Cystic fibrosis (CF) bone disease (CFBD) has attracted considerable recent interest from researchers, although several aspects of CFBD pathophysiology remain poorly understood. The objective of this ...research was to investigate CFBD in children with CF and its relation to clinical and bone metabolism markers.
In a prospective observational study of 68 patients with CF and 63 healthy controls, we studied bone turnover biomarkers and bone mineral density (BMD). The biomarkers included osteocalcin, total-alkaline phosphatase, bone-alkaline phosphatase, N-terminal propeptide of type-1-procollagen, osteoprotegerin (OPG), interleukine-6, tumor necrosis factor alpha (TNF-α), type-1-collagen cross-linked C-telopeptide (CTX), parathormone (PTH), 25-vitamin D, 1,25-vitamin D, calcium and phosphorus. BMD was examined in lumbar spine, comparing two healthy Spanish populations. Two regression analyses were applied to any significant associations to evaluate predictors of BMD and of CF, expressed as odds ratios (OR) with 95% confidence intervals.
After adjusting for age, sex, and height Z-score, gains in BMD LS in children and adolescents (6–16 years) with CF were not less than in healthy reference population. Patients with CF showed significant associations with different bone turnover biomarkers. Age, gender, body mass index, PTH, CTX and OPG were significant predictors of BMD (R2 = 0.866, p < 0,001). Moreover, we found that PTH (OR = 1.070; 95% CI 1.019–1.123), and TNFα (OR = 2.173; 95% CI 1.514–3.118) were significantly linked to CF, and calcium (OR = 0.115; 95% CI 0.025–0.524), 1,25-vitamin D (OR = 0.979; 95% CI 0.962 0.996) and OPG (OR = 0.189; 95% CI 0.073–0.489) were significant reduced.
A normal bone mineral density along with altered remodeling was found in CF patients with a normal nutritional status and without acute lung disease.
•Normal vertebral density observed in clinically stable children and adolescents with CF•An imbalance between bone formation and resorption processes is seen in subjects with CF.•Clinically stable patients with CF have hyper-resorptive bone physiology.
Cystic fibrosis (CF) is the most common autosomal recessive disorder in the Caucasian population, with an incidence of 1:5000 live births. In 2011, the screening of CF was implemented in the ...Andalusian Public Health newborn screening program by using immunoreactive trypsinogen and chloride sweat test (IRT/IRT/sweat test) determinations. Since then, 79 children have been diagnosed with CF in our health area (Western Andalusia). The aim of this study was to evaluate the efficiency of this screening method and to examinate the characteristics of those CF infants who had a negative screening but who were later diagnosed.
In the 2011–2021 period 462,049 newborns were screened for CF using a two‐step IRT determination and chloride sweat test. Sixty‐three infants were diagnosed with CF in our health area thanks to the screening, and 15 CF children had a negative screening result and were finally diagnosed by molecular sequencing of the CFTR gene. The most frequent symptoms that led to the diagnosis of those false negative (FN) patients were hyponatremic dehydration (mean age 9.75 ± 1.5 months) and recurrent wheezing (mean age 24 ± 14.5 months). The molecular analysis of the CFTR gene on those FN showed a diversity of genotypes, identifying more than 10 different mutations.
Conclusion
The rate of FN patients obtained in this study is inadmissibly high, and the protocol used in this region has not been updated despite the advances in genetic testing in the past 10 years. An improvement on CF newborn screening should be implemented, adding molecular analysis of the CFTR gene.
INTRODUCTIONCystic fibrosis neonatal screening (CFNS), based on double determination of immunoreactive trypsinogen (IRT IRT1/IRT2), has been available in Andalusia since May 2011. If screening is ...positive, a sweat test is performed, and if that is positive or inconclusive, genetic testing is requested. OBJECTIVETo analyze CFNS, based on results from the first 4.5 years of the program. MATERIALS AND METHODSProspective descriptive study of neonates undergoing CFNS. IRT levels, sweat chloride, and mutations were recorded. Statistical analysis was performed using SPSS 12.0. RESULTSBetween May 2011 and December 2016, 474,953 neonates underwent CFNS. Of these, 1,087 (0.23%) had elevated IRT2. Since CFNS was introduced, 73 cases of cystic fibrosis were diagnosed; 60 were diagnosed by positive CFNS, and 13 were diagnosed by other means. In one case, the patient developed a typical clinical picture of cystic fibrosis, but had not undergone CFNS at the decision of the parents; the remaining 12 had a negative CFNS (false negatives). Of these, one patient was diagnosed before symptoms developed, as his twin brother had a positive CFNS result; another had chloride at the upper limit of normal, and was subsequently diagnosed with genetic testing before symptoms appeared; and 10 patients developed clinical signs and symptoms. Excluding patients with meconium ileus, sensitivity and specificity of the CFNS program were 85.71% and 99.78%, respectively. The incidence of the disease in Andalusia is 1/6,506 live births. CONCLUSIONThese results are a basis for reflection on possible areas for improvement of the CFNS algorithm, and thought may be given to the introduction of genetic studies to increase sensitivity and reduce false positives.
Newborn Screening Programs (NSP) in Spain were born in the
city of Granada in 1968. Till the 1980s, they were developed around
the so-called “National Plan for Preventing Subnormality”, covering
up ...to 30% of the Spanish newborns. From 1982, when the health
system management was transferred to the different autonomous regions,
the NSP began to expand, and the bases to transform them into
an organized and multidisciplinary activity, integrated and coordinated
from the National Health System were settled. Despite this expansion,
it is not until the 1990s when their coverage reaches almost
100% newborns in Spain.
NSP grew up asymmetrically across the different autonomous
regions. In 2005 and 2006 the scientific societies SEQC (Spanish
Society of Clinical Chemistry) and AECNE (Spanish Society of
Newborn Screening), coordinated by the Health Promotion Area of
the General Directorate of Public Health, gathered together the necessary
information to elaborate a report on the NSP in Spain addressed
to the Interterritorial Council of the National Health System. In July
2013, that Council approved the seven diseases that should be part of
each region newborn screening panel, being the first step towards the
NSP harmonization in Spain. Currently, the NSP include between 8
and 29 diseases in their panels, thus more still more efforts are needed
in order to achieve a higher uniformity.
Los Programas de Cribado Neonatal (PCN) nacen en España en
Granada en el año 1968. Posteriormente, y hasta los años 80, se fueron
desarrollando en torno al llamado “Plan Nacional de Prevención
de la Subnormalidad” con una cobertura cercana al 30% de los recién
nacidos españoles. A partir de 1982, con el inicio de la gestión de
la sanidad a las comunidades autónomas (CCAA), los PCN se expandieron
y se comenzaron a sentar las bases para que éstos se convirtieran
en una actividad organizada y multidisciplinar, integrados y
coordinados desde el Sistema de Salud. A pesar de dicha expansión
no es hasta el inicio de la década de los 90 cuando se consigue una
cobertura próxima al 100% de los RN en España.
Los PCN fueron creciendo de forma muy asimétrica en las diferentes
CCAA y en los años 2005 y 2006 las Sociedades Científicas
SEQC (Sociedad Española de Química Clínica) y AECNE
(Asociación Española de Cribado Neonatal), con la coordinación
del Área de Promoción de la Salud de la Dirección General de Salud
Pública, recopilaron la información y elaboraron un informe, sobre
los PCN en España para el Consejo Interterritorial del sistema
Nacional de Salud (CISNS). En julio de 2013 este Consejo aprobó
las siete enfermedades que debían formar parte del panel de detección
de los PCN territoriales, primer paso hacia la armonización de
estos programas. Actualmente, los PCN incluyen entre 8 y 29 enfermedades
por lo que es necesario seguir trabajando para conseguir una
mayor uniformidad.
The aim of this study was to present the results obtained in the Newborn Screening Program (NSP) for sickle cell disease (SCD) in western Andalusia and the autonomous city of Ceuta in the first 3 ...years of implementation, and to describe the discrepancies found in the diagnosis of hemoglobinopathies between the screening method and the confirmatory tests.
A descriptive and retrospective study was carried out, and the findings obtained in the newborns included in the NSP between November 2018 and December 2021 were analyzed.
A total of 111,205 samples were screened by high-performance liquid chromatography (HPLC). The birth prevalence of SCD, sickle cell trait, hemoglobin C carriers, and the compound heterozygosity Hb C/β-thalassemia was 1/12,356, 1/467, 1/1,278, and 1/55,602 newborns, respectively. Although there was a correlation between the first-line HPLC screening technique (VARIANTnbs HPLC analyzer, Bio-Rad) and the confirmatory tests in most cases, major discrepancies were found in detecting carriers of G-Philadelphia, D, E, and O-Arab hemoglobin variants, with the former having an incidence of 1/10,110 and the others 1/22,241. The carrier status of Hb G-Philadelphia produced an FAD pattern on the screening method that could be mistaken as Hb D, while Hb O-Arab was identified as an FA5 pattern. Hb D was initially recognized as Hb D in two cases.
An NSP requires at least two different combined methods in order to identify the hemoglobin variant with sufficient certainty. Furthermore, even though software solutions for HPLC suggest a pattern, it must be confirmed with another technique to obtain a correct interpretation of the chromatograms.
· The NSPs are an essential activity in preventive medicine.. · At least two different combined methods are required to correctly identify hemoglobin variants.. · Different variants can produce a similar or identical pattern by a single method..
Background
Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X‐linked agammaglobulinemia (XLA) improves outcome of affected children. ...T‐cell‐receptor‐excision circles (TRECs) and kappa‐deleting‐recombination‐excision circles (KRECs) determination from dried blood spots (DBS) identify neonates with severe T‐ and/or B‐lymphopenia. No prospective data exist of the impact of gestational age (GA) and birth weight (BW) on TRECs and KRECs values.
Methods
TRECs and KRECs determination using triplex RT‐PCR (TRECS‐KRECS‐β‐actin‐Assay) from prospectively collected DBS between 02/2014 and 02/2015 in three hospitals in Seville, Spain. Cut‐off levels were TRECs < 6/punch, KRECs < 4/punch and ‐β‐actin>700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (NBS quality assurance program, CDC) were included.
Results
A total of 5160 DBS were tested. Re‐punch was needed in 77 samples (1.5%) due to insufficient β‐actin (<700 copies/punch). Pre‐term neonates (GA<37 weeks) and neonates with a BW<2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeat positive results five neonates were re‐called (<0.1%): Fatal chromosomopathy (n = 1; TRECs 1/KRECs 4); extreme pre‐maturity (n = 2; TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); neonates born to mothers receiving azathioprine during pregnancy (n = 2; TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All internal and external controls were correctly identified.
Conclusions
TRECS‐KRECS–β‐actin‐Assay correctly identifies T‐ and B‐cell lymphopenias. Pre‐maturity and low BW is associated with lower TREC and KREC levels. Extreme pre‐maturity and maternal immune suppressive therapy may be a cause for false positive results of TRECs and KRECs values, respectively. To reduce the rate of insufficient samples, DBS extraction and storage need to be improved.
The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) population of Andalusia, assessing the correlation with the phenotype and the usefulness in predicting the ...response to treatment with tetrahydrobiopterin. We conducted a retrospective observational study between January 1980 and January 2010 in 147 Andalusian PKU patients assessing phenotype, genotype and response to a 24-h BH4 loading test. Our cohort of patients exhibited 65 different mutations, 69.2% corresponding to the missense type, in a total of 123 different genotypes. IVS10nt-11g>a was the most common mutation (10.9%). Four novel missense mutations were identified: p.L258P; p.E66K, p.R155C and p.P122S. Although generally there is a good genotype-phenotype correlation, for eight of the repeated genotypes a slightly different phenotype was observed. In 96 PKU subjects BH4 challenge was carried out. Patients with previously reported unresponsive mutations on both alleles showed a negative response, while 95.5% (28/29) of the responsive patients carry at least one missense mutation previously associated to the BH4. Our data reveal a great genetic heterogeneity in the Andalusian population. Genotype is quite a good predictor of the phenotype and of the responsiveness to tetrahydrobiopterin, which is relevant for patient management and follow-up.
Parapneumonic effusions with pH < 7.20 or glucose < 0.40 g/l or lactate dehydrogenase (LDH) > 1000 U/l have indication of treatment with endothoracic drainage tube (EDT). The aim of the present study ...was to determine the accuracy of partial pressure of carbon dioxide (pCO2) measurement in pleural fluid for the subsequent treatment indication with EDT in parapneumonic effusions, by analyzing the area under curve ROC (AUC) and determining the optimal cut off value.
207 pleural fluids were studied. Glucose, LDH, pCO2, and pH were measured, and data concerning the etiology of pleural effusion and whether EDT treatment was needed were collected after patients were discharged from hospital.
Forty-six out of 207 pleural fluids studied were parapneumonic effusions. Thirty-two were treated with EDT. AUC values were 0.888 (p < 0.0001), 0.890 (p < 0.0001), 0.816 (p < 0.0001), and 0.801 (p < 0.0001) for pCO2, pH, glucose, and LDH, respectively. No significant differences were found among them. Optimal cut off value for pCO2 was 48.6 mmHg, exhibiting 90.6% sensitivity and 78.6% specificity. All parapneumonic effusions showing pCO2 > 60.9 mmHg were treated with EDT. Remarkably, 3 out of 46 parapneumonic effusions (6.5%) that had been improperly treated following pH, glucose or LDH values, were correctly treated following pCO2.
pCO2 determination in pleural fluid appears to be the best way to decide the indication of EDT in parapneumonic effusions.
Background: The main justification of this study
was to describe our experience in neonatal screening and
to define the prevalence of the diseases included in the
neonatal screening program in ...Andalusia, among which
are congenital hypothyroidism, expanded screening (aminoacidopathies,
mitochondrial beta-oxidation defects and
organic acidurias), cystic fibrosis, and screening for sickle
cell anemia.
Methods: The study was carried out in the
Metabolopathies Unit of the Virgen del Rocío Hospital
in Seville with samples of newborns from Western
Andalusia (Cádiz, Córdoba, Huelva and Seville) and autonomous
city of Ceuta. A total of 435,141 newborns were
studied (from the period from April 1st 2009 to December
31st 2019) to rule out congenital hypothyroidism and expanded
screening; 378,306 for cystic fibrosis from May
1st 2011 to the same date described above. Finally, sickle
cell anemia screening was included, which comprised a
total of 55,576 newborns from November 26th, 2018 to
the same period as the previous ones. Statistical analysis
was performed using IBM SPSS software (version 22,
SPSS INC., USA).
Results: The study revealed a prevalence of 1:1565
newborns for congenital hypothyroidism, 1:1532 newborns
for extended screening, 1:6.878 newborns for cystic
fibrosis, and a 1:11.115 newborns for sickle cell disease.
Conclusions: The neonatal screening program
allows a large number of newborns to benefit from the
early detection of certain serious congenital diseases. This
aim improves the morbidity and mortality of those who
suffer from them.
Fundamentos: La principal justificación del trabajo
fue describir nuestra experiencia en cribado neonatal y
definir la prevalencia de cada una de las enfermedades incluidas
en el programa de cribado neonatal de Andalucía,
entre las que se encuentran el hipotiroidismo congénito,
cribado ampliado expandido (aminoacidopatías, defectos
de la beta-oxidación mitocondrial y acidurias orgánicas),
fibrosis quística y enfermedad de células falciformes.
Métodos: El estudio se realizó en la Unidad del
Laboratorio de Metabolopatías del Hospital Universitario
Virgen del Rocío de Sevilla con muestras de recién nacidos
de Andalucía Occidental (Cádiz, Córdoba, Huelva y
Sevilla) y la ciudad autónoma de Ceuta. Para descartar
hipotiroidismo congénito y cribado ampliado expandido
se estudiaron un total de 435.141 recién nacidos, con fecha
de inicio el 1 de abril de 2009. El cribado de fibrosis
quística comenzó el 1 de mayo de 2011, siendo estudiados
un total de 378.306 recién nacidos. Por último, el 26 de
noviembre de 2018 se incorporó el cribado de anemia de
células falciformes, que comprendió un total de 55.576 recién
nacidos. La fecha fin de estudio fue el 31 de diciembre
de 2019 para todas las patologías descritas anteriormente.
El análisis estadístico se realizó usando el software
IBM SPSS (versión 22, SPSS INC., EEUU).
Resultados: El estudio reveló una prevalencia de
1:1.565 recién nacidos para hipotiroidismo congénito,
1:1.532 para cribado ampliado expandido, 1:6.878 para fibrosis
quística y 1:11.115 recién nacidos para enfermedad
de células falciformes.
Conclusiones: El programa de cribado neonatal permite
que se beneficien gran número de recién nacidos en
la detección precoz de determinadas enfermedades congénitas
graves y, con ello, mejora la morbimortalidad de
aquellos que las padecen.
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