Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Increased Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio in Chronic and Severe Urticaria.

Chronic spontaneous urticaria (CSU) is a disturbing skin condition often severely detrimental to quality of life. Haematological markers of inflammation such as neutrophil-to-lymphocyte and platelet-to-lymphocyte may be used in the assessment of inflammatory skin diseases. Their usefulness in urticaria is unknown. Neutrophil- to-lymphocyte, platelet-to-lymphocyte, and total serum IgE were investigated in urticaria patients: acute spontaneous urticaria (ASU) versus CSU, children versus adults with CSU, and patients with mild-to-moderate versus severe CSU. This retrospective cohort study included patients of all ages diagnosed with urticaria between 2005 and 2020 and blood counts within 30 days of diagnosis. Patients with comorbidities influencing blood cells (infection, surgery, malignancy) were excluded. Neutrophil-to-lymphocyte and platelet-to-lymphocyte were evaluated in patients with ASU vs CSU and mild-to-moderate CSU vs severe CSU (defined by the use of systemic medications or hospitalizations). A total of 13,541 urticaria patients were included in the study. CSU patients (n = 5,021) had higher neutrophil-to-lymphocyte and platelet-to-lymphocyte, as well as serum IgE levels compared with ASU patients (n = 8,520). Adults had higher neutrophil-to-lymphocyte and platelet-to-lymphocyte than children. Severely affected patients (n = 53) had higher neutrophil-to-lymphocyte and platelet-to-lymphocyte compared with mild-to-moderately affected patients (n = 4,968). Patients with higher neutrophil-to-lymphocyte and platelet-to-lymphocyte had higher odds of having CSU rather than ASU and severe urticaria rather mild-to-moderate. In conclusion, neutrophil-to-lymphocyte and platelet-to-lymphocyte are simple and available markers that can be used to predict and assess severe and chronic urticaria.

Association of hematological ratios with psoriasis: a nationwide retrospective cohort study.

BACKGROUND: Psoriasis is a common skin disorder linked to systemic inflammation and immune dysregulation. It is believed to involve activated T cells and neutrophils. Recent research has highlighted the potential role of hematological ratios, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR), eosinophil-to-neutrophil ratio (ENR), and eosinophil-to-monocyte ratio (EMR), as markers for inflammatory skin diseases, including psoriasis. OBJECTIVES: We aimed to investigate hematological ratios between children and adults, patients and controls, and patients with moderate-to-severe and mild psoriasis. MATERIALS AND METHODS: This national retrospective cohort study included over 16,000 psoriasis patients in Israel. Patients with comorbidities influencing blood counts were excluded. Ratios were calculated from blood counts taken within 30 days of diagnosis. Multivariable logistic regression, including age, gender, ethnicity, smoking status, and socioeconomic status, was performed. RESULTS: Findings revealed age-specific variations in blood counts, hematological ratios, and differences between mild and moderate-severe patients and patients versus controls. Moderate-severe psoriasis patients had elevated neutrophil and eosinophil counts (4.57 vs. 4.25, P < 0.001, and 0.24 vs. 0.22, P = 0.047, respectively), as well as increased NLR (2.46 vs. 2.29, P < 0.001). Multivariable logistic regression analysis confirmed the significance of neutrophil and platelet counts as well as NLR and PLR in predicting psoriasis severity. LIMITATIONS: This was a retrospective study without subjective data on disease severity. CONCLUSION: This study highlights hematologic ratios' diagnostic and prognostic potential in psoriasis.

Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study.

BACKGROUND: The prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF. METHODS: This retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment. RESULTS: Fifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05). CONCLUSIONS: For the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

Foreign body aspiration score (FOBAS)-a prospectively validated algorithm for the management and prediction of foreign body aspiration in children.

Foreign body aspiration (FBA) is a common cause of pediatric morbidity, but a standardized protocol to guide decision-making about bronchoscopy is lacking. We aimed to validate a new Foreign body aspiration score (FOBAS) for the pediatric emergency department (ED). Patients aged 0-18 years referred to the ED for suspected FBA were prospectively enrolled. FOBAS was calculated according to clinical features of a choking episode, sudden cough, exposure to nuts, absence of fever and rhinitis, stridor, and unilateral auscultatory and radiological findings. FBA risk was evaluated based on the total score (low, 1-3; moderate, 4-6; high, 7-10). Low-risk children were discharged from the ED and followed clinically. Moderate-risk children were hospitalized and evaluated by a pediatric pulmonologist, and high-risk children were referred directly for therapeutic bronchoscopy. Among the 100 enrolled children (59% males; median age 20 [interquartile range 11-39] months), a foreign body was diagnosed in 1/49 (2%), 14/41 (34.1%), and 9/10 (90%) with low, moderate, and high FOBAS, respectively (P < .001). Logistic regression indicated a higher risk for FBA with higher scores. The odds ratio for each additional point was 2.75 (95% confidence interval 1.78-4.24), and FOBAS showed a high predictive value for FBA (area under the curve 0.89). FOBAS implementation significantly reduced the rate of negative bronchoscopies, from 67.4% annually during 2016-2019 to 50% in 2020 (P = .042). CONCLUSION: FOBAS reliably predicts FBA in cases of suspected FBA and improves management and in-hospital decision-making. WHAT IS KNOWN: • Foreign body aspiration is a major cause of pediatric morbidity and mortality. • Currently, there is no unified protocol for children referred to the emergency department for suspected FBA, therefore, a well-defined algorithm is needed to improve the decision-making process. WHAT IS NEW: • The pediatric Foreign body aspiration score (FOBAS) is a new, prospectively validated clinical score that shows high sensitivity and specificity for the presence of FBA in children. • FOBAS reduces unnecessary admissions and invasive procedures and leads to better clinical outcomes.

The new face of cystic fibrosis in the era of population genetic carrier screening.

BACKGROUND: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features. METHODS: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected. RESULTS: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p=  0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04). CONCLUSIONS: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF.

Evaluation of Foreign body aspiration score (FOBAS) in children- A retrospective cohort study.

Foreign Body Aspiration (FBA) is a common medical emergency among young children, but the evaluation and management of a suspected FBA case can vary across physicians and centers. We aimed to identify which clinical, laboratory, and radiological findings can predict FBA in children and to evaluate a clinical score to improve FBA prediction. This is a retrospective cohort study of patients aged 0-18 years admitted to Soroka University Medical Center between 2010 and 2020 with suspected FBA. All patients underwent flexible bronchoscopy and were divided into positive and negative FBA groups. A newly developed foreign body aspiration score (FOBAS), based on medical history, physical examination, and chest X-ray findings, was evaluated for its predictability. The study included 412 children (median age 21 months, 56.8% females), of whom 154 (37.4%) had FBA and 258 (62.6%) did not. Multivariate regression analysis showed exposure to nuts/seeds, unilateral wheezing or decreased breath sounds, stridor, and suggestive findings on chest X-ray were significant risk factors for FBA (OR [95%CI] -1.994[1.290-3.082], 1.487[1.206-1.832], 1.883 [1.011-3.509] and 2.386[1.917-2.970], respectively). However, a choking episode, acute cough, and absence of fever and rhinorrhea did not predict FBA. FOBAS showed an increased risk of FBA for each additional point of the score, with an odds ratio of 1.572 (95% CI-1.389-1.799).  Conclusion: FOBAS is a good predictor for the presence of FBA in children. Once prospectively validated, FOBAS could aid in decision-making at the emergency department, enabling more standardized care, reducing unnecessary procedures, and leading to better clinical outcomes. What is Known: • The evaluation and management of a child with suspected foreign body aspiration (FBA) vary across physicians and centers, without a consensus regarding the indications and criteria for performing bronchoscopy. • Flexible bronchoscopy is the standard procedure for the diagnosis and sometimes treatment of FBA in children, but it may hold potential complications. What is New: • We propose a newly developed foreign body aspiration score (FOBAS), based on medical history, physical examination, and chest X-ray findings, for the prediction of FBA in children at the emergency department. • The FOBAS is a good predictor of FBA in children. The score enables more standardized care and may reduce unnecessary procedures.

Comparison of chest X-ray interpretation by pediatric pulmonologists, pediatric radiologists, and pediatric residents in children with suspected foreign body aspiration-a retrospective cohort study.

Chest X-ray (CXR) is an important tool in the assessment of children with suspected foreign body aspiration (FBA), although it can falsely be interpreted as normal in one-third of the cases. The aim of this study is to evaluate the positive predictive value of CXR in children hospitalized with suspected FBA, when interpreted by three disciplines: pediatric pulmonology, pediatric radiology, and pediatric residents. This is a retrospective study that included children aged 0-18 years, admitted with suspected FBA, between 2009 and 2020 in one tertiary center. All patients underwent CXR and a flexible/rigid bronchoscopy for the definitive diagnosis of FBA, up to 1 week apart. Two physicians from each discipline interpreted the CXR, independently. Intra-raters' and inter-raters' agreements were assessed. Sensitivity, specificity, and area under the curve (AUC) were calculated for each discipline. Four hundred seventy-three children were included in the study, 175 (37%) with FBA and 298 (63%) without FBA on flexible/rigid bronchoscopy. The most common radiological findings, as interpreted by a pediatric pulmonologist, were unilateral hyperinflation (47%), radiopaque FB (37.6%), lobar atelectasis (10.3%), unilateral hyperinflation with atelectasis (3.4%), and lobar consolidation (1.7%). Intra-raters' agreement ranged from 0.744 (p < 0.001) among pediatric pulmonologists to 0.326 (p < 0.001) among pediatric radiologists. AUC for predicting FBA based on a CXR was 0.81, 0.77, and 0.7 when interpreted by pediatric pulmonologists, pediatric residents, and radiologists, respectively (p < 0.001). CONCLUSIONS: CXR has a high positive predictive value and independently predicts FBA in children; however, normal CXR should not rule out FBA. Predictability is variable among different disciplines. WHAT IS KNOWN: • Chest X-ray is an important tool in the assessment of children with suspected foreign body aspiration (FBA). • Chest X-ray can be interpreted as normal in one-third of the cases. WHAT IS NEW: • Chest X-ray independently predicts FBA in children, with a high positive predictive value. • The ability of chest x-ray to predict FBA in children differs between pediatric residents, pediatric radiologists, and pediatric pulmonologists.

Flexible bronchoscopy in pediatric patients with Down syndrome: A case-control study of the indications, findings, and complications.

BACKGROUND: Children with Down syndrome (DS) often undergo flexible bronchoscopies (FB) due to common respiratory symptoms. OBJECTIVE: To examine the indications, findings, and complications of FB in pediatric DS patients. METHODS: A retrospective case-control study on FB performed in DS pediatric patients between 2004 and 2021 in a tertiary center. DS patients were matched to controls (1:3) based on age, gender, and ethnicity. Data collected included demographics, comorbidities, indications, findings, and complications. RESULTS: Fifty DS patients (median age 1.36 years, 56% males) and 150 controls (median age 1.27 years, 56% males), were included. Evaluation for obstructive sleep apnea and oxygen dependence were more common indications among DS (38% vs. 8%, 22% vs. 4%, p < 0.01, respectively). Normal bronchoscopy was less frequent in DS compared with controls (8% vs. 28%, p = 0.01). Soft palate incompetence and tracheal bronchus were more frequent in DS (12% vs. 3.3%, p = 0.024, 8% vs. 0.7%, p = 0.02, respectively). Complications were more frequent in DS (22% vs. 9.3%, incidence rate ratio [IRR] 2.36, p = 0.028). In DS, cardiac anomalies (IRR 3.96, p < 0.01), pulmonary hypertension (IRR 3.76, p = 0.006), and pediatric intensive care unit (PICU) hospitalization before the procedure (IRR 4.2, p < 0.001) were associated with higher complication rates. In a multivariate regression model, history of cardiac disease and PICU hospitalization before the procedure, but not DS, were independent risk factors for complications with an IRR of 4 and 3.1, respectively (p = 0.006, p = 0.05). CONCLUSION: DS pediatric patients undergoing FB are a unique population with specific indications and findings. DS pediatric patients with cardiac anomalies and pulmonary hypertension are at the highest risk for complications.

Foreign body aspiration in Israeli children during the COVID-19 pandemic.

BACKGROUND: Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there has been a decline in pediatric emergency department visits. Our aim was to assess the pattern of pediatric foreign body aspiration (FBA) during the first year of the COVID-19 pandemic, in comparison to the prior years. METHODS: In this retrospective multicenter study, we compared the number of children who presented with FBA during the COVID-19 year (March 1, 2020 to February 28, 2021) to the annual average of the years 2016-2019. We also compared the lockdown periods to the postlockdown periods, and the percentage of missed FBA, proven FBA, and flexible bronchoscopy as the removal procedure. RESULTS: A total of 345 children with FBA from six centers were included, 276 in the pre-COVID-19 years (average 69 per year) and 69 in the COVID-19 year. There was no difference in the prevalence of FBA between the COVID-19 year and any of the prior 4 years. Examining the lockdown effect, the monthly incidence of FBA dropped from a pre-COVID-19 average of 5.75 cases to 5.1 cases during lockdown periods and increased to 6.3 cases in postlockdown periods. No difference in the percentage of missed FB or proven FB was observed. There was a significant rise in the usage of flexible bronchoscopy as the removal procedure (average of 15.4% vs. 30.4%, p = 0.001). CONCLUSION: There were fewer cases of pediatric FBA during lockdown periods, compared to post-lockdown periods, presumably related to better parental supervision, with no difference in the prevalence of FBA during the COVID-19 year.

Non-tuberculous mycobacteria infection treated with intermittently inhaled high-dose nitric oxide.

Mycobacterium abscessus is an emerging multidrug-resistant non-tuberculous mycobacterium (NTM) with high prevalence in patients with cystic fibrosis. However, studies on antimicrobial susceptibilities and effective treatments against M. abscessus are still limited. Nitric oxide (NO) is important in innate immune response to various infections, including mycobacterial infections. In this case study, we describe a compassionate treatment of inhaled NO (iNO) at 150-250 ppm for 4 weeks. The dosing strategy proposed for this treatment was selected to minimise the potential of adverse events, while maximising the antibacterial effectiveness of NO, and was found to be safe, well tolerated and resulted in positive clinical findings including improvement in patient well-being, CT scan values, quality of life and bacterial load. Taken together, these observations may indicate that iNO could play a crucial role and potentially serve as a reliable option in the treatment of patients with chronic refractory NTM lung infection.

From rigid to flexible bronchoscopy: a tertiary center experience in removal of inhaled foreign bodies in children.

Rigid bronchoscopy is the procedure of choice for removal of inhaled foreign bodies. In this retrospective study, we assessed the safety and efficacy of flexible bronchoscopy use in the removal of inhaled foreign bodies in children. One hundred eighty-two patients (median age of 24 months, 58% males) underwent an interventional bronchoscopy for the removal of inhaled foreign body between 2009 and 2019, 40 (22%) by flexible, and 142 (78%) by rigid bronchoscopy. 88.73% of rigid and 95% of flexible bronchoscopies were successful in foreign bodies removal (p value = 0.24). Complication rate was higher among rigid bronchoscopy (9.2% vs. 0%, p = 0.047). From 2017 onwards, following the implementation of flexible bronchoscopy for foreign bodies removal, 64 procedures were performed, 33 (51.6%) flexible, and 31 (48.4%) rigid. Procedure length was shorter via flexible bronchoscopy (42 vs 58 min, p = 0.016). Length of hospital stay was similar.Conclusion: In our hands, flexible bronchoscopy is an efficient and safe method for removal of inhaled foreign bodies in children, with shorter procedure time and minimal complication rate. Flexible bronchoscopy could be considered as the procedure of choice for removal of inhaled foreign bodies in children, by an experienced multidisciplinary team. What is Known: • Rigid bronchoscopy is currently the gold standard for removal of inhaled foreign bodies in children. • Rigid bronchoscopy has a relatively high complication rate compared to flexible bronchoscopy. What is New: • Flexible bronchoscopy is a short, safe, and efficient procedure to remove inhaled foreign bodies in children, compared to rigid bronchoscopy. • Flexible bronchoscopy could be proposed as the procedure of choice for removal of inhaled foreign bodies in children, if an experienced operator is available.

Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression.

BACKGROUND: With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. AIM: To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. METHODS: A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. RESULTS: Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. CONCLUSION: Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

A 9-Year-Old Boy With Recurrent Chest Pain and Nonresolving Pneumonia.

CASE PRESENTATION: A previously healthy, 9-year-old boy presented with five recurrent episodes of left-sided chest pain with low-grade fever over the last 18 months. The pain usually lasted for few hours, was severe and consistent, and resolved spontaneously. It worsened during inspiration, physical activity, and swallowing. He did not experience any cough, dyspnea, chills, cold sweats, or weight loss. His medical and family history was unremarkable.

Altered slow-wave sleep activity in children with rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation syndrome.

STUDY OBJECTIVES: Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare condition. Little is known about sleep/wake and slow-wave activity in this condition, although the central hypothalamic dysfunction associated with autonomic dysregulation would make the occurrence of SWA deregulation most likely. METHODS: Two children with clinical presentation of ROHHAD syndrome were evaluated, diagnosed, and treated. Their polysomnographic studies were compared with 4 matched children with obstructive sleep apnea and 6 controls. RESULTS: Children that were clinically diagnosed with ROHHAD exhibited significantly weaker slow-wave activity power and shallower slow-wave activity slopes during the first 2 sleep cycles compared with children with obstructive sleep apnea or controls. CONCLUSIONS: This study shows that children with ROHHAD have suppressed slow-wave activity, possibly because of hypothalamic dysregulation that may contribute to their rapid-onset obesity and excessive daytime sleepiness.

A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency.

BACKGROUND: Multiple sulfatase deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents. METHODS: We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model. RESULTS: We report on two MSD patients-the first neonatal type reported in Israel-both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1-encoded variant of formylglycine-generating enzyme is highly instable and lacks catalytic function. CONCLUSION: The obtained results confirm genotype-phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD.