Acinar Dysplasia in a Full-Term Newborn with a NKX2.1 Variant.

Acinar dysplasia (AcDys) is one of the three main diffuse developmental disorders of the lung. The transcription factor NK2 homeobox 1 (NKX2.1) partly controls the synthesis of surfactant proteins by type 2 alveolar epithelial cells (AEC2), and germline mutations are known to be associated with brain-lung thyroid syndrome. We report the case of a full-term neonate who developed refractory respiratory failure with pulmonary hypertension requiring venoarterial extracorporeal membrane oxygenation. Histological examination of the lung biopsy specimen was consistent with the diagnosis of AcDys. Molecular analyses led to the identification of the missense heterozygous variant in NKX2.1 (NM_001079668) c.731A>G p.(Tyr244Cys), which is predicted to be pathogenic. After 5 weeks, because AcDys is a fatal disorder and the patient's status worsened, life-sustaining therapies were withdrawn, and she died after a few hours. This study is the first to extend the phenotype of NKX2.1 pathogenic variant, to a fatal form of AcDys.

Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice.

Neonatal acute respiratory distress syndrome (ARDS) has high morbidity and mortality rates worldwide, but there is a lack of pharmacologic treatment and clinical targeted therapies. In this study, we aimed to explore the effects of Lipocalin-2 (LCN2) on ferroptosis-mediated inflammation and oxidative stress in neonatal ARDS and the potential mechanism. In this study, we established an in vivo ARDS mouse model and an in vitro ARDS cell model by LPS (Lipopolysaccharide) stimulation. Lung tissue injury was evaluated by wet/dry ratios and histopathological examination. LCN2 expression was detected by qRT-PCR and Western blot. Inflammatory factors, oxidative stress and apoptosis were also detected. Ferroptosis was identified by detection of Fe2+ level and ferroptosis-associated protein expressions. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) pathway signaling was examined by Western blot analysis. The data revealed that LCN2 expression was significantly upregulated in neonatal mice with ARDS. Interference with LCN2 protected LPS-induced lung in neonatal mouse by reducing the radio of wet/dry and alleviating pathological damages. In addition, LCN2 silencing repressed LPS-induced inflammation, oxidative stress in vivo and in vitro, as well as apoptosis. Meanwhile, decreased level of Fe2+ and transferrin while increased levels of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) were observed. The expression MAPK/ERK pathway was inhibited by depletion of LCN2. The present results suggest that LCN2 knockdown protected LPS-induced ARDS model via inhibition of ferroptosis-related inflammation and oxidative stress by inhibiting the MAPK/ERK pathway, thereby presenting a novel target for the treatment of ARDS.

Role of surfactant protein C in neonatal genetic disorders of the surfactant system: A case report.

RATIONALE: Respiratory distress syndrome (RDS) refers to the symptoms of progressive dyspnea and respiratory failure in newborns shortly after birth. The clinical and genetic characteristics of patients with neonatal RDS have not been extensively reported. PATIENT CONCERNS: A infant was in critical condition with repeated paroxysmal blood oxygen decline. Oxygen inhalation and noninvasive ventilator-assisted breathing relief were not effective. The etiology was unclear, and there was no family history of lung disease. Surface-active substance replacement therapy and positive pressure-assisted ventilation support were ineffective. DIAGNOSIS: The infant was clinically diagnosed with RDS. Genetic tests revealed a heterozygous missense mutation in the c.168 surfactant protein C (SFTPC) gene. INTERVENTIONS: Tracheal intubation was performed with invasive ventilator-assisted breathing, pulmonary surfactant was administered. Supportive treatment for liver protection and administration of a cardiotonic diuretic, vasodilator, human immunoglobulin (intravenous infusion), fresh frozen plasma, and suspended red blood cells were performed. OUTCOMES: The infant showed poor responses to respiratory and circulatory support, antibiotic treatment, and other treatment methods. The patient was discharged from hospital against the advice of us, cut off from us. The long-term prognosis of the patient after discharge remains unknown. LESSONS: SFTPC gene mutations may be an important risk factor for the development of common lung diseases. Because of the important roles of surfactant functions and metabolism, mutations in these genes can affect the production and function of pulmonary surfactant, leading to severe lung disease in term newborns.

Structure-Based Understanding of ABCA3 Variants.

ABCA3 is a crucial protein of pulmonary surfactant biosynthesis, associated with recessive pulmonary disorders such as neonatal respiratory distress and interstitial lung disease. Mutations are mostly private, and accurate interpretation of variants is mandatory for genetic counseling and patient care. We used 3D structure information to complete the set of available bioinformatics tools dedicated to medical decision. Using the experimental structure of human ABCA4, we modeled at atomic resolution the human ABCA3 3D structure including transmembrane domains (TMDs), nucleotide-binding domains (NBDs), and regulatory domains (RDs) in an ATP-bound conformation. We focused and mapped known pathogenic missense variants on this model. We pinpointed amino-acids within the NBDs, the RDs and within the interfaces between the NBDs and TMDs intracellular helices (IHs), which are predicted to play key roles in the structure and/or the function of the ABCA3 transporter. This theoretical study also highlighted the possible impact of ABCA3 variants in the cytosolic part of the protein, such as the well-known p.Glu292Val and p.Arg288Lys variants.

Whole exome sequencing identifies a novel variant in ABCA3 in an individual with fatal congenital surfactant protein deficiency.

BACKGROUND: Adenosine triphosphate-binding cassette subfamily A member 3 (ABCA3) gene variants, which cause severe respiratory distress syndrome (RDS) in term newborns, can cause death, especially due to the lack of congenital surfactant protein. The relationship between the types, pathophysiology and effects of ABCA3 gene variants on surfactant metabolism and the clinical phenotype have not yet been fully clarified, but the ABCA3 genotype is known to affect clinical severity. CASE: In our study, in a term newborn with a diagnosis of RDS resulting in death, we detected the c.3677 T > C (p.Leu1226Pro) variant homozygous variant in the ABCA3 gene according to the NM_001089.3 transcript, which, to our knowledge, was identified for the first time in the literature. CONCLUSIONS: We consider that this case report contributes to the literature on RDS by showing the presence of c.3677 T > C (p.Leu1226Pro), a new homozygous variant of ABCA3 in our patient.

Novel homozygous missense mutation in ABCA3 protein leading to severe respiratory distress in term infant.

The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membrane disease (HMD). Baby was ventilated and treated with surfactant. Because of the persistence of high ventilation needs with X-ray pictures consistent with HMD with a transient response to surfactant every time, the possibility of an inherited disorder of surfactant metabolism was kept. Whole-exome sequencing revealed a novel homozygous missense mutation in the gene for ATP binding cassette transporter protein A3. The baby died after 100 days of ventilation.

DMBT1 is upregulated in lung epithelial cells after hypoxia and changes surfactant ultrastructure.

BACKGROUND: Hypoxia and asphyxia are known to induce surfactant inactivation in newborns. Deleted in Malignant Brain Tumors 1 (DMBT1) is an innate immunity protein with functions in epithelial differentiation and angiogenesis. It was detected in hyaline membranes of infants with respiratory distress syndrome. Human recombinant DMBT1 is able to increase the surface tension of exogenous surfactant preparations in a dose-dependent manner. METHODS: Immunohistochemistry was performed on lung sections of infants who died due to pre-, peri- or postnatal hypoxia. The lung epithelial cell line A549 was stably transfected with a DMBT1 (DMBT1+ cells) expression plasmid or with an empty plasmid (DMBT1- cells). The cells were cultured in normoxic or hypoxic conditions, and then DMBT1 as well as HIF-1α RNA expression were analyzed by using real-time-polymerase chain reaction. Human recombinant DMBT1 was added to the modified porcine natural surfactant Curosurf to examine the effect of DMBT1 on surfactant ultrastructure with electron microscopy. RESULTS: DMBT1 expression was upregulated in human lung tissue after fetal/peri-/postnatal hypoxia. In addition, in vitro experiments showed increased DMBT1 RNA expression in A549 cells after hypoxia. HIF-1α was upregulated in both DMBT1+ and DMBT1- cells in response to hypoxia. The addition of human recombinant DMBT1 to Curosurf caused an impaired surfactant ultrastructure. CONCLUSIONS: DMBT1 is upregulated in response to hypoxia and there seems to be a link between hypoxia and surfactant inactivation.

Mannose-binding lectin gene polymorphism and its effect on short term outcomes in preterm infants / Polimorfismo do gene da lectina ligante de manose e seu efeito em desfechos de curto prazo em bebês prematuros

Abstract Objective: Mannose-binding lectin, which belongs to the collectin family, is an acute-phase reactant that activates the complement system. This study aimed to investigate the effect of MBL2 gene polymorphism on short-term outcomes in preterm infants. Method: Infants of <37 gestational weeks who were admitted to the neonatal intensive care unit during a two-year period were enrolled in this prospective study. The neonates were categorized into two groups according to their MBL2 genotypes. Normal MBL2 genotype was defined as MBL2 wild-type (AA genotype), whereas mutant MBL2 genotype was defined as MBL2 variant-type (AO/OO genotype). The relationship between MBL2 genotype and short-term morbidity and mortality was evaluated. Results: During the two-year study period, 116 preterm infants were enrolled in this study. In MBL2 variant-type, mannose-binding lectin levels were significantly lower and incidences of mannose-binding lectin deficiency (MBL level < 700 ng/mL) were higher (p < 0.001). In this group, the prevalence of respiratory distress syndrome and mortality was significantly higher (p < 0.001, p = 0.03 respectively). In the MBL2 wild-type group, the prevalence of necrotizing enterocolitis (NEC) was higher (p = 0.01). Logistic regression analyses revealed that MBL2 variant-type had a significant effect on respiratory distress syndrome development (odds ratio, 5.1; 95% confidence interval, 2.2-11.9; p < 0.001). Conclusions: MBL2 variant-type and mannose-binding lectin deficiency are important risk factors for respiratory distress syndrome development in preterm infants. Additionally, there is an association between MBL2 wild-type and NEC. Further studies on this subject are needed.

Resumo Objetivo: A lectina ligante de manose (MBL, do inglês mannose-binding lectin), que pertence à família das colectinas, é um reagente de fase aguda que ativa o sistema complemento. Este estudo teve como objetivo investigar o efeito do polimorfismo do gene MBL2 em desfechos de curto prazo em prematuros. Método: Este estudo prospectivo incluiu crianças com menos de 37 semanas de gestação admitidas na unidade de terapia intensiva neonatal durante dois anos. Os neonatos foram categorizados em dois grupos de acordo com os genótipos do MBL2. O genótipo normal do gene MBL2 foi definido como MBL2 do tipo selvagem (genótipo AA), enquanto o genótipo mutante do gene MBL2 foi definido como o gene variante (genótipo AO/OO). Foi avaliada a relação entre o genótipo MBL2 e a morbidade e mortalidade em curto prazo. Resultados: Durante o período de dois anos, 116 bebês prematuros foram incluídos neste estudo. Os níveis de lectina ligante de manose foram significativamente menores nos variantes do MBL2 e as incidências de deficiência de lectina ligante de manose (nível de MBL < 700 ng/mL) foram maiores (p < 0,001). Nesse grupo, a prevalência de síndrome do desconforto respiratório (SDR) e a mortalidade foram significativamente maiores (p < 0,001, p = 0,03, respectivamente). No grupo MBL2 do tipo selvagem, a prevalência de enterocolite necrosante foi maior (p = 0,01). Análises de regressão logística revelaram que os genes variantes do MBL2 apresentaram um efeito significativo no desenvolvimento da síndrome do desconforto respiratório (odds ratio, 5,1; intervalo de confiança de 95%, 2,2-11,9; p < 0,001). Conclusões: As variantes do MBL2 e a deficiência de lectina ligante de manose são importantes fatores de risco para o desenvolvimento da síndrome do desconforto respiratório em neonatos prematuros. Além disso, existe uma associação entre MBL2 do tipo selvagem e a enterocolite necrosante. Mais estudos são necessários sobre esse assunto.

Enfermedad por coronavirus (COVID-19) en terapia intensiva: informe de un caso / Coronavirus disease (covid-19) in critical care: a case report

Una de las características de la afección pulmonar por enfermedad por coronavirus (COVID-19) es la disociación entre la gravedad de la hipoxemia y el mantenimiento de una mecánica respiratoria relativamente conservada. En este contexto se ha establecido una teoría en relación con dos fenotipos de pacientes con síndrome de distrés respiratorio del adulto (SDRA): un fenotipo Low, caracterizado por baja elastancia y baja reclutabilidad, y un fenotipo High, con características de alta elastancia y alta reclutabilidad. Presentamos el caso de un paciente que cursó internación en la Unidad de Terapia Intensiva de Adultos de nuestro hospital, con clínica, mecánica ventilatoria y patrón tomográfico compatible con el fenotipo Low de SDRA por COVID-19. (AU)

Dissociation between severity of hypoxemia and relative preserved respiratory mechanics is a characteristic observed in lung impairment due to coronavirus disease (COVID-19). Patients with COVID-19 that present adult respiratory distress syndrome (ARDS) are identified for one of two phenotypes according to a theory recently established. The Low phenotype is distinguished by low elastance and low recruitability; and the High phenotype, by high elastance and high recruitability. The case describes a patient admitted in the adult Intensive Care Unit of Hospital Italiano de Buenos Aires with observed symptoms, ventilatory mechanics and tomographic pattern that are compatible with Low phenotype of ARDS due to COVID-19. (AU)

Combined mutations of NKX2-1 and surfactant protein C genes for refractory low oxyhemoglobin saturation and interstitial pneumonia: A case report.

RATIONALE: Mutations of the NKX2-1 gene are associated with brain-lung-thyroid syndrome, which is characterized by benign hereditary chorea, hypothyroidism, and pulmonary disease with variable presentation. Surfactant protein C (SFTPC) gene mutations result in chronic interstitial lung disease in adults or severe neonatal respiratory distress syndrome. PATIENT CONCERNS: Recurrent hypoxemia was observed shortly after birth in a baby at a gestational age of 40 weeks and birth weight of 3150 g. The need for respiratory support gradually increased. He had hypothyroidism and experienced feeding difficulties and irritability. DIAGNOSIS: Genetic examination of the peripheral blood revealed combined mutations of the NKX2-1 and SFTPC genes. INTERVENTIONS: The patient was administered respiratory support, antibiotics, low-dose dexamethasone, supplementary thyroxine, venous nutrition, and other supportive measures. OUTCOMES: The patient's guardian stopped treatment 3 months after commencement of treatment, due to the seriousness of his condition and the patient died. LESSONS: Combined mutations of NKX2-1 and SFTPC genes are very rare. Thus, idiopathic interstitial pneumonia with hypothyroidism and neurological disorders require special attention.

Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia.

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.

Haploinsufficiency of NKX2-1 in Brain-Lung-Thyroid Syndrome with Additional Multiple Pituitary Dysfunction.

INTRODUCTION: Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome incorporating primary hypothyroidism, respiratory distress, and neurological disturbances. CASE PRESENTATION: We report a patient presenting in the neonatal period with multiple pituitary hormone deficiency including central hypothyroidism and hypoadrenalism, growth hormone deficiency, undetectable gonadotrophins, and a small anterior pituitary on MRI. CGH microarray revealed haploinsufficiency for NKX2.1 and during subsequent follow-up, she has exhibited the classic triad of brain-lung-thyroid syndrome with undetectable tissue on thyroid ultrasonography. Whilst the role of NKX2-1 is well described in murine pituitary development, this report constitutes the first description of multiple pituitary dysfunction in humans associated with the syndrome and haploinsufficiency NKX2-1. CONCLUSION: The report highlights a potential need for pituitary screening in patients with established brain-lung-thyroid syndrome and implicates NKX2.1 in human pituitary disease.

A New ABCA3 Gene Mutation c.3445G>A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome.

Mutations in adenosine triphosphate-binding cassette transporter A3 (ABCA3) (OMIM: 601615) gene constitute the most frequent genetic cause of severe neonatal respiratory distress syndrome (RDS) and interstitial lung disease (ILD) in children. Interstitial lung disease in children and especially in infants, in contrast to adults, is more likely to appear as a result of developmental deficits or is characterized by genetic aberrations of pulmonary surfactant homeostasis not responding to exogenous surfactant administration. The underlying ABCA3 gene mutations are commonly thought, regarding null mutations, to determine the clinical course of the disease while there exist mutation types, especially missense variants, whose effects on surfactant proteins are difficult to predict. In addition, clinical and radiological signs overlap with those of surfactant proteins B and C mutations making diagnosis challenging. We demonstrate a case of a one-term newborn male with lethal respiratory failure caused by homozygous missense ABCA3 gene mutation c.3445G>A (p.Asp1149Asn), which, to our knowledge, was not previously reported as a causative agent of newborn lethal RDS. Therapeutic strategies for patients with ABCA3 gene mutations are not sufficiently evidence-based. Therefore, the description of the clinical course and treatment of the disease in terms of a likely correlation between genotype and phenotype is crucial for the development of the optimal clinical approach for affected individuals.

Effects of MiR-26a on respiratory distress syndrome in neonatal rats via the wnt/ß-catenin signaling pathway.

OBJECTIVE:   Micro ribonucleic acids (miRNAs) are crucial to post-transcriptional regulation of the gene expression. Whether miR-26a affects respiratory distress syndrome (RDS) in neonatal rats through the Wnt/ß-catenin signaling pathway was investigated in this study. PATIENTS AND METHODS: The neonatal rat model of RDS was established, and the expressions of miR-26a and glycogen synthase kinase-3ß (GSK-3ß) in RDS in neonatal rats and their correlation were analyzed. The cascade relationship between miR-26a and the Wnt/ß-catenin signaling pathway and the influence of miR-26a on the expression of inflammatory cytokines were subsequently verified. Finally, the influences of miR-26a on the expressions of important markers, receptor for advanced glycation endproducts (RAGE), high mobility group box 1 (HMGB1), and plasminogen activator inhibitor-1 (PAI-1), through the Wnt/ß-catenin signaling pathway were analyzed. RESULTS: Compared with those in normal tissues, the expression of miR-26a in lung tissues of neonatal rats with RDS was significantly decreased (p<0.05), while the expression of GSK-3ß messenger RNAs (mRNAs) was notably increased (p<0.01), and the GSK-3ß expression was negatively correlated with the miR-26a expression (r=-0.6693, p=0.0064). In addition, miR-26a mimics significantly inhibited the GSK-3ß protein expression and activated the Wnt/ß-catenin signaling pathway. Moreover, miR-26a could reduce the expressions of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6, as well as RAGE, HMGB1, and PAI-1. CONCLUSIONS: MiR-26a can affect inflammatory responses and markers through the Wnt/ß-catenin signaling pathway in neonatal rats with RDS.

Surfactant deficiency syndrome in an infant with a C-terminal frame shift in ABCA3: A case report.

Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C-terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids. The frame shift spares membrane spanning and nucleotide binding domains, but disrupts a highly conserved C-terminal domain, which includes sequence motifs necessary for the function of human paralogs ABCA1, ABCA4, and the bacterial homolog DrrA. This observation suggests the C-terminal domain is also required for normal function of ABCA3.

The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency.

Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA.

Tread carefully: A functional variant in the human NADPH oxidase 4 (NOX4) is not disease causing.

In this study, we report a paediatric patient with a lethal phenotype of respiratory distress, failure to thrive, pancreatic insufficiency, liver dysfunction, hypertrophic cardiomyopathy, bone marrow suppression, humoral and cellular immune deficiency. To identify the genetic basis of this unusual clinical phenotype and potentially make available the option of future prenatal testing, whole exome sequencing (WES) was used followed by functional studies in a bid to confirm pathogenicity. The WES we identified a homozygous novel variant, AK298328; c.9_10insGAG; p.[Glu3dup], in NOX4 in the proband, and parental heterozygosity for the variant (confirmed by Sanger sequencing). NADPH Oxidase 4 NOX4 (OMIM 605261) encodes an enzyme that functions as the catalytic subunit of the NADPH oxidase complex. NOX4 acts as an oxygen sensor, catalysing the reduction of molecular oxygen, mainly to hydrogen peroxide (H2O2). However, although, our functional data including 60% reduction in NOX4 protein levels and a 75% reduction in the production of H2O2 in patient fibroblast extracts compared to controls was initially considered to be the likely cause of the phenotype in our patient, the potential contribution of the NOX4 variant as the primary cause of the disease was clearly excluded based on following pieces of evidence. First, Sanger sequencing of other family members revealed that two of the grandparents were also homozygous for the NOX4 variant, one of who has fibromuscular dysplasia. Second, re-evaluation of more recent variant databases revealed a high allele frequency for this variant. Our case highlights the need to re-interrogate bioinformatics resources as they are constantly evolving, and is reminiscent of the short-chain acyl-CoA dehydrogenase deficiency (SCADD) story, where a functional defect in fatty acid oxidation has doubtful clinical ramifications.

Arterial tortuosity syndrome: 40 new families and literature review.

PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. METHODS: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-ß signaling with immunohistochemistry for pSMAD2 and CTGF. RESULTS: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-ß signaling. CONCLUSION: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1-2years of age, residual capabilities reach a plateau. We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period.