De-novo missense variant in PBX1 leading to severe respiratory insufficiency in a newborn (Case Report)

We report on a male full-term newborn with a de-novo missense variant within the PBX1 gene. Clinically, the patient presented postnatally with respiratory distress and muscular hypotonia, requiring urgent CPAP-ventilation with high oxygen supply. Infectious, metabolic and autoimmune causes of respiratory failure were ruled out. The infants condition improved slowly after 2 weeks and administration of high dosage of prednisolone, but CPAP with supplemental oxygen was still required. Further examinations revealed a PDA and PFO, as well as mild pulmonary hypertension (PH) and cryptorchidism. Radiological suspicion of childhood interstitial lung disease was followed by trio whole genome sequencing identifying a pathogenic de-novo missense variant within the PBX1 gene (ENST00000420696.7: c.704 G>A (p.Arg235Gln)). ChILD encompasses over 200 rare pediatric respiratory disorders that may affect not only the interstitium but also the alveoli, capillary network, and terminal bronchioles. Affected children present with tachypnea, dyspnea, hypoxemia and/or dry cough and may need non-invasive/invasive ventilation. Pre-B cell leukemia factor 1 (PBX1) is an important transcription factor, which has a major role in lung development and regulation of lung perfusion and ventilation by affecting gene expression of vasoactive mediators and fibroblast growth factor 10 (FGF10), which is involved in lung branching morphogenesis. To date, only a limited number of cases with PBX1 deficiency have been reported, characterized by congenital renal and urogenital tract anomalies with/without hearing loss, abnormal ears and developmental delay (CAKUTHED-syndrome), PH, lung hypoplasia, diaphragmatic hernia, congenital heart defects or cryptorchidism. However, a detailed characterization of the pulmonary phenotype is still lacking. This case presented with chronic hypercapnic respiratory failure due to muscular hypotonia and generalized bronchomalacia. Transbronchial lung biopsies revealed normal alveolarization without signs of interstitial lung disease. The patient was discharged with respiratory support consisting of nCPAP during sleep and low-flow oxygen therapy while awake. Follow-up examinations are planned. Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany