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PKD1L1 Is Involved in Congenital Chylothorax.

ABSTRACT: Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in PKD1L1 in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of Pkd1l1 mutant mouse embryos revealed about 20% of Pkd1l1^-/- embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in Pkd1l1^-/- embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of PKD1L1 in congenital lymphatic anomalies, including CCTs.

SUBMITTER: Whitchurch JB

PROVIDER: S-EPMC10814685 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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PKD1L1 Is Involved in Congenital Chylothorax.

Whitchurch Jonathan B JB Schneider Sophia S Hilger Alina C AC Köllges Ricarda R Stegmann Jil D JD Waffenschmidt Lea L Dyer Laura L Thiele Holger H Dhabhai Bhanupriya B Dakal Tikam Chand TC Müller Andreas A Norris Dominic P DP Reutter Heiko M HM

Cells 20240112 2

Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous va ...[more]

PMID: 38247840

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Project description:Background: Pleural effusion and chylothorax are common complications in the treatment of congenital diaphragmatic hernia (CDH). We set out to identify risk factors for chylothorax development in patients with CDH and to investigate the association of pleural effusion and chylothorax with neonatal morbidity and mortality. Methods: In this retrospective cohort study, we included 396 neonates with CDH treated at our institution between January 2013 and June 2019. Preoperative and postoperative chest radiographs and clinical data were evaluated and correlated with morbidity, complications and mortality. Results: Laboratory-confirmed chylothorax occurred in 58 (18.6%) of all CDH cases. Pleural effusion was frequently observed as a postoperative complication but also occurred as a pre-existing condition. Neonates with large defects of size C and D, patch repair, the need for presurgical and/or postsurgical ECMO support, pulmonary hypertension, liver-up phenomenon and lower relative fetal lung volume were associated with higher occurrences of chylothorax. After stepwise logistic regression, larger CDH defects (p < 0.0001) and the need for postsurgical ECMO (p = 0.0158) remained significant risk factors for CTX to occur (AUC 0.71). The same potential risk factors were used to assess their association with both presurgical and postsurgical pleural effusion. After stepwise logistic regression, only the need for presurgical ECMO remained significantly associated with presurgical PE (p < 0.01, AUC 0.65) and patch repair as the therapeutic intervention remained significantly associated with the occurrence of postsurgical PE (p < 0.0001, AUC 0.80). Patients with CTX had longer durations of both MV (p < 0.0001) and subsequent ventilatory assistance with spontaneous breathing (p = 0.0004), increased total lengths of hospitalization (p < 0.0001), increased durations of ECMO (p < 0.01) and increased incidences of CLD (p < 0.0001) compared to patients without CTX. No significant difference could be found for survival in both groups (p = 0.12). Conclusions: Our data suggest that the incidence of chylothorax is associated with large diaphragmatic defects, the need for postsurgical ECMO and the development of chronic lung disease, but not with survival.

Project description:Chylothorax is a rare condition characterized by the accumulation of chyle in the pleural space. While it accounts for a small percentage of pleural effusions, chylothorax can lead to significant morbidity and mortality. This article provides a comprehensive overview of chylothorax, covering its relevant anatomy, aetiology, pathophysiology, clinical features, diagnosis, and management. Injury or disruption to the thoracic duct (which is responsible for chyle transport) leads to the development of chylothorax. This may result from trauma, such as iatrogenic injury during surgery, or non-traumatic causes, including malignancy, lymphatic disorders, and heart failure. Recognition of the underlying cause is essential to tailor management. Clinical presentation varies, with symptoms linked to rate of chyle accumulation and the causative condition. Diagnosis relies on pleural fluid analysis, with demonstration of elevated triglyceride levels (>110 mg/dL) and reduced cholesterol levels (<200 mg/dL) being the key diagnostic criteria employed in clinical practice. Various imaging modalities, including computed tomography (CT) scans and lymphatic-specific investigations, may be utilised to aid identification of the site of chyle leak, as well as determine the likely underlying cause. Chylothorax management is multifaceted, with conservative approaches such as dietary modification and pharmacological interventions often initiated as first-line treatment. Drainage of chylous effusion may be necessary for symptom relief. When conservative methods fail, interventional procedures like thoracic duct ligation or embolization can be considered. Due to the diverse aetiological factors and patient characteristics associated with chylothorax, individualized management strategies are recommended. Nonetheless, management of chylothorax is an evolving field with a paucity of high-quality evidence or standardized guidelines, highlighting the importance of ongoing research and a multidisciplinary approach to optimize individual patient care.

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PKD1L1 Is Involved in Congenital Chylothorax.

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<i>PKD1L1</i> Is Involved in Congenital Chylothorax.

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