Pulmonary hypertension screening in children with sickle cell disease.

BACKGROUND: Screening for pulmonary hypertension (PHT) is recommended in children with sickle cell disease (SCD). However, best approaches are poorly described. We examined the utility of PHT symptoms, echocardiogram (ECHO), N-terminal-pro hormone brain natriuretic peptide (NT-proBNP), and BNP to screen for PHT in the SCD pediatric population. METHODS: Children (8-18 years old) with SCD-HbSS and HbSthal° were prospectively included and underwent PHT screening. The screening consisted of a comprehensive PHT symptoms evaluation, ECHO measurement, and NT-proBNP and BNP levels. RESULTS: A total of 73 patients were included (mean age 12 ± 5.7 years; >80% on hydroxyurea), of which 37% had a symptom consistent with PHT, including exertional dyspnea (26.5%), fatigue (17.6%), palpitation (14.7%), and chest pain (10.3%). ECHO was obtained in 53 (72.6%) patients, with only ECHO of 48 patients included in the final analysis. Elevated ECHO peak tricuspid regurgitant jet velocity (TRV) >2.5 m/s or indirect findings to suggest PHT were seen in only two of 48 (4.2%). No significant differences were seen between those with and without PHT symptoms when compared for NT-proBNP, BNP, hemoglobin, pulmonary function testing, fractional exhaled nitric oxide, asthma, oxygen saturation, and sleep apnea. CONCLUSION: PHT symptoms are not consistent with ECHO, NT-proBNP nor BNP findings in children with SCD. PHT prevalence based on TRV was low in children on hydroxyurea, therefore screening may not be warranted for this group.

The RSPH4A Gene in Primary Ciliary Dyskinesia.

The radial spoke head protein 4 homolog A (RSPH4A) gene is one of more than 50 genes that cause Primary ciliary dyskinesia (PCD), a rare genetic ciliopathy. Genetic mutations in the RSPH4A gene alter an important protein structure involved in ciliary pathogenesis. Radial spoke proteins, such as RSPH4A, have been conserved across multiple species. In humans, ciliary function deficiency caused by RSPH4A pathogenic variants results in a clinical phenotype characterized by recurrent oto-sino-pulmonary infections. More than 30 pathogenic RSPH4A genetic variants have been associated with PCD. In Puerto Rican Hispanics, a founder mutation (RSPH4A (c.921+3_921+6delAAGT (intronic)) has been described. The spectrum of the RSPH4A PCD phenotype does not include laterality defects, which results in a challenging diagnosis. PCD diagnostic tools can combine transmission electron microscopy (TEM), nasal nitric oxide (nNO), High-Speed Video microscopy Analysis (HSVA), and immunofluorescence. The purpose of this review article is to provide a comprehensive overview of current knowledge about the RSPH4A gene in PCD, ranging from basic science to human clinical phenotype.

Hermansky-Pudlak Syndrome.

Hermansky-Pudlak syndrome (HPS) is a multisystemic autosomal recessive disorder characterized by oculocutaneous albinism, bleeding diathesis, and lethal pulmonary fibrosis (PF) in some HPS subtypes. During middle adulthood, ground-glass opacities, reticulation, and traction bronchiectasis develop with progression of PF. HPS is an orphan disease occurring in 1 in 500,000 to 1,000,000 individuals worldwide, though the prevalence is 1 in 1,800 in individuals with Puerto Rican heritage. Recessive mutations or disruptions in HPS genes alter the function of HPS proteins which are components of biogenesis of lysosome-related organelle complexes and are critical for intracellular protein trafficking. Diagnosis and management of HPS-related comorbidities represent a challenge to physicians, and a multidisciplinary clinical approach is necessary for early detection, health management, and surveillance of PF in patients with HPS types 1, 2, and 4. Treatment options for individuals with HPS-PF include pirfenidone and lung transplantation. In this article, we describe the epidemiology, genetics, clinical manifestations, and management of HPS.

The Tip of the Iceberg: Genotype of Puerto Rican Pediatric Obesity.

Childhood obesity is a significant public health concern, particularly among Hispanic populations. This study aimed to elucidate the genetic predisposition to obesity in Puerto Rican children of Hispanic descent, addressing a notable gap in existing research. A cohort of 103 children with obesity and hyperphagia underwent genetic screening for rare obesity-related variants. Clinical assessments and family history evaluations were conducted to characterize the demographic and clinical characteristics of the cohort. Genetic testing revealed a high prevalence of variants, with 73% of subjects having at least one reported variant. Pathogenic variants, predominantly associated with obesity-related ciliopathies, were identified in 7% of cases. Additionally, 90% of cases had variants of uncertain significance, highlighting the complexity of genetic contributions to obesity. This study emphasizes the critical need for further investigation into the genetic foundations of obesity, particularly within Hispanic communities. The findings emphasize the importance of early medical evaluation, vigilant monitoring for hyperphagia onset, and targeted interventions tailored to the unique genetic landscape of Puerto Rican children. This research provides a foundational framework for future studies to mitigate the impact of genetic obesity within this population.

Respiratory Aspects of Primary Ciliary Dyskinesia.

This review article explores the respiratory aspects of primary ciliary dyskinesia (PCD), a rare, heterogenous, genetic disorder characterized by impaired motile ciliary function. It discusses the clinical diagnosis and management strategies for PCD-related respiratory disease, including chronic sinusitis, otitis media with effusion, recurrent pneumonia, and bronchiectasis. The review emphasizes the need for a multidisciplinary approach to optimize care and clinical trials to improve outcomes in individuals with PCD, highlighting the importance of accurate diagnosis.

Neutrophil-to-Lymphocyte Ratio Dynamics From Pre-diagnosis to End-Stage Amyotrophic Lateral Sclerosis (ALS): A Case Study on Association With Progression and Clinical Events.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons, resulting in muscle weakness and paralysis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential marker for monitoring disease severity and progression in ALS, yet longitudinal analyses of NLR are limited. Our study conducts an in-depth examination of NLR dynamics from before diagnosis through the disease's progression to its end stage. We analyze the case of a 56-year-old Puerto Rican male with ALS, tracking his NLR over 13 years - six years before and seven years after his diagnosis - alongside assessments of clinical symptoms and lung function. Our findings indicate that NLR values were initially normal but significantly increased with the onset of symptoms. NLR remained elevated above the normal range, with a notable exception during a period of edaravone therapy when levels normalized. The study demonstrates a clear elevation in NLR associated with ALS progression and critical clinical events, such as symptom onset, diagnosis, and the initiation of respiratory support. This research is, to our knowledge, the first to provide a detailed characterization of NLR changes from the pre-diagnostic phase to end-stage ALS, showing its correlation with clinical deterioration, decreased pulmonary function, and key clinical events. Our results contribute to the body of evidence on NLR's role in ALS while enhancing our understanding of ALS's natural progression.

Advancing Primary Ciliary Dyskinesia Diagnosis through High-Speed Video Microscopy Analysis.

Primary ciliary dyskinesia (PCD) is an inherited disorder that impairs motile cilia, essential for respiratory health, with a reported prevalence of 1 in 16,309 within Hispanic populations. Despite 70% of Puerto Rican patients having the RSPH4A [c.921+3_921+6del (intronic)] founder mutation, the characterization of the ciliary dysfunction remains unidentified due to the unavailability of advanced diagnostic modalities like High-Speed Video Microscopy Analysis (HSVA). Our study implemented HSVA for the first time on the island as a tool to better diagnose and characterize the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in Puerto Rican patients. By applying HSVA, we analyzed the ciliary beat frequency (CBF) and pattern (CBP) in native Puerto Rican patients with PCD. Our results showed decreased CBF and a rotational CBP linked to the RSPH4A founder mutation in Puerto Ricans, presenting a novel diagnostic marker that could be implemented as an axillary test into the PCD diagnosis algorithm in Puerto Rico. The integration of HSVA technology in Puerto Rico substantially enhances the PCD evaluation and diagnosis framework, facilitating prompt detection and early intervention for improved disease management. This initiative, demonstrating the potential of HSVA as an adjunctive test within the PCD diagnostic algorithm, could serve as a blueprint for analogous developments throughout Latin America.

Effect of an In-Home Palivizumab Administration Program for Children with Medical Complexity.

BACKGROUND: In-home palivizumab administration programs (PH) have shown promise in reducing RSV-associated infections. These programs may be particularly beneficial for children with medical complexity (CMC) by limiting their exposure to healthcare-associated infections (HAIs) from non-RSV-related pathogens during transportation and visits to medical facilities. METHODS: In this prospective study, 41 children with CMC less than 2 years of age were randomized by their health insurance to receive PH or in the clinic (PC) during the RSV season (October 2018-April 2019). Patients were stratified by home ventilation. The primary outcome was the total number of face-to-face encounters. Secondary outcomes were unscheduled clinic visits and hospitalizations secondary to the non-RSV LRTIs. Standard frequentist and Bayesian analyses were performed. RESULTS: All demographic factors and strata were matched between PH ("n" = 13, mean age 22 mo. SD ± 1), and PC ("n" = 28, mean age: 18 mo. SD ± 1). There was a decrease in the number of total face-to-face encounters (adjusted for mechanical ventilation and baseline diagnosis) [(4.5 vs. 8.8), (RR: 1.8, 95% CI: 1.3-2.5, p = 0.001)], and hospitalizations [(0.3 vs. 1.25), (RR: 3.8, 95% CI: 1.3-11.3, p = 0.016)], in the PH vs PC groups. Bayesian analysis showed a 93% probability of benefit in favor of fewer face-to-face encounters in the PH group. CONCLUSIONS: This study suggests that PH administration may reduce healthcare utilization in CMC. Minimizing exposure to healthcare facilities and supporting home-based interventions are promising strategies for this population.

HL-60 cells as a valuable model to study LPS-induced neutrophil extracellular traps release.

Neutrophil Extracellular Traps (NETs) present a paradoxical role in infectious diseases, contributing to both immunity and pathogenesis. The complex nature of this process necessitates further characterization to elucidate its clinical implications. However, studying NETs faces challenges with primary neutrophils due to their heterogeneity, short lifespan, and lack of adequate cryopreservation. Researchers often turn to alternative models, such as differentiated HL-60 cells (dHL-60). This study explored LPS-induced NETs formation in dHL-60 cells, revealing significant responses to LPS from Pseudomonas aeruginosa, although significantly lower than primary neutrophils. Moreover, Spleen Tyrosine Kinase (SYK) inhibition with R406, the active metabolite of the drug Fostamatinib, previously demonstrated to suppress NETs in primary neutrophils, effectively reduced NETs release in dHL-60 cells. dHL-60 cells, offering easier manipulation, consistent availability, and no donor variability in functional responses, possess characteristics suitable for high-throughput studies evaluating NETosis. Overall, dHL-60 cells may be a valuable in vitro model for deciphering the molecular mechanisms of NETosis in response to LPS, contributing to our available tools for understanding this complex immune process.

Evaluation of Open-Source Ciliary Analysis Software in Primary Ciliary Dyskinesia: A Comparative Assessment.

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by alterations in motile cilia function. The diagnosis of PCD is challenging due to the lack of standardized methods in clinical practice. High-speed video microscopy analysis (HSVA) directly evaluates ciliary beat frequency (CBF) in PCD. Recently, open-source ciliary analysis software applications have shown promise in measuring CBF accurately. However, there is limited knowledge about the performance of different software applications, creating a gap in understanding their comparative effectiveness in measuring CBF in PCD. We compared two open-source software applications, CiliarMove (v219) and Cilialyzer (v1.2.1-b3098cb), against the manual count method. We used high-speed videos of nasal ciliary brush samples from PCD RSPH4A-positive (PCD (RSPH4A)) patients and healthy controls. All three methods showed lower median CBF values for patients with PCD (RSPH4A) than in healthy controls. CiliarMove and Cilialyzer identified lower CBF in patients with PCD (RSPH4A), similarly to the manual count. Cilialyzer, CiliarMove, and manual count methods demonstrated statistical significance (p-value < 0.0001) in the difference of median CBF values between patients with PCD (RSPH4A) and healthy controls. Correlation coefficients between the manual count values against both software methods demonstrated positive linear relationships. These findings support the utility of open-source software-based analysis tools. Further studies are needed to validate these findings with other genetic variants and identify the optimal software for accurate CBF measurement in patients with PCD.

Long-Term Follow-up of Untreated Adult Patients with Spondylothoracic Dysostosis (Jarcho-Levin Syndrome).

BACKGROUND: Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is a rare autosomal recessive disorder affecting the formation of the spine, characterized by a complete bilateral fusion of the ribs at the costovertebral junction, producing a "crablike" appearance of the thorax. Despite being declared a core indication for a V-osteotomy vertical expandable prosthetic titanium rib (VEPTR) expansion thoracoplasty of the posterior thorax, the natural history of STD in untreated subjects remains poorly documented. In this study, we report radiographic and pulmonary function findings and Patient-Reported Outcomes Measurement Information System (PROMIS) and 24-Item Early Onset Scoliosis Questionnaire (EOSQ-24) scores for untreated adult subjects with STD to gain insights into the natural history. METHODS: We identified 11 skeletally mature, untreated subjects with STD. Findings on medical evaluation, demographics, radiographic parameters, pulmonary function, genetic testing results, PROMIS measures, and EOSQ-24 scores were assessed. RESULTS: Five male and 6 female subjects (mean age, 32.3 years [range, 15 to 70 years]) with a confirmed STD diagnosis based on radiographs and genetic testing were evaluated. Mean body mass index (BMI) was 24.4 kg/m 2 (range, 18 to 38.9 kg/m 2 ), and mean thoracic height was 16 cm (range, 12 to 17 cm). Pulmonary function tests (PFTs) showed a mean forced vital capacity (FVC) of 22% of predicted, mean forced expiratory volume in 1 second (FEV1) of 24% of predicted, and FEV1/FVC ratio of 107% of predicted. The mean PROMIS dyspnea score was 40 ± 8 points (range, 27.7 to 52.1 points). The mean total EOSQ-24 score was 77.3 ± 18 points (range, 43.9 to 93.2 points). CONCLUSIONS: Our study characterizes the natural history of STD in untreated subjects. We confirmed the expected restrictive pattern in pulmonary function, but interestingly, our subjects exhibited better EOSQ scores compared with those reported in neuromuscular populations. PFT results and thoracic height did not correspond to PROMIS and EOSQ scores, questioning the use of those parameters as a surgical indication. We therefore suggest that the STD diagnosis as an absolute indication for VEPTR expansion thoracoplasty surgery be reconsidered. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

CFTR-Related Metabolic Syndrome: Genetic Variants Increasing Pancreatitis Risk in the Pediatric Puerto Rican Population.

CFTR-related metabolic syndrome (CRMS) is a novel diagnosis due to widespread use of and advances in the newborn screening (NBS) process for cystic fibrosis (CF) in the United States of America, allowing for the diagnosis of asymptomatic children with CF. Before 2015, a large Puerto Rican pediatric population was not screened for CF in the NBS test. Studies have shown that patients presenting with idiopathic recurrent or chronic pancreatitis have an increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We present a retrospective chart review of 12 pediatric cases (n = 12) that were presented to an outpatient community clinic with clinical manifestations associated with CF. The pancreatic insufficiency prevalence (PIP) score was calculated on CFTR mutations. The mutations considered for the calculation of the PIP score were: F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519_1521del), and L1335P (c.4004T > C). V201M mutation was classified as mild in both PIP scores, and a correlation with pancreatitis was noted. Clinical manifestations vary in cases with the V201M variant (c.601G > A). One case was diagnosed with CFTR-related disorder (CRD) and recurrent pancreatitis. It is important to consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico due to the implications and increased risk of pancreatitis and other CF-related complications.

Bronchiectasis Assessment in Primary Ciliary Dyskinesia: A Non-Invasive Approach Using Forced Oscillation Technique.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder that results from the dysfunction of motile cilia, which can cause chronic upper and lower respiratory infections leading to bronchiectasis. However, there is a need for additional tools to monitor the progression of bronchiectasis in PCD. The forced oscillation technique (FOT) is an effort-independent lung function test that can be used to evaluate respiratory mechanics. In this retrospective study, we aimed to describe the radiographic findings associated with respiratory impedance (resistance (Rrs) and reactance (Xrs)) measured by FOT in six adult PCD patients and one pediatric with the (RSPH4A (c.921+3_921+6delAAGT (intronic)) founder mutation. We compared the radiographic findings on a high-resolution chest computed tomography (CT) scan with the FOT results. Our findings suggest that respiratory impedance measured by FOT may be a valuable tool for detecting and monitoring the progression of bronchiectasis in PCD patients with the (RSPH4A (c.921+3_921+6delAAGT (intronic)) founder mutation. However, further research is necessary to validate these results and determine the sensitivity and specificity of bronchiectasis monitoring in PCD patients with other genetic mutations.

The Genetics of Primary Ciliary Dyskinesia in Puerto Rico.

Primary ciliary dyskinesia (PCD) has been linked to more than 50 genes that cause a spectrum of clinical symptoms, including newborn respiratory distress, sinopulmonary infections, and laterality abnormalities. Although the RSPH4A (c.921+3_6delAAGT) pathogenic variant has been related to Hispanic groups with Puerto Rican ancestry, it is uncertain how frequently other PCD-implicated genes are present on the island. A retrospective chart review of n = 127 genetic reports from Puerto Rican subjects who underwent genetic screening for PCD variants was conducted from 2018 to 2022. Of 127 subjects, 29.1% subjects presented PCD pathogenic variants, and 13.4% were homozygous for the RSPH4A (c.921+3_6delAAGT) founder mutation. The most common pathogenic variants were in RSPH4A and ZMYND10 genes. A description of the frequency and geographic distribution of implicated PCD pathogenic variants in Puerto Rico is presented. Our findings reconfirm that the presence of PCD in Puerto Rico is predominantly due to a founder pathogenic variant in the RSPH4A (c.921+3_6delAAGT) splice site. Understanding the frequency of PCD genetic variants in Puerto Rico is essential to map a future genotype-phenotype PCD spectrum in Puerto Rican Hispanics with a heterogeneous ancestry.

Nasal Nitric Oxide Levels: Improving the Diagnosis of Primary Ciliary Dyskinesia in Puerto Rico.

Primary Ciliary Dyskinesia (PCD) is a rare genetic disease characterized by motile cilia dysfunction with a prevalence of 1 in 16,309 individuals in Hispanic populations. In Puerto Rico, the prevalence of PCD is unknown. Diagnosis of PCD in Puerto Rico is challenging due to the lack of diagnostic technology. Algorithms for PCD diagnosis include clinical history, genetic testing, ciliary biopsy, and nasal Nitric Oxide (nNO) levels. For the first time, this study successfully implemented and measured the nNO levels in subjects with the RSPH4A (c.921+3_921+6del (intronic)) as a diagnostic tool to complement the current algorithm for PCD diagnosis on the island. The nNO level differentiated homozygous subjects with PCD due to the RSPH4A (c.921+3_921+6del (intronic)) founder mutation compared to healthy gender-age matched controls and subjects with VUS or negative genetic testing for PCD. The acquisition of state-of-the-art diagnostic tools such as nNO positively impacted and expanded our current PCD diagnostic capabilities in Puerto Rico for our founder genetic mutation. The addition of nNO technology promotes earlier disease screening and recognition for patients with PCD on the island. The access to nNO helped us to properly characterize the PCD diagnosis for patients with the RSPH4A (c.921+3_921+6del (intronic)). As a result, our findings will allow us to be part of the national PCD foundation registry and represent Puerto Rican Hispanics in future PCD multicentric clinical trials.

Mycoplasma pneumoniae and Bronchiolitis Obliterans: How a Common Organism Leads to a Rare Pulmonary Disease in Pediatrics.

A rare lung disease, bronchiolitis obliterans (BO) is characterized by airway obstruction and fibrosis of the terminal and respiratory bronchioles. It usually occurs after lung and bone marrow transplants, hematopoietic stem cell transplantation (HSCT), inhalation of toxins, respiratory infections, or in association with several different connective tissue or irritable bowel diseases. When BO is caused by an infection it is referred to as post-infectious bronchiolitis obliterans (PIBO). The prevalence of BO is unknown but has been seen to occur worldwide. The pathophysiology of BO is not fully understood but there is evidence of fibroproliferation leading to abnormal airway remodeling with inflammatory mediators and granulation tissue that narrows the bronchial lumen. Diagnosis of BO is achieved via a combination of clinical manifestations, patient history, pulmonary function test (PFT), radiological imaging, and lung biopsy as the gold standard. Since there is limited literature on pediatric cases with BO and diagnosis may sometimes be challenging, we aim to bring awareness to a pediatric case where PIBO developed after a common pulmonary infection of Mycoplasma pneumoniae.

Primary Ciliary Dyskinesia Diagnostic Challenges: Understanding the Clinical Phenotype of the Puerto Rican RSPH4A Founder Mutation.

Primary ciliary dyskinesia (PCD) is a rare, heterogeneous ciliopathy resulting in chronic oto-sino-pulmonary disease, bronchiectasis, newborn respiratory distress, and laterality defects. PCD diagnosis can be achieved by following diagnostic algorithms that include electron microscopy, genetics, and ancillary testing. Genetic mutations in more than 45 genes, including RSPH4A, can lead to PCD. RSPH4A mutations located on chromosome six, affect radial spokes and results in central complex apparatus abnormalities. The RSPH4A [c.921 + 3_6delAAGT] founder mutation was described as one cause of PCD without laterality defects in Puerto Rico. Additionally, there are further diagnostic challenges present in the Puerto Rican population to diagnose PCD. We describe the demographics, clinical features, and RSPH4A genetic variants in 13 patients with clinical PCD affecting 11 Puerto Ricans from unrelated families.

Rapid-Onset Obesity Due to Impulsive Food-Seeking Behavior in a Puerto Rican Child With CHRNA7 15q13.3 Microdeletion.

A microdeletion in the 15q13.3 locus is an exceedingly rare condition affecting the CHRNA7 gene. There have been 11 pediatric cases of this mutation reported worldwide. Clinical characteristics of the 15q13.3 microdeletion are rapid-onset obesity, hypotonia, autism, seizures, congenital cardiac defects, and neuropsychiatric disorders including impulsive hyperphagia. We describe the case of a four-year-old female with CHRNA7 15q13.3 microdeletion presenting with morbid obesity due to impulsive food-seeking behavior. We have also conducted a literature review on 15q13.3 microdeletion and compared the clinical features with other rapid-onset obesity disorders in the pediatric population. The goal of this case report is to increase awareness concerning CHRNA7 15q13.3 microdeletion as part of the differential diagnosis of rapid-onset obesity associated with neuropsychiatric disorders in pediatrics.

Allergic Bronchopulmonary Aspergillosis With or Without Asthmatic Symptoms?

Allergic bronchopulmonary aspergillosis (ABPA) is a localized inflammatory airway disease seen in patients sensitized to Aspergillus fumigatus (A. fumigatus) antigens. The disease presents with productive cough, wheezing, episodic fever, as well as central bronchiectasis (CB) and mucus plugs on computed tomography (CT) scans. If treated accordingly, symptoms and pulmonary damage caused by ABPA can be reverted. Currently, the diagnostic criteria for ABPA require the diagnosis of predisposing pulmonary diseases such as asthma and cystic fibrosis (CF) in order to establish the diagnosis. There has been an increasing number of cases reporting ABPA without evidence of past asthmatic history or symptoms. This reflects the need for more sensitive diagnostic tests in order to prevent progression to irreversible lung injury. Here we report a 22-year-old Puerto Rican male who went undiagnosed for ABPA for 12 months due to the absence of asthma or CF history.