACD and HLHS caused by de novo likely pathogenic c.209_214del (p.Thr70_Leu71del) variant in FOXF1 was described [20]. However, screening of FOXC2 and FOXL1 in patients with HLHS revealed no point mutations in those genes [21].…”