16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn

Abstract

Objective Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-CGH in persistent pulmonary hypertension of the newborn (PPHN) and multiple congenital malformations. Design Descriptive case report Setting Genetic department and neonatal intensive care unit of a tertiary care children’s hospital Patient We report the case of a preterm male infant, born at 26 weeks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 weeks of gestation. Karyotype analysis was normal and a 22q11.2 microdeletion was excluded by FISH analysis. A Caesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hours of life. An autopsy revealed partial atrio-ventricular canal malformation and showed bilateral dilatation of the renal pelvocaliceal system with bilateral ureteral stenosis, and annular pancreas. Array-CGH analysis (Agilent oligoNT 44K) showed an interstitial microdeletion encompassing the FOX gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Some features were less prominent due to the gestational age. Conclusions Our review of the literature shows that ACD/MPV is rare, but probably underreported. Prematurity is not a usual presentation and histological features are difficult to interpret. In our case, array-CGH revealed a 16q24.1 deletion leading to the final diagnosis of ACD/MPV. It emphasises the usefulness of array-CGH analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory PPHN and multiple congenital malformations.

Interstitial Lung Disease in Children Made Easier…Well, Almost

“…Approximately one-third of cases also have associated pulmonary lymphangiectasia (13). Mutations or deletions in Forkhead box F1 (FOXF1) have been found in up to 40% of infants with ACD-MPV, and there is a high (up to 80%) association with cardiac, gastrointestinal, and genitourinary anomalies (14)(15)(16).…”

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

“…This recommendation is based upon the observation that up to 40% of newborns with hypoxemia and severe pulmonary hypertension due to ACD-MPV have FOXF1 deletions or mutations, according to two case reports (165,166) and a case series (107). The recommendation reflects our judgment that the benefits of identifying patients with such mutations (i.e., avoiding the risks and burdens of surgical lung biopsy, patient and family preferences) exceed the cost of genetic testing (Table E1).…”

Alveolar capillary dysplasia with multiple congenital anomalies and bronchoscopic airway abnormalities

“…10,11 The craniofacial dysmorphism seen in our patient was most likely due to the larger microdeletion disorder, but the primary phenotype can be ascribed to the deletion of the FOX gene cluster (FOXF1,FOXC & FOXL) as there are multiple similarities between our patient and those described by Stankiewicz et al, who reported ACD caused by the loss of function of FOXF1. 7,[12][13][14] ACD should be considered in neonates of any gestational age presenting with pulmonary hypertension or hypoxemic respiratory failure, especially if associated with cardiovascular or gastrointestinal anomalies or mutations of the FOX gene cluster. Our description of bronchial abnormalities in association with ACD, as well as the documented association between ACD and subglottic stenosis by Shimizu et al, suggest that ACD should be a diagnostic consideration in neonates with pulmonary hypertension and/or hypoxemic respiratory failure and proximal airway anomalies.…”