Improvement in Echocardiographic and Diagnostic Biomarkers after Systemic Glucocorticoid Therapy in Infants with Pulmonary Hypertension.

OBJECTIVE: To assess the effect of treating pulmonary hypertension (PH) in infants younger than 1 year of age with systemic glucocorticoids while using echocardiographic and diagnostic biomarkers as measures of efficacy. STUDY DESIGN: A retrospective chart review was performed on 17 hospitalized infants younger than 1 year of age at St Louis Children's Hospital who received a 5- to 7-day course of systemic glucocorticoid treatment followed by a 3-week taper with no significant intracardiac shunts from January 1, 2017, to December 31, 2021. Quantitative echocardiographic indices for PH, N-terminal pro b-type natriuretic peptide, and/or b-type natriuretic peptide levels were collected before glucocorticoid treatment, after the glucocorticoid burst, and after the 21-day taper. RESULTS: Mean (±SD) gestational age was 32.1 (±5.8) weeks, 5 infants were (29%) concomitantly treated with sildenafil, and 8 were male. Twelve were classified as World Health Organization group 3 PH (71%) and 5 as World Health Organization group 1 PH. There were significant improvements 30 days after glucocorticoid initiation in b-type natriuretic peptide levels (P = .008), PCO2 (P = .03), eccentricity index (P = .005), right ventricular ejection time (P = .04), pulmonary artery acceleration time (P = .002), and pulmonary artery acceleration time-to-right ventricular ejection time ratio (P = .02). Tricuspid regurgitation velocity was not able to be assessed. There were no mortalities during the study timeline. CONCLUSIONS: In our retrospective study, systemic glucocorticoid therapy was well tolerated and appeared to be associated with significant improvement in cardiopulmonary function in infants with PH. Further prospective study in a larger sample is warranted.

Monitoring and evaluation of the surgical Potts shunt physiology using 4-dimensional flow magnetic resonance imaging.

OBJECTIVE: The reversed Potts shunt is an increasingly applied mode of surgical palliation of severe pulmonary hypertension (PH). However, the long-term flow hemodynamic effect of the Potts shunt physiology and desirable long-term hemodynamic end points are not defined. The purpose of this descriptive study was to analyze a series of pediatric patients who underwent surgical Potts shunt as a part of end-stage PH palliation using 4-dimensional (4D)-flow magnetic resonance imaging (MRI) to (1) quantitate the flow through the anastomosis, (2) correlate the shunting pattern with phases of cardiac cycle and PH comorbidities, and (3) describe chronologic changes in shunting pattern. METHODS: This was a 2-center study evaluating 4 patients seen in the Pulmonary Hypertension Clinic at Children's Hospital Colorado who were evaluated and selected to undergo surgical reverse Potts shunt at Washington University School of Medicine and were serially followed using comprehensive imaging including cardiac MRI and 4D-flow MRI. RESULTS: After the procedure, each child underwent 2 4D-flow MRI evaluations. Pulmonary pressure offload was evident in all patients, as demonstrated by positive systolic right-to-left flow across the Potts shunt. All patients experienced some degree of the flow reversal, which occurs primarily in diastole. Interventricular dyssynchrony further contributed to flow reversal across the Potts shunt. Lastly, systemic and pulmonary blood mixing in the descending aorta results in secondary helical flow persisting throughout the diastole. CONCLUSIONS: 4D-flow MRI demonstrates that children who have undergone a Potts shunt for severe PH can experience shunt flow reversal. Cumulatively, this left-to-right pulmonary shunt adds to right ventricular volume overload. We speculate that a valved conduit may decrease the left to right shunting and improve overall cardiac output.

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension.

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Midterm outcomes of the Potts shunt for pediatric pulmonary hypertension, with comparison to lung transplant.

OBJECTIVE: For children with severe pulmonary hypertension, addition of Potts shunt to a comprehensive palliation strategy might improve the outcomes afforded by medications and delay lung transplantation. METHODS: A prospective analysis was conducted of all children undergoing Potts shunt (first performed in 2013) or bilateral lung transplant for pulmonary hypertension from 1995 to present. RESULTS: A total of 23 children underwent Potts shunt (20 surgical, 3 transcatheter), and 31 children underwent lung transplant. All children with Potts shunt had suprasystemic right ventricle pressures despite maximal medical treatment. In the majority of patients, the Potts shunt was performed through a left thoracotomy approach (90%, 18/20), by direct anastomosis (65%, 13/20), and without the use of extracorporeal support (65%, 13/20). Perioperative outcomes after Potts shunt were superior to lung transplant including mechanical ventilation time (1.3 vs 10.2 days, P = .019), median hospital length of stay (9.8 vs 34 days, P = .012), and overall complication rate (35% [7/20] vs 81% [25/31], P = .003). Risk factors for operative mortality after Potts shunt (20%, 4/20; compared with 6%, 2/31 for lung transplant, P = .195) included preoperative extracorporeal membrane oxygenation and significant right ventricle dysfunction. In midterm follow-up (median 1.8, maximum 6.1 years), patients with Potts shunt had durable equalization of right ventricle/left ventricle pressures and improved functional status. There was no significant survival difference in patients with Potts shunt and patients with lung transplant (P = .258). CONCLUSIONS: Potts shunt is an effective palliation for children with suprasystemic pulmonary hypertension that may become part of a strategy to maximize longevity and functional status for these challenging patients.

Rapid development of pulmonary hypertension during treatment of paediatric cancer.

Paediatric pulmonary hypertension has been described as a secondary complication of multiple diseases and their treatment. Limited information exists about the relationship between pulmonary hypertension and cancer in children. A review of charts was performed in all patients treated for cancer and developed pulmonary hypertension. A total of four patients developed pulmonary hypertension during treatment of cancer. All patients had solid tumors, had echocardiographic evidence of elevated right ventricular pressures, and required intensive care stays. Treatment courses included inhaled and oral pulmonary vasodilators along with systemic steroids. Each had normalisation of echocardiograms and resolution of pulmonary symptoms. Prompt diagnosis of pulmonary hypertension and treatment with pulmonary vasodilators and steroids are considered important measures followed by chemotherapy and radiation regimens.

Potts Shunt Improves Right Ventricular Function and Coupling With Pulmonary Circulation in Children With Suprasystemic Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease with poor outcomes in children. Right ventricular (RV) function is the most important determinant of the prognosis. Novel application of Potts shunt between left pulmonary artery and descending aorta has been introduced in an attempt to improve the survival. However, the effect of Potts shunt creation on RV function, RV-PA coupling, and survival has not been studied. METHODS AND RESULTS: We evaluated the first 12 consecutive pediatric patients (9 male, median age 11.2 years and weight 32.8 kg) who underwent elective Potts shunt placement for suprasystemic pulmonary arterial hypertension between 2013 and 2017 with echocardiographic indices of RV function, RV work, RV-PA coupling, and pulmonary hemodynamics. Of 12 patients, 1 was excluded because of insufficient preshunt data, 2 died, 1 required lung transplant, and 8 survived for a median of 27 months postshunt. In survivors, WHO functional class significantly ( P=0.01) improved and the majority (5 of 8) came off pulmonary vasodilators at the most recent follow-up. Postshunt RV systolic function improved ( P=0.03), RV afterload decreased ( P <0.01), RV work decreased ( P=0.02), and RV-proximal PA coupling improved ( P<0.01). CONCLUSIONS: This proof of concept study shows that Potts shunt allows improvement in functional status and mid-term transplant-free survival in the majority of the recipients by improvement in RV systolic function and RV-PA coupling in children with suprasystemic pulmonary arterial hypertension.

CD19-positive antibody-secreting cells provide immune memory.

Long-lived antibody-secreting cells (ASCs) are critical for the maintenance of humoral immunity through the continued production of antibodies specific for previously encountered pathogen or vaccine antigens. Recent reports describing humoral immune memory have suggested the importance of long-lived CD19- bone marrow (BM) ASCs, which secrete antibodies recognizing previously encountered vaccine antigens. However, these reports do not agree upon the unique contribution of the CD19+ BM ASC subset toward humoral immunity. Here, we found both CD19+ and negative ASCs from human BM were similar in functional capacity to react to a number of vaccine antigens via ELISpot assays. The CD19+ cells were the predominant ASC population found in lymphoid tissues, and unlike the CD19- ASCs, which were found only in spleen and BM, the CD19+ ASCs were found in tonsil and blood. CD19+ ASCs from the BM, spleen, and tonsil were capable of recognizing polio vaccine antigens, indicating the CD19+ ASC cells play a novel role in long-lasting immune defense. Comparative gene expression analysis indicated CD19+ and negative BM ASCs differed significantly by only 14 distinct messenger RNAs and exhibited similar gene expression for cell cycle, autophagy, and apoptosis control necessary for long life. In addition, we show identical CDR-H3 sequences found on both BM ASC subsets, indicating a shared developmental path. Together, these results provide novel insight for the distribution, function, genetic regulation, and development of long-lived ASCs and may not only impact improved cell therapies but also enhance strategies for vaccine development.

Pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia: a longitudinal study.

Pulmonary arteriovenous malformations (PAVMs) often occur in children with hereditary hemorrhagic telangiectasia (HHT). A 14-year longitudinal study of PAVMs in children with HHT was undertaken to assess the prevalence, the clinical impact, and progression of these malformations. This was a retrospective, single-center study from May 2002 to December 2016 of 129 children with HHT diagnosed using Curacao criteria and/or confirmed by genetic testing. Transthoracic contrast echocardiography (TTCE) was the primary screening modality in all patients and PAVMs were diagnosed based on Barzilai criteria. Moderately positive TTCE (Barzilai criteria ≥ 2) was confirmed with subsequent contrast chest CT. New PAVMs were diagnosed with a positive TTCE after an initial negative TTCE. Embolization of PAVMs were performed according to HHT consensus guidelines. Of 129 children with HHT, 76 (59%) were found to have PAVMs. Sixty-seven (88%) were positive for PAVMs on initial screening. Of 63 children without PAVMs on initial screening, 31 were followed for >1 year. Nine of the 31 (29%) developed new PAVMs after initial negative study. Thirty-eight (50%) of the total 76 children with PAVMs had or developed lesions large enough to be treated with embolization. Nine patients with PAVMs initially too small to be treated with embolization, developed progression of disease and ultimately were treated with embolization over time. The majority, 60% (23/38), of the children with large PAVMs had no related clinical symptoms. After embolization, 21% (8/38), of patients underwent repeat interventions. Genetic diagnosis, age, and gender were not associated with risk of having PAVM nor with need for repeat interventions. Nearly 60% of children with HHT develop PAVMs. The risk for new PAVMs to develop, small PAVMs to become large, and previously embolized PAVMs to require further intervention remains throughout childhood. Thus, children with HHT require continued follow-up until adulthood.

Treatment of Pediatric Pulmonary Hypertension.

Pulmonary hypertension (PH) is an increasingly recognized problem in children, particularly within tertiary pediatric hospitals. This increase is, in large part, due to ever improving survival among previously fatal conditions, such as extreme prematurity and complicated congenital heart disease. This increased recognition has paralleled burgeoning pharmacologic and interventional PH-specific treatment options. Unfortunately, most PH-specific therapies have not been tested in children with rigorous, randomized, controlled trials. As a result, most treatment of PH in children is based upon expert consensus and practitioners' experience. In this article, we highlight some of the current and recent advances in therapies available for children with PH. The role that a Potts shunt may have in ameliorating severe PH in children is highlighted.

Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation.

OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation. STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications. RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings. CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.

Isolated Major Aortopulmonary Collateral as the Sole Pulmonary Blood Supply to an Entire Lung Segment.

Congenital systemic-to-pulmonary collateral arteries or major aortopulmonary collaterals are associated with cyanotic congenital heart disease with decreased pulmonary blood flow. Though it is usually associated with congenital heart diseases, there is an increased incidence of isolated acquired aortopulmonary collaterals in premature infants with chronic lung disease. Interestingly, isolated congenital aortopulmonary collaterals can occur without any lung disease, which may cause congestive heart failure and require closure. We present a neonate with an echocardiogram that showed only left-sided heart dilation. Further workup with a CT angiogram demonstrated an anomalous systemic artery from the descending thoracic aorta supplying the left lower lobe. He eventually developed heart failure symptoms and was taken to the catheterization laboratory for closure of the collateral. However, with the collateral being the only source of blood flow to the entire left lower lobe, he required surgical unifocalization. Isolated aortopulmonary collaterals without any other congenital heart disease or lung disease are rare. Our patient is the first reported case to have an isolated aortopulmonary collateral being the sole pulmonary blood supply to an entire lung segment. Due to its rarity, there is still much to learn about the origin and development of these collaterals that possibly developed prenatally.

A critical appraisal of continence in bladder exstrophy: Long-term outcomes of the complete primary repair.

INTRODUCTION: Long-term continence outcomes for patients with bladder exstrophy are lacking in the literature. The complete primary repair of exstrophy (CPRE) is a widely adopted approach that seeks to normalize anatomy at the initial repair, thereby allowing early bladder filling and cycling. Previous reports of continence following CPRE, however, are limited by variable follow-up duration and continence definitions. OBJECTIVE: To assess continence and factors associated with a positive outcome in a cohort of patients following CPRE with long-term follow-up. STUDY DESIGN: A retrospective chart review was conducted of all patients with primary bladder closure using CPRE at the present institution for classic bladder exstrophy from 1990 to 2010. Patients <6 years of age or with an incomplete continence assessment at last follow-up were excluded. Continence was defined as voiding volitionally with dry intervals of ≥3 h, which was consistent with other high-volume series in the literature. RESULTS: Twenty-nine of the 52 patients (56%) were eligible for inclusion. Twelve patients were continent at last follow-up, including seven boys and five girls. Mean follow-up for the entire cohort was 148 months. The Summary table displays comparisons between continent and incontinent patients. Of patients achieving continence, 42% did not require further continence operations, while 17% required only one additional continence operation. DISCUSSION: Long-term CPRE continence rates were lower than previously reported, but comparable to other series in the literature. Of those achieving continence, 59% will do so with zero or one additional operation. Sex and osteotomy status were not associated with continence outcomes, although age at follow-up was a predictor of continence, favoring older patients in the present series. The study was limited by lack of standardized, patient-reported continence outcomes and by the retrospective nature of the review. However, the data add to the literature of long-term continence outcomes and are important for counseling families both at initial repair and follow-up. CONCLUSIONS: Complete primary repair of exstrophy can achieve continence without additional operations in a subset of patients. Some patients, however, may not achieve continence until adolescence, underscoring the need for long-term urologic follow-up in patients with bladder exstrophy.

Recommendations for utilization of the paracorporeal lung assist device in neonates and young children with pulmonary hypertension.

The management of decompensating critically ill children with severe PH is extremely challenging and requires a multidisciplinary approach. Unfortunately, even with optimal care, these children might continue to deteriorate and develop inadequate systemic perfusion and at times cardiac arrest secondary to a pulmonary hypertensive crisis. Tools to support these children are limited, and at times, the team should proceed with offering extracorporeal support, especially in newly diagnosed patients who have not benefitted from medical therapy prior to their acute deterioration, in patients with severe pulmonary venous disease and in patients with alveolar capillary dysplasia. Currently, the only approved mode for extracorporeal support in pediatric patients with PH eligible for lung transplantation is ECMO. To decrease the risks associated with ECMO, and offer potential for increased duration of support, extubation, and rehabilitation, we transitioned four small children with refractory PH from ECMO to a device comprising an oxygenator interposed between the PA and LA. This work describes in great detail our experience with this mode of support with emphasis on exclusion criteria, the implantation procedure, and the post-implantation management.

Α-Dystrobrevin-1 recruits Grb2 and α-catulin to organize neurotransmitter receptors at the neuromuscular junction.

Neuromuscular junctions (NMJs), the synapses made by motor neurons on muscle fibers, form during embryonic development but undergo substantial remodeling postnatally. Several lines of evidence suggest that α-dystrobrevin, a component of the dystrophin-associated glycoprotein complex (DGC), is a crucial regulator of the remodeling process and that tyrosine phosphorylation of one isoform, α-dystrobrevin-1, is required for its function at synapses. We identified a functionally important phosphorylation site on α-dystrobrevin-1, generated phosphorylation-specific antibodies to it and used them to demonstrate dramatic increases in phosphorylation during the remodeling period, as well as in nerve-dependent regulation in adults. We then identified proteins that bind to this site in a phosphorylation-dependent manner and others that bind to α-dystrobrevin-1 in a phosphorylation-independent manner. They include multiple members of the DGC, as well as α-catulin, liprin-α1, Usp9x, PI3K, Arhgef5 and Grb2. Finally, we show that two interactors, α-catulin (phosphorylation independent) and Grb2 (phosphorylation dependent) are localized to NMJs in vivo, and that they are required for proper organization of neurotransmitter receptors on myotubes.

Potts Shunt and Pediatric Pulmonary Hypertension: What We Have Learned.

BACKGROUND: A Potts shunt has been proposed as effective palliative therapy in children with severe pulmonary hypertension (PH) who have suprasystemic right ventricular pressures. METHODS: A retrospective single-center study was performed to assess outcomes in 5 children who underwent a Potts shunt for severe PH. RESULTS: All 5 children were in World Health Organization functional class IV. Only 3 children were classified as having idiopathic pulmonary arterial PH. Preoperatively, 4 children were receiving intravenous prostacyclins, and 3 were placed on intravenous inotropes for acute right-side heart failure. Three children were potential lung transplant candidates. All but 1 child had evidence for suprasystemic right heart pressures immediately before their operation. All 5 children survived the procedure without significant complications. Four of the 5 children were successfully discharged from the hospital and have had sustained clinical improvement with follow-up ranging from approximately 5 to 16 months. The child who did not have suprasystemic right-side heart pressures before the operation did not benefit from the Potts shunt. CONCLUSIONS: The Potts shunt can be an effective palliation for children with severe PH. Our results further suggest that (1) a Potts shunt should be considered early in a child's clinical course, before right ventricular deterioration develops; (2) a Potts shunt should be considered in any child with severe, intractable PH regardless of etiology; (3) one might consider a Potts shunt in lieu of intravenous prostacyclins; and (4) a Potts shunt should be considered before lung transplantation and does not preclude future transplantation candidacy.

Reconstruction of the symphysis pubis to repair a complex midline hernia in the setting of congenital bladder exstrophy.

PURPOSE: A 40-year-old man with congenital midline defect and wide pubic symphysis diastasis secondary to bladder exstrophy presented with a massive incisional hernia resulting from complications of multiple prior abdominal repairs. Using a multi-disciplinary team of general, plastic, and urologic surgeons, we performed a complex hernia repair including creation of a pubic symphysis with rib graft for inferior fixation of mesh. METHODS: The skin graft overlying the peritoneum was excised, and the posterior rectus sheath mobilized, then re-approximated. The previously augmented bladder and urethra were mobilized into the pelvis, after which a rib graft was constructed from the 7th rib and used to create a symphysis pubis using a mortise joint. This rib graft was used to fix the inferior portion of a 20 × 25 cm porcine xenograft mesh in a retro-rectus position. With the defect closed, prior skin scars were excised and the wound closed over multiple drains. RESULTS: The patient tolerated the procedure well. His post-operative course was complicated by a vesico-cutaneous fistula and associated urinary tract and wound infections. This resolved by drainage with a urethral catheter and bilateral percutaneous nephrostomies. The patient has subsequently healed well with an intact hernia repair. The increased intra-abdominal pressure from his intact abdominal wall has been associated with increased stress urinary incontinence. CONCLUSIONS: Although a difficult operation prone to serious complications, reconstruction of the symphysis pubis is an effective means for creating an inferior border to affix mesh in complex hernia repairs associated with bladder exstrophy.

Structure of a modular polyketide synthase.

Polyketide natural products constitute a broad class of compounds with diverse structural features and biological activities. Their biosynthetic machinery, represented by type I polyketide synthases (PKSs), has an architecture in which successive modules catalyse two-carbon linear extensions and keto-group processing reactions on intermediates covalently tethered to carrier domains. Here we used electron cryo-microscopy to determine sub-nanometre-resolution three-dimensional reconstructions of a full-length PKS module from the bacterium Streptomyces venezuelae that revealed an unexpectedly different architecture compared to the homologous dimeric mammalian fatty acid synthase. A single reaction chamber provides access to all catalytic sites for the intramodule carrier domain. In contrast, the carrier from the preceding module uses a separate entrance outside the reaction chamber to deliver the upstream polyketide intermediate for subsequent extension and modification. This study reveals for the first time, to our knowledge, the structural basis for both intramodule and intermodule substrate transfer in polyketide synthases, and establishes a new model for molecular dissection of these multifunctional enzyme systems.

Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins.

Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung-specific long non-coding RNA (lncRNA) gene LINC01081 intact. In the second patient with severe neonatal-onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV.

Molecular and phenotypic characterization of atypical Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a multisystemic genomic disorder typically caused by a recurrent ˜1.5-1.8 Mb deletion on 7q11.23. Atypical deletions can provide important insight into the genotype-phenotype correlations. Here, we report the phenotypic and molecular characterization of a girl with a de novo 81.8 kb deletion in the WBS critical region, which involves the ELN and LIMK1 genes only. The patient presented at 2 months of age with extensive vascular abnormalities, mild facial dysmorphism and delays in her fine motor skills. We discuss potential molecular mechanisms and the role of ELN and LIMK1 in the different phenotypic features. We compare the findings in our patient with previously reported overlapping deletions. The phenotypic variability among these patients suggests that other factors are important in the phenotype and possibly include: position effects related to copy number variation size, variations in the non-deleted alleles, genetic modifiers elsewhere in the genome, or reduced penetrance for specific phenotypes.