Russian Journal of Woman and Child Health
ISSN 2618-8430 (Print), 2686-7184 (Online)

Clinical prognostic relevance of elastin and laminin in children with undifferentiated connective tissue disease

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DOI: 10.32364/2618-8430-2021-4-4-351-354

N.S. Cherkasov1, T.N. Doronina1, A.V. Prakhov2, Yu.A. Lutsenko3

1Astrakhan State Medical University, Astrakhan, Russian Federation

2Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation

3Children’s City Polyclinics No. 150, Moscow, Russian Federation;

Aim: to determine clinical prognostic relevance of elastin and laminin in children with undifferentiated connective tissue disease (UCTD).

Patients and Methods: 47 children with UCTD aged 3–6 were enrolled. The diagnosis was verified by ruling out genetic disorders via analyzing family tree, genetic consultation, etc. Phenotypic and visceral signs were interpreted based on "Congenital and multifactorial connective tissue diseases in children" guidelines (2016). The results of cardiovascular and urinary tract ultrasound were analyzed. Serum levels of elastin and laminin were measured by the sandwich ELISA using high-sensitive kits. All tests were performed at admission and after two years.

Results: prognostic relevance (prognostic coefficient) of individual phenotypic and visceral signs and lab tests and prognostic threshold value (the sum of prognostic coefficients indicating high, moderate, or low risk of UCTD progression) were determined. It was demonstrat ed that measuring elastin and laminin levels improves the efficacy of UCTD progression risk assessment. This phenomenon was supported by the values of their prognostic coefficient, which were comparable to the values of significant phenotypic and visceral signs. Furthermore, the accuracy of prognosis based on the use of a set of prognostic indicators (phenotypic, visceral, and biochemical) was supported by the escalation of dysplasia signs. After two years, disease progression was reported in 36 out of 38 children with a moderate and high risk of UCTD progression as identified by the initial evaluation.

Conclusion: given the relevance of elastin and laminin in dysplasia pathogenesis, these parameters are considered informative to assess the risk of dysplasia progression in children aged 3–6. It is reasonable to use elastin and laminin levels as additional criteria to evaluate the risk of UCTD progression.

Keywords: undifferentiated connective tissue disease, prediction, c hildren, phenotypic signs, laminin, elastin, risk of progression, cardiovascular system, urinary system.

For citation: Cherkasov N.S., Doronina T.N., Prakhov A.V., Lutsenko Yu.A. Clinical prognostic relevance of elastin and laminin in children with undifferentiated connective tissue disease. Russian Journal of Woman and Child Health. 2021;4(4):351–354 (in Russ.). DOI: 10.32364/2618-8430-2021-4-4-351-354.

Background

Impaired synthesis and (or) degradation of connective tissue extracellular matrix components are known to have an essential role in the development of undifferentiated connective tissue disease (UCTD). Imbalance in this complex system, either abnormal tissue proliferation or collagen degradation, defects of structural genes, or abnormalities of gene modifications, results in dysplasia [1–3]. Elastin and laminin are essential proteins of the extracellular matrix. These proteins regulate interactions between elastic core and microfibrils. In addition, laminin interacts with all structural components of basal membranes. Therefore, complex measurements of the levels of these proteins improve the informative value of diagnostic tests for dysplasia, thereby justifying a need for simultaneous study of these proteins to evaluate dysplastic processes [4–8].

Given a potential progression of dysplasia in children, it is helpful to predict its risk early in childhood [1, 2, 4]. Published data describe prediction methods identifying phenotypic signs and their quantitative estimation.

In recent years, phenotypic and visceral signs of UCTD have been studied simultaneously. In addition, various abnormalities of heart valves and chords, pyelectasis, and caliectasis are unfavorable predictive criteria for dysplasia. Therefore, evidence-based methods of personalized prognosis of severe dysplasia risks are essential for prediction [1, 2, 9].

Current laboratory tests measuring cortisol, magnesium, secretory IgA, anti-collagen antibodies, and lactate dehydrogenase cannot be used as a basis for predicting the risk of UCTD progression [10]. Therefore, to improve the accuracy of predicting UCTD progression, it is helpful to measure the levels of other extracellular matrix proteins, i.e., laminin and elastin.

Given a poorly explored UCTD pathogenesis, challenging diagnosis, and progressive course, researches in this field are considered relevant.

Aim

To determine the clinical prognostic value of elastin and laminin in children with UCTD.

Patients and Methods

Forty-seven children with UCTD aged 3-6 were enrolled. The control group included 20 age-matched children without phenotypic or visceral signs of UCTD. The diagnosis was verified by ruling out genetic disorders via analyzing family trees, genetic counseling, etc. Phenotypic and visceral signs were interpreted according to the "Hereditary and Multifactorial Connective Tissue Disorders in Children" guidelines (2016) [1].

UCTD was diagnosed by the presence of six or more phenotypic signs plus one or more visceral signs. In addition, cardiovascular and urogenital ultrasound findings were analyzed.

Serum levels of elastin and laminin were measured by sandwich ELISA using highly sensitive kits for elastin (HBE-337 Hu No. 4 DF58C0861) and laminin (HBE082Hu No. 7B578DDCCD, Cloud-Clone Corp, USA). These measurements were performed twice, i.e., at admission and after two years.

Mathematical modeling based on calculating predictor coefficients (PCs) was used for prediction. PCs for any factor and its grading were calculated using the Bayes' rule information variant:

, where:

P(X/A) = prevalence of factor X in state A, P(X/B) = prevalence of factor X in alternative state B.

Their informative relevance translated into quantitative values of signs. First, predictive signs were determined using the E.V. Gubler technique [11] to construct a prediction table [12]. Next, the overall score was calculated for each sign (presence/absence) and compared with a threshold value. Finally, Pearson's correlation coefficient was applied to assess relationships between signs (Statistica 10).

Results 

The following phenotypic signs were seen in the study group: high-arched palate (n=9, 19.1%), moderate joint hypermobility (n=7, 14.9%), platythorax (n=5, 10.6%), flat feet grade 1-2 (n=5, 10.6%), kyphosis grade 1 (n=2, 4.2%), facial dysmorphia (n=2, 4.2%), cutis laxa (n=1, 2.1%), etc. Combinations of signs were detected in 27 children (57.4%).

Among visceral signs, mitral valve prolapse with regurgitation grade 1 (n=12, 25.5%), anomalous left ventricular chords (n=11, 23.4%), patent foramen ovale (n=9, 19.1%), dilated ascending aorta (n=5, 10.6%), pyelectasis grade 1-2 (n=8, 17.0%), and nephroptosis grade 1 (n=7, 14.9%) were identified. Combinations of signs were detected in 18 children (57.4%).

All children were divided into two groups based on laboratory test results. Group 1 included 27 children (57.4%) with the levels of elastin 5.2-9.2 ng/ml and laminin 23.4-42.0 pg/ml. Group 2 included 20 children (42.6%) with levels of elastin 9.3-13.7 ng/ml and laminin 42.1-47.3 pg/ml. Borderline values were obtained after statistical processing of protein levels [12]. Biochemical parameter values detected were significantly different from those in the control group (р<0.05, p1<0.01). Elastin levels less than 5.2 ng/ml and laminin levels less than 23.4 pg/ml were found occasionally and cannot be applied for prediction. We determined the prognostic value of individual phenotypic, instrumental, and laboratory factors (100). Twenty-eight most common factors were selected to be used for direct PC calculations. The signs were graded, PCs were calculated.

The most relevant signs were kyphosis (PC=0.5), platythorax (PC=0.25), moderate joint hypermobility (PC=0.75), patent foramen ovale (PC=0.7), anomalous left ventricular chords (PC=2.75), pyelectasis (PC=1.8), nephroptosis (PC=0.5), combination of visceral signs (PC=2.5), increased elastin (PC=2.75) and laminin (PC=3.5). Other signs were characterized by less prognostic value. Note that PC values of some phenotypic signs and instrumental tests were significantly lower than PC values of biochemical tests. This phenomenon accounts for laminin and elastin levels' importance in predicting UCTD progression.

We calculated prognostic thresholds derived from summing PCs. Given these thresholds, the risk of UCTD progression was graded as high (15-17), moderate (8-14), or low/no risk (4-7).

The threshold value was 15-17 in 24 children, 8-14 in 14 children, and 4-7 in 9 children during the initial examination.

The prediction results were confirmed during the dynamic examination of these children after two years. UCTD progression was detected in 36 children, and no progression was detected in 11 children who predominantly belonged to the low-risk group. These findings are supported by an increase in the number and severity of phenotypic and visceral signs in high- and moderate-risk groups. Furthermore, retrospective analysis of children with UCTD progression has demonstrated an increase in the number of phenotypic signs from 6 to 9 and visceral signs from 1 to 4 in one patient and their escalation. Therefore, the accuracy of prognosis based on a complex of prognostic factors (phenotypic, visceral, biochemical parameters) was confirmed dynamically. All of that illustrates high efficacy (79%) of prediction based on laminin and elastin levels.

Discussion 

Phenotypic signs and the severity of visceral signs have an essential role in predicting UCTD progression risk. However, their use allows for a highly reliable prognosis of the risk of dysplasia progression in children older than 7 years [1, 2, 4]. Meanwhile, the accuracy of this prognosis is lower in young children. We have demonstrated that measuring elastin and laminin levels to assess UCTD progression risk improves its accuracy. This risk is either high or low, thereby indicating a potential association with various types of the course of dysplasia processes in UCTD. The crucial prognostic relevance of these proteins is supported by PC values which are similar or higher compared to principal phenotypic and visceral signs.

Given the pathogenic importance of these proteins in dysplasia development, these parameters are considered informative for assessing UCTD progression risk in children aged 3-6 years. The high prognostic relevance of elastin and laminin is expected to be associated with the age of the study population. Measuring changes in their levels and PCs improves the quality of prognosis. Hence, the parameters studied are to be applied as additional criteria for predicting the risk of UCTD progression in children under 7 years.

Timely prediction of UCTD progression risk allows early prevention of severe UCTD. In addition, current preventive measures reduce the likelihood of severe UCTD variants.

Conclusions

Complex investigation of phenotypic and visceral signs and biochemical parameters revealed their prognostic relevance for UCTD in children aged 3-6. Among many factors, we identified the most informative parameters, i.e., kyphosis, platythorax, joint hypermobility, patent foramen ovale, anomalous left ventricular chords, pyelectasis, nephroptosis (PC=0.5), a combination of visceral signs, and increased elastin and laminin levels. Therefore, it is reasonable to use elastin and laminin levels as additional criteria to evaluate the risk of UCTD progression. In elastin levels of 9.3 ng/ml to 13.7 ng/ml and laminin levels of 42.1 pg/ml to 47.3 pg/ml, a high risk of UCTD progression can be predicted in children aged 3-6. In general, the complex use of phenotypic and visceral signs and biochemical parameters improves our ability to predict connective tissue dysplasia risk.


About the authors:

Nikolay S. Cherkasov — Dr. Sc. (Med.), Professor, professor of the Department of Hospital Pediatrics with the Course of Postgraduate Education, Astrakhan State Medical University; 121, Bakinskaya str., Astrakhan, 414000, Russian Federation; ORCID iD 0000-0001-9532-5446.

Tatyana N. Doronina — Dr. Sc. (Med.), Associate Professor, professor of the Department of Hospital Pediatrics with the Course of Postgraduate Education, Astrakhan State Medical University; 121, Bakinskaya str., Astrakhan, 414000, Russian Federation; ORCID iD 0000-0001-7353-3615.

Andrey V. Prakhov — Dr. Sc. (Med.), Professor, professor of the Department of Hospital Pediatrics, Privolzhsky Research Medical University; 10/1, Minin and Pozharsky sq., Nizhny Novgorod, 603950, Russian Federation; ORCID iD 0000-0002-7978-3831.

Yuliya A. Lutsenko — nephrologist, Children’s City Polyclinics No. 150; 1, Bratislavskaya str., Moscow, 109341, Russian Federation; ORCID iD 0000-0001-6336-7887.

Contact information: Nikolay S. Cherkasov, e-mail:
kafedra1@mail.ru.

Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.

There is no conflict of interests.

Received 27.09.2021.

Revised 20.10.2021.

Accepted 16.11.2021.



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