Screening for cystic fibrosis: identification of a dangerous monogenic pathology that is asymptomatic. Heel test in a newborn: why do the first screening for a child

Date: 11.04.2019

Home> Abstract

Organization of neonatal screening for cystic fibrosis, adrenogenital syndrome and galactosemia

Cystic fibrosis(cystic fibrosis; CF) is a frequent monogenic autosomal recessive disease characterized by damage to the exocrine glands and vital organs and systems and usually heavy course and forecast. The prevalence of CF varies in different European populations from 1: 600 to 1: 12000 (average 1: 5000) newborns. Adrenogenital syndrome(AGS, congenital adrenal hyperplasia) is a group of diseases with an autosomal recessive type of inheritance, the development of which is associated with impaired secretion of corticosteroids due to a congenital defect in enzymes responsible for the biosynthesis of these hormones. Screening of newborns is carried out for 21 hydroxylase deficiency, the frequency of which ranges from 90% to 95% of all variants of AHS. The frequency of ASH in Europe is almost the same and varies in the range from 1: 10,000 to 1: 14,000 live births. Galactosemia- a group of hereditary diseases caused by a deficiency of enzymes involved in the metabolism of galactose. Mass screening of newborns is aimed at identifying classic galactosemia (type I), which is the most severe pathology that requires urgent correction of the pathology. The frequency of galactosemia in Europe ranges from 1: 18000 to 1: 180,000, with an average of 1: 47000. The frequency of galactosemia in Japan is 1: 667000. In order to implement the national project "Health" in the Krasnodar Territory in 2006. in addition to PKU and VH, screening for cystic fibrosis, adrenogenital syndrome and galactosemia began.

Table 8 The results of newborn screening for hereditary metabolic diseases in the Krasnodar Territory for the period from 1.07.06. until 30.06.08.
Disease	Examination of newborns	Number of primary deviations in analyzes	Number of re-examined children	Number of repeated deviations in analyzes	Number of identified patients
cystic fibrosis
AGS
galactosemia

For 24 months (July 2006 - June 2008) 114,253 (99.7%) newborns were examined for AGS and cystic fibrosis, 10 children with cystic fibrosis, 15 patients with adrenogenital syndrome were identified. For galactosemia for 24 months (October 2006-September 2008), 116,041 (99.2%) newborns were examined, 6 patients were identified (Table 8). Primary elevated levels of IRT and 17-OHP were detected in 1.1%, total galactose in 1.9% of the examined children. In order to identify possible reasons affecting the increase in the studied metabolites in the blood of newborns, we analyzed the adverse factors affecting the development of the child during pregnancy and after birth. The following factors were analyzed: placental insufficiency, anemia of pregnant women, preterm labor, delivery stimulation, operative delivery, newborn body weight less than 2 kg and more than 4 kg, hypoxia, jaundice, congenital infections and infusion therapy. The influence of the above factors on the level of 17-OHP and galactose was not revealed. Revealed the dependence of the level of IRT in the blood of newborns on anemia of pregnant women, jaundice and hypoxia of newborns, infusion therapy (Table 9).

Table 9 Factors influencing the increase in neonatal RTI
	Number of newborns with increased RTI (n = 305)		Control group n = 20,000
		infusion therapy was not performed	Control group n = 20,000

infusion therapy
anemia of pregnancy
hypoxia

Of 1201 newborns with a high level of RTI, a second study of RTI in the informative period (at the age of 21-28 days of life) was carried out in 717 (59.7%) children, in 132 (18.4%) a second increased level of RTI was determined. Children with elevated RTI were born on average by 39 + 2 weeks pregnant with body weight 3329 + 620 grams with an average body length of 52.0 + 3.0 cm.When examined in the maternity hospital, the IRT level ranged from 70.0 to 556.0 ng / ml, averaging 110.0 + 56.0 ng / ml. During retest, the IRT level ranged from 6.0 to 448.0 nmol / l, averaging 67.0 + 41.0 ng / ml. The dependence of the level of IRT on the weight of newborns was not revealed. For a more reliable assessment of the dependence of the RTI level on the physical development of children, we determined the mass-growth index (MRI). In children with MRI less than 90, indicating a deficiency in body weight, the average RTI level was 107 + 44 ng / ml. With normal MRI values (from 90 to 99), the average level of IRT is 107 + 43 ng / ml. With MRI of 100 or more, indicating overweight, the average level of IRT is 113 + 71 ng / ml. Thus, no correlation was found between the level of neonatal RTI and the height and weight indices of newborns. As noted above, when examining 114,253 newborns, 10 children with cystic fibrosis were identified, which made it possible to determine the preliminary frequency of cystic fibrosis 1: 11425. We analyzed the detection of CF depending on the level of IRT during retest. In MGK, 83 children with a positive retest were examined. In the largest group of newborns with an IRT level of less than 100 ng / ml, consisting of 71 people, 3 children with CF were identified (4.2%). Among 8 children with RTIs from 100 to 200 ng / ml, cystic fibrosis was detected in 3 (37.5%). Out of 4 infants with RTIs over 200 ng / ml, 2 patients (50%) were identified. Thus, there is a direct relationship between the degree of increase in the biochemical marker and the proportion of identified patients. In children with cystic fibrosis, the primary level of IRT ranged from 88 to 346 ng / ml (average 162 + 85 ng / ml), with retesting - from 70 to 448 ng / ml (average 162 + 129 ng / ml). Identified patients by physical indicators did not differ from newborns in the control group. Children were born on average 39 + 1 week of pregnancy. Their average body length was 51 + 2 cm (48 to 55), average weight 3094 + 432 grams (from 2700 to 4100), MRI 92 + 10. The sweat test was carried out at the age of 37-157 days of life, the level of chlorides in the sweat fluid ranged from 54 to 144 mmol / l (average 92 + 38 mmol / L). Average age diagnosis of cystic fibrosis was 92 + 40 days of life. Within the framework of neonatal screening, we carried out a molecular genetic study of mutations in the CFTR gene using the CF-9 and CF-5 kits, developed by the State Institution of the Moscow State Scientific Center of the Russian Academy of Medical Sciences. 4 types of mutations were established out of 14 studied (del21kb, delF508, delI507, 1677delTA, 2143delT, 2184insA, 394delTT, 3821delT, G542X, W1282X, N1303K, L138ins, R334W, 3849 + 10kbc-> T): in 3 children, delF508 in 6 delF508 in a compound state (2 with 2184insA mutation, 1 with del21kb mutation, 1 with 3849 + 10kbC → T mutation, 2 with unknown mutation). The studied mutations were not identified in 1 child. Thus, the total information content of chromosomes for the studied spectrum of mutations was 80.0%. The frequency of the delF508 major mutation was 60.0%. Out of 1212 newborns with a high level of 17-ОНР, 878 (72.4%) children were re-examined, 92 (10.5%) children were under dynamic observation in connection with the second elevated level 17-ONR. 15 children with adrenogenital syndrome were identified. The preliminary frequency of the AGS is 1: 7617. The main part of the diagnoses (10 patients - 66.7%) was noted in the group of children with a level of 17-0HP during the initial examination of more than 100.0 nmol / L (mean value 602.2 + 384.4 nmol / L). In 8 children, the salt-wasting form of AHS was diagnosed, in 2 - viril. In the group of children with primary 17-OHP less than 100.0 nmol / L, 5 patients were identified, of which 3 with the viril form, 2 with the salt-wasting form. The average level of neonatal 17-OHP was 41.1 + 31.6 nmol / l. The results of the first 2 years of screening for AGS showed that the primary blood sampling for 17-OHP in the identified patients was carried out on average for 4 + 1 day of life, repeated blood sampling - from 10th to 34th day of life, on average 18 + Day 8. Patients were started at the age of 20 + 12 days of life.

Table 10 Indicators of the level of 17-OHP in newborns depending on the timing of gestation
Gestational age	Number of examined	Percentiles 17-OHP nmol / l
Gestational age	Number of examined

The introduction of the Neoscreen software package made it possible to carry out a statistical analysis of the 17-ОНР level in healthy newborns and determine its values for the 99th percentile depending on weight and gestational age (Table 10). The results of our studies showed a decrease in the level of 17-OHP from 150.0 nmol / L with a gestation period of 30 weeks to 28.5 nmol / L with a gestation period of 40 weeks. ОНР "test systems were modified, which led to a change in the results obtained. In order to determine new cut-off levels of 17-OHP concentration in dry blood spots, we carried out a comparative analysis of the 17-OHP level in 1740 newborns, depending on the "Neonatal 17-OHP" kits used: kit A024-110 (modified version ) or kit A015-110 (previous version) (table 11).

Table 11 Indicators of the level of 17-OHP in newborns using the Neonatal 17α-OH-progesterone kit A024-110 and kit A015-110
Gestation period (weeks)	Birth weight (grams)	Percentiles 17-OHP (nmol / l)
		Neonatal set 17α-OHP kit A024-110	Neonatal set 17α-OHP kit A015-110

As our studies have shown, when working with the kits of the modified version of A024-110, the cut-off value of 17-OHP concentration in term infants was 2.5 times lower than when working with the kits. old version A015-110 (12.2 nmol / L and 30.6 nmol / L, respectively). A similar trend was noted in premature infants, however, the small number of subjects in these groups does not allow to reliably evaluate the statistical data obtained. Thus, the systematic monitoring of the screening results using the Neoscrin software package allows you to calculate the threshold level of the determined metabolites depending on the gestational age and the weight of the newborn, evaluate the data obtained and avoid errors associated with misinterpretation of the results. Of 2205 newborns with high galactose levels, 51 (2.3%) were born before 37 weeks, 2154 (97.7%) - at 37 to 42 weeks of gestation. The average gestational age was 39 + 3 weeks. Average weight newborn 3362 + 526 grams, average body length 51 + 4 cm, MRI 93 + 15. At the threshold level of galactose in dry blood spots of 7.1 mg / dl, the range of its increased values according to the results of stage I of screening ranged from 7.1 to 85.0 mg / dl, the average level was 8.7 mg / dl. In 86.8% of initially positive cases, the galactose level did not exceed 10.0 mg / dL. The dependence of the Gal level on the weight of newborns was not revealed. A repeated study was carried out in 1849 (83.9%) children, an average of 18 + 8 day of life. 174 (9.4%) children were under dynamic observation due to a secondary increased level of Gal. Six children with galactosemia were identified: 2 with classical galactosemia, 4 with Duarte's variant. The preliminary frequency of galactosemia is 1: 19340 (classic 1: 58021, Duarte 1: 29010). In children with classical galactosemia, the primary levels of Gal were 20.4 and 85.0 mg / dl, with retest 17.5 and 22 mg / dl, respectively. Average weight 3390 + 205 grams, average body length 51 + 1 cm, MRI 101 + 3. At the initial examination, both children showed regurgitation, icterus of the skin and sclera, the second child - vomiting, loose stools, hepatomegaly. A molecular genetic study revealed the Q188R and K285N mutations in the compound state in one child, and the K285N mutation in the second. heterozygous state, the second mutation has not been identified. In children with Duarte's galactosemia, the primary level of Gal ranged from 7.2 to 33.4 mg / dL, with retesting - from 11.5 to 18.4 mg / dL. Average weight 3483 + 505 grams, average body length 53 + 3 cm, MRI 100 + 9. During the initial examination, three children had subicteric sclera, two had regurgitation, one had loose stools, and one had a weeping navel. A molecular genetic study revealed the Q188R and N314D mutations in the compound state in two children, and the N314D mutation in the homozygous state in two children.

Computerization and Neonatal Screening Software

Neonatal screening is a multifaceted complex of measures that requires the constant participation and attention of a number of medical services. Screening involves examining every newborn in the population. At the first stages, the coverage of newborns by screening was monitored by comparing the number of examined children and children born alive. In the first year (1987) of screening, 61.7% of newborns were examined; - 88.0%. More than 10% of newborns remained not examined due to the lack of information about their surname and place of residence, which made it impossible to call children to the Moscow City Hall for examination. In 1990. we developed and implemented a system of personal registration of newborns, which provided for the monthly receipt of lists of children born from all maternity hospitals in the region to KMMGK, comparison of lists and received samples, identification of unexamined ones. Emergency notifications were sent to the chief doctors of medical facilities about the need to urgently send unexamined children to KMMGC. Through the regional health department, service letters were regularly sent to the heads of the territorial health authorities "The results of the neonatal screening program in obstetric institutions of the Krasnodar Region." This system of organizing screening made it possible to increase the level of those examined at PKU up to 99.0% in 1997. Due to the established relationship with obstetric institutions of the region during neonatal screening for PKU, in 1994. screening for congenital hypothyroidism has been introduced without much difficulty. Usage manual labor, associated with the registration and registration of the examined newborns, required significant labor costs of the KMMGK employees. The statistical processing of the large volume of information recorded in the work logs was complex and often inaccurate, which necessitated re-calculation. Dynamic changes in screening data made it difficult to keep statistics on paper. All this required an improvement in the methods of organizing screening. To optimize the screening, mutual coordination of the actions of obstetric institutions and KMMGK, we in 1997. a computer program was developed "Neonatal screening", which made it possible to automate the registration of test forms received by KMMGK, to take into account the quality and delivery time of samples, to register data on born and examined children. Every month, from each maternity hospital, KMMGK received information on the number of newborns and examined newborns with an attached handwritten list of children. The data on the number of newborns examined in each territory were entered into the form of the computer program "Control by lists", taking into account the date of birth and the date of the analysis. Based on the results of the registered information, the program created a monthly automated report containing information on the quality and timing of delivery of blood samples to the Moscow City Center, the level of screening coverage. Reconciliation of information of maternity hospitals about newborns with received blood samples made it possible to identify children who were not covered by screening. In order to control their examination, the information was registered in the form “Uninvestigated” of the computer program “Neonatal screening”. The introduction of this program made it possible to switch to more high level assess the quality of neonatal screening, analyze the performance of each area and take measures to improve the organization of screening. Screening coverage for PKU and VH increased from 99.0% in 1997 to 99.6% in 2007. In 2006. 3 new diseases were added to the existing screening for PKU and GV - adrenogenital syndrome, cystic fibrosis and galactosemia. Since it is extremely important in the diagnosis of AHS and galactosemia to establish a diagnosis in the first 2 weeks of life, which allows timely initiation of treatment and prevention of early death of newborns, we have improved the previously existing algorithm for examining newborns. To this end, in 2007. we have developed a software package "Neoscreen", consisting of two separate programs: "Registration of newborns in the maternity hospital" and "Newborn screening". The programs are created using Microsoft Office Access 2003, which is included in the professional edition of Microsoft Office 2003. The program "Registration of newborns in the maternity hospital" is designed to enter information about births, transfer data about them to the Moscow City Center on electronic media, form a territorial register of newborns, daily quality assessment screening, reporting. This program was integrated into all maternity hospitals of the region after conducting training seminars for those responsible for neonatal screening. In order to unify information flows coming from all maternity hospitals, the KMMGK has established the Newborn Screening program. Figure 2 shows a diagram of information interaction of the Neoskrin software package.

Rice. 2 Scheme of information flows of the Neoscreen software package.

Program "Registration of newborns in the maternity hospital" is the main source of data on births. The main file of the program "screen.mde" can be placed on the computer of the maternity hospital in any convenient place. In addition to this file, the delivery includes an additional file "List of newborns .mbd". This is an intermediary file required to transfer data to and from KMMGK. The main form that appears when the program "Registration of newborns in the maternity hospital" is launched is shown in Fig. 3. Information about the birth is entered in the newborn's card, which opens after clicking the "Cards" button in the main form. The features of the course of pregnancy, childbirth, medication intake, diagnosis in the maternity hospital, Apgar scale, etc. are noted. Data entered in the maternity hospital in newborn cards are sent to the file "List of newborns.mbd", which is transferred to the KMMGK. In the "Main form" of the program, the time interval corresponding to the date of birth of children, whose analyzes will be sent to KMMGK, is marked. When you press the button "Preview information for MGC", a table with a list of newborns born in a given period of time will appear. The table shows the date the blood was taken for the test form, or the reason the blood was not drawn.

Fig.3 The main form of the program "Registration of newborns in the maternity hospital".

The list formed in the maternity hospital is preliminarily verified with blood samples from newborns intended for sending to KMMGK. If the information is the same, the table is exported to the file "List of newborns .mbd", which is delivered to the registry of the neonatal screening laboratory KMMGK on an electronic carrier together with test forms. Registry staff check the quality of the delivered test forms, check them against the list and transfer information about newborns to the register of medical genetic consultation. Each child is assigned a personal number, the day and hour of receipt of blood samples in the laboratory are indicated. After that, the MGK data are already recorded on an electronic carrier and sent by courier to the territory. The feedback received from the KMMGK allows the doctor responsible for neonatal screening in the territory to independently and timely analyze the quality of the first stage of neonatal screening (maternity hospital - MHC). The Newborn Screening Program, established at the Moscow City Conservatory, brings together all information about newborns coming from the territory of the region. By analogy with the program "Registration of newborns in a maternity hospital", there is a newborn card (Figure 4), which automatically includes information about the newborn received from the maternity hospital and the results of screening.

Rice. 4 Card of the newborn of the computer program "Screening of newborns".

In case of deviations in the analyzes, the program automatically generates a call and sends it by e-mail to the name of the head physician of the healthcare facility (Figure 5). At the end of the month, the program generates and sends by e-mail reports on the results of screening to each territory. The program "Registration of newborns in the maternity hospital" generates a similar report. Employees of the maternity hospital check the generated report with the report received from the Moscow City Clinical Hospital, which makes it possible to quickly control the quality of the screening. The Newborn Screening program also optimizes the performance of the neonatal screening laboratory. After entering the information received by the MGK from the territories, the program automatically generates a list of samples for research using the Victor-2 laboratory complex, which can significantly reduce personnel labor costs and the likelihood of errors in preparing samples for research. The accumulation of statistical information during the operation of the Neoscreen software package allows for a personalized analysis of research results and determination of the threshold concentration levels for each screened disease for a specific population.

Fig. 5 Automated form of calling children with high screening results, sent by e-mail

CONCLUSIONS

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	17-oxyhydroprogesterone
	adrenogenital syndrome
	congenital hypothyroidism
	total galactose
	immunoreactive trypsin
	iodine deficiency
	Krasnodar region
	Kuban interregional medical and genetic consultation
	medical institutions
	cystic fibrosis
	medical genetic consultation
	mass growth index
	hereditary metabolic diseases
	general intelligence
	polymerase chain reaction
	thyroid-stimulating hormone
	phenylalanine
	phenylalanine hydroxylase
	phenylketonuria
	central nervous system

Newborn screening, or "heel test" is massively carried out in Russia, Europe, and the USA. Usually the analysis is done in the hospital on the 4th or 5th day of the baby's life. Results come in three weeks on average. Most often, during this examination, a disease called cystic fibrosis is found in children.

Screening of newborns (from English screening - sorting) is one of the most effective methods diagnostics genetic diseases neonatal period. Genetic research is being carried out at the initiative of the World Health Organization (WHO). In Russia, screening is included in the list of mandatory diagnostic activities over the past fifteen years. From a large list of genetic diseases, it is recommended to diagnose five pathologies, taking into account such factors: prevalence, severity of diseases, as well as the ability to obtain reliable test results and apply effective treatment.

Screening terms and conditions

How is newborn screening done?

In full-term babies, the analysis is done on day 4 at the hospital.
Premature babies are screened on the 7th day of life and later.
If the child was discharged from the hospital earlier, the baby is analyzed at home or in the clinic at the place of residence.
Peripheral blood (from the heel) is taken for screening, hence the heel test.
The blood is applied to 5 separate blanks (circles) of filtered paper.
The analysis is taken on an empty stomach, you can not feed the newborn 3 hours before screening.

When to do the screening? If you do the analysis earlier - on the 2nd or 3rd day of life - the results can be both false positive and false negative. It is advisable to pass the test within the first 10 days of life. Early detection of genetic metabolic disorders is important for a favorable prognosis.

Diagnostics of pathologies of the gene level

What kind congenital diseases diagnosed by screening in Russia? The list includes those diseases that can be cured or reduced in severity at an early stage of detection. These are pathologies associated with various metabolic disorders. This, for example, does not include the diagnosis of a chromosomal disease such as Down syndrome.

Hypothyroidism This disease is associated with a violation of the production of thyroid hormones. The consequences of this disease are severe: general physical and mental retardation. On average, one case of hereditary hypothyroidism is recorded per 5 thousand newborns, and girls are more likely to get sick. The chances of completely curing the disease detected after positive screening results are quite high, hypothyroidism can be defeated. Required hormone therapy... Read more about hypothyroidism in our other article.
Cystic fibrosis. With this disease, the production of secretions in the lungs and the digestive tract is disrupted. The fluid secreted by the cells becomes thick, this leads to serious dysfunctions of the lungs, liver, and pancreas. Cystic fibrosis is one of the most common diseases that is detected during screening; one case is registered in 2-3 thousand newborns. The prognosis is favorable if timely treatment begins.
Adrenogenital syndrome... It is rare, about one case in 15 thousand newborns. This includes a group of genetic diseases that are triggered by a violation of the production of cortisol (in the adrenal cortex). What are the consequences of this disease? The development of the genitals is delayed, the kidneys, heart, blood vessels are affected. Possibly fatal if not provided health care... Treatment consists of lifelong hormonal therapy.
Galactosemia. The cause of this disease is a deficiency of an enzyme that breaks down galactase. This substance enters the body with glucose and is contained in lactose. Symptoms of galactosemia appear gradually, and the newborn appears to be a perfectly healthy baby. But after a few weeks, vomiting, loss of appetite, swelling, protein in the urine, jaundice may appear. Galactosemia is dangerous for its consequences: serious violations of liver function, decreased visual acuity, retarded physical, intellectual development. This is the rarest disease diagnosed at screening, occurs once in 30 thousand newborns. Treatment for galactosemia is a strict dairy-free diet.
Phenylketonuria. A rare hereditary disease that occurs once in 15 thousand newborns. Phenylketonuria occurs as a result of a disruption in the production of an enzyme that is supposed to destroy the acid of phenylalanine. The breakdown products of phenylalanine negatively affect the entire body and accumulate in the blood. First of all, the central nervous system, the brain suffers, convulsions appear. To avoid complications of the disease, a strict diet is required, which excludes the intake of phenylalanine into the body.

In medicine, there are about five hundred diseases associated with metabolic disorders, or metabolism. For example, in Germany, 14 genetic diseases are diagnosed through newborn screening, in the United States - over 40 diseases. In Russia, neonatal screening is carried out to diagnose the five most dangerous pathologies that begin to develop at an early age. At the request of the parents, if the baby is at risk, screening can be expanded to 16 diseases.

There is a lot of controversy around the topic of newborn screening. Parents who have experienced stress after a false positive result in a baby are not advised to undergo the procedure. Other mothers and fathers, whose babies were diagnosed with serious diagnoses, are grateful to this diagnosis, because they managed to save the child from serious consequences, to suspend or cure the disease.

5 questions parents worry

Screening is anxiety for many mums and dads, and the waiting period is filled with anxiety and fear. Especially anxious moms may even have lactation problems. Perhaps that is why in some maternity hospitals they do not notify mothers at all, for what purposes the analysis is taken.

When can you get the result? The analysis is carried out within three weeks. If the results are negative (and this is the case in most cases), no one reports it. But the data is recorded in the baby's medical record. If there is a positive result, then they will definitely call back from the clinic and ask to take the test again. Most often false positive tests are on cystic fibrosis.
If re-screening confirmed the previous test? Parents are invited to a conversation with a geneticist. He gives referrals to narrow specialists, where additional examination is carried out: coprogram, DNA diagnostics, analysis of a dry blood spot, and if cystic fibrosis is suspected, a sweat test. If, after additional tests, the diagnosis is nevertheless confirmed, the question of the tactics of treating the baby is being decided.
Can newborn screening be done at home? If, for some reason, screening was not carried out in the hospital or the discharge was on the 3rd day, the analysis is done at the polyclinic at the place of residence. Some mothers, commenting on the situation, share their experience: someone called the nurse at home, someone went to the clinic, and someone came home and took a blood sample for screening. If there are difficulties, and the time frame for taking blood for screening is running out, you can do an analysis in a paid laboratory. You can also contact the higher health authorities, which are subordinate to the district maternity hospital and polyclinic, and ask how to act in this situation.
How reliable is the screening? If the analysis is carried out on time, if the baby has not eaten 3 hours before blood sampling, the reliability of the tests is high. But the diagnosis is never made after the first positive result. There are rare cases when screening shows false negative results. In this case, the disease is detected late, when symptoms already appear.
Can I opt out of screening? Yes, you can. Parents take responsibility and sign a document refusing to screen their newborn. This paper is glued into the baby's card. The nurse or the doctor of the district clinic will call, come home, leave notes with a request to undergo screening until a parental refusal is written.

It is important to know that pathological metabolic disorders can be not only hereditary diseases. Children with cystic fibrosis, hypothyroidism, galactosemia, phenylketonuria, adrenogenital syndrome can be born to perfectly healthy parents. It is also important to know that when confirming the diagnosis, one should not delay treatment and neglect the recommended diet for phenylketonuria or galactosemia.

Newborn screening at the maternity hospital is quick, free and painless for babies. Health professionals recommend that parents consciously approach this diagnosis, which is carried out under the state program and the WHO initiative. Unfortunately, late detection of genetic metabolic diseases leads to irreversible consequences, disability and mortality of children.

Screening for cystic fibrosis in the maternity hospital is aimed at determining the disease even before the onset clinical signs... Its main task is the early detection of sick children and the timely appointment of adequate therapy. This method is based on determining the level of immunoreactive trypsin (IRT) in a dry spot of the capillary blood of newborns. Unlike prenatal screening, it is done after the baby is born. At the moment, neonatal screening is a mandatory procedure for newborns. Screening for cystic fibrosis can be confirmed at different stages of this diagnosis. The first stage is blood sampling from the heel (on special filter paper) of the newborn on 4-7 days of life. Then, in a dried blood spot, the content of immunoreactive trypsin is counted on a special test blank. A normal reading can be considered 65-70ng / l. If these indicators are exceeded 5 or even 10 times, we can talk about the transition to the second stage of diagnosing the disease of cystic fibrosis. Neonatal screening of the second stage is carried out on the 21-28th day of the child's life. This stage is a repetition of the first. A blood sample is also taken from a child to determine immunoreactive trypsin. Normally, the readings in this period of life should not exceed 40ng / l. If the screening for cystic fibrosis is positive, then a third stage is necessary. At this stage, it is necessary to carry out a sweat test and genetic tests. Since during these tests, there may be false positive results. The third stage will allow doctors to confirm or deny the possibility of making this diagnosis. False indications can occur in the following conditions:

the second screening was later than the due date (21-28 days of life);
with fetal hypoxia;
with intrauterine infections;
the indicator is not always informative for meconium ileus;
the level of immunoreactive trypsin increases and when renal failure, intestinal atresia.

Nowadays, the sweat test is the most reliable diagnosis of cystic fibrosis in newborns and children under 2 years of age. For the accuracy of the result, the test is carried out several times (2-3).

Normal readings are sample numbers of no more than 40 mmol / l. With an increase in the result for samples for cystic fibrosis, the screening proceeds to the fourth stage. It is carried out with an increase in the result of a sweat test from 40 to 60 mmol / l. In this case, a DNA diagnosis is prescribed for 10-20 mutations common in the immediate area. If the result of the sweat test is unambiguously positive, where the values exceed 60 mmol / l, the diagnosis is confirmed. The child is registered at the nearest cystic fibrosis center.

If the disease is not confirmed, such a child is observed for a year and then repeated sweat tests are performed and an analysis of feces for the content of elastase-1 is prescribed.

E.I. Kondratyeva, Doctor of Medical Sciences, Professor, V.D. Sherman, Ph.D., N.I. Kapranov, Doctor of Medical Sciences, Professor, N.Yu. Kashirskaya, doctor of medical sciences, professor, non-profit organization of cystic fibrosis, FSBSI "MGNTs", GBUZ "DGKB No. 13 named after N.F. Filatov DZM ", Moscow

Cystic fibrosis (CF), or cystic fibrosis (cystic fibrosis), is one of the most common monogenic hereditary diseases with multiple organ pathology, dramatically reducing the duration and quality of life of patients without adequate complex treatment throughout life. CF is common among the world's population, but most often affects Caucasians: on average, with an incidence of 1 in 2500-4500 newborns. More recently, patients with cystic fibrosis died in an early childhood or even in the first year of life from pneumonia and malabsorption malabsorption wasting.
Keywords: diagnostics, genetics, mutations, neonatal screening, sweat test, fecal elastase.
Key words: cystic fibrosis, diagnosis, genetics, mutation, newborn screening, sweat test, fecal elastase.

The disease is primarily characterized by increased production of viscous bronchial secretions, frequent lung infections and obstruction respiratory tract... As pulmonary disease progresses, areas of atelectasis are formed, emphysema develops, the parenchyma of the lungs is gradually destroyed with the development of bronchiectasis and areas of pneumosclerosis, and the patient has a high risk of dying from pulmonary heart failure. In the final stage of the disease, transplantation of the heart-lung complex remains the only hope for the patient. In addition to the bronchopulmonary system, the pancreas is affected in most patients with cystic fibrosis, and this occurs intrauterinely. Lack of pancreatic enzymes leads to impaired absorption of fats and proteins, the development of nutritional deficiency. As a result, patients are stunted and suffer from hypotrophy. Insulin production can also be impaired, leading to the development of diabetes. Frequent complications of the course of cystic fibrosis include osteoporosis, as well as fatty hepatosis with the transition to cirrhosis. In the presence of a "soft" mutation, clinical manifestations develop gradually, monosymptoms prevail, the diagnosis of "cystic fibrosis" is established late or accidentally.

Timely diagnosis of cystic fibrosis, which in most cases provides early initiation of therapy, including at the preclinical stage, improves the prognosis of the disease, increases the effectiveness of treatment, and prevents the development of severe complications, a significant lag in physical development, and in some cases, irreversible changes in the lungs. Early diagnosis allows the family to timely resolve the necessary issues related to the birth of a healthy child (genetic counseling, prenatal diagnosis of CF in subsequent pregnancies).

Diagnostics are divided into:

1) prenatal diagnosis;
2) diagnostics by neonatal screening (before clinical manifestations or at their debut);
3) diagnostics for clinical manifestations:

patients who were not included in the neonatal CF screening program, which has been conducted since 2006-2007. Risk groups: patients with gastrointestinal tract pathology, bronchopulmonary disorders, pathology of other organs;

false negative results from neonatal screening and sweat test;

patients with neonatal hypertrypsinogenemia who have not received a sweat test;

4) diagnostics among relatives of patients.

Currently, prenatal diagnostics of cystic fibrosis is being established in promising and informative families (Moscow, St. Petersburg, Ufa, Tomsk, Krasnoyarsk, Rostov-on-Don, Vladivostok and some other cities), which, of course, is important for the prevention of this severe pathology. Prenatal diagnostics is possible in the form of DNA diagnostics during amniocentesis (obtaining amniotic fluid in early date-13-14 weeks and late - usually 16-20 weeks of pregnancy) in a family of carriers of one CFTR gene mutation and having a sick child. The diagnosis can be suspected by intrauterine ultrasound of the fetus in the presence of a characteristic ultrasound characteristic in the form of a hyperechoic intestine. Ultrasound during pregnancy is recommended at screening times: 11-14, 18-21 and 30-34 weeks of pregnancy. Re-examination is mandatory. In 50-78% of cases, this condition will be associated with CF and manifest as meconium ileus. In this case, the diagnosis can be made even before the baby is born. At the same time, this symptom is not highly specific for CF, it can be a transient phenomenon, as well as associated with other pathological conditions... At the same time, the DNA diagnostics of the parents provides the necessary information about the presence of mutations in each of the parents and allows one to assume that the child has a disease at birth.

Clinical signs

1. Diagnosis of the classic form of CF is usually not difficult. The classic phenotype of the patient is the result of the presence of two mutant copies of the cystic fibrosis transmembrane regulator (CFTR) gene and is characterized by chronic bacterial infection of the respiratory tract and paranasal sinuses, steatorrhea due to exocrine pancreatic insufficiency, male infertility due to obstructive azoospermia, and sweat fluid.
2. Problems in the diagnosis of CF, as a rule, are associated with the phenotypic diversity of its forms, caused by genetic polymorphism.

In some cases of atypical course of CF, it can be diagnosed in adulthood. As a rule, in this group of patients there is a milder course of the disease due to the preservation of the function of the pancreas and mild damage to the respiratory organs.

In the vast majority of cases, CF can be diagnosed in early childhood (in 90% of cases, in the first year of life). Unfortunately, CF is often diagnosed in adults with a classic phenotype.

Diagnosis of CF in carriers of "soft" genotypes (relevant for children born before 2006-2007 and adults):

late debut;

monodebut, mono-defeat, monosymptomatic from the respiratory system;

clinical symptoms of lung damage are erased, or not expressed, or masked (bronchial asthma, pneumonia);

a relatively high proportion of negative, doubtful or not sharply elevated sweat chlorides;

mutations are often not among the mutations most commonly identified in genetic counseling and require sequencing;

consultation of an ENT doctor, andrologist is necessary.

Currently, there are several CF risk groups.

The main risk group for the disease in the Russian Federation is currently newborns with neonatal hypertrypsinogenemia. Considering the possibility of obtaining false-negative results of neonatal screening, as well as the fact that in the Russian Federation neonatal screening for CF has been carried out since 2006-2007, the analysis of risk groups, including patients with pathology of the gastrointestinal tract, bronchopulmonary disorders, pathology of other organs and relatives of CF patients (Table 1).

Table 1.

Risk groups for differential diagnosis of cystic fibrosis

I. Bronchopulmonary disorders

1. Repeated and recurrent pneumonia with a protracted course, especially bilateral
2. Bronchial asthma refractory to traditional therapy
3. Recurrent bronchitis, bronchiolitis, especially with seeding Ps. aeruginosa
4. Bilateral bronchiectasis

II. Changes in the gastrointestinal tract

1. Syndrome of impaired intestinal absorption unclear genesis
2. Meconium ileus and its equivalents
3. Hyperechogenicity of the intestine of the fetus
4. Jaundice of obstructive type in newborns with a protracted course
5. Liver cirrhosis
6. Diabetes mellitus
7. Gastroesophageal reflux
8. Rectal prolapse

III. Pathology from other organs

1. Violation of growth and development
2. Delayed sexual development
3. Male infertility
4. Chronic sinusitis
5. Nasal polyps
6. Electrolyte disturbances

IV. Family members of patients with cystic fibrosis

Among the clinical manifestations characteristic of CF, highly and less specific ones can be distinguished (Table 2). The conditions presented in the left column of the table are found in the vast majority of cases in CF patients. The conditions in the right column can be caused by other diseases, for example, primary ciliary dyskinesia, humoral immunodeficiency, etc.

Table 2.

Clinical manifestations specific to CF

Highly specific for CF	Less specific for CF
Gastrointestinal: Meconium ileus Exocrine pancreatic insufficiency in children	Gastrointestinal: Lagging physical development Hypoproteinemia Fat-soluble vitamin deficiency Rectal prolapse Biliary cirrhosis Portal hypertension GSD in children without hemolytic syndrome Primary sclerosing cholangitis Exocrine pancreatic insufficiency in adults Recurrent pancreatitis
Chronic mucoid infection Ps. aeruginosa Bronchiectasis in the upper lobes of both lungs Persistent B. cepacia infection Nasal polyps in children	From the respiratory tract: Chronic or recurrent St. aureus, Ps. aeruginosa, Ach. xilosoxidans, H. Influenzae X-ray signs of bronchiectasis, atelectasis, hyperinflation, or chronic infiltration on chest x-ray Hemoptysis associated with diffuse lung disease other than tuberculosis or vasculitis Chronic and / or productive cough Nasal polyps in adults X-ray signs of chronic pansinusitis
Other: Hypochloremic alkalosis in the absence of vomiting Congenital bilateral absence of the vas deferens	Other: Thickening of the terminal phalanges Osteopenia / Osteoporosis in Age<40 лет Atypical diabetes

Table 3 presents the features of the manifestations of CF in different age periods. Knowledge of these features helps professionals who are observing a patient with certain symptoms to include CF in the list of diseases for differential diagnosis. This is especially true for young children, when the clinical picture may still be incomplete, but some manifestations will pay attention to themselves, for example, meconium ileus at birth or salt loss syndrome, which has no connection with kidney pathology. In this case, the diagnosis can be made even before the baby is born. At the same time, this symptom is not highly specific for CF, it can be a transient phenomenon, as well as associated with other pathological conditions.

Table 3.

Clinical features of CF manifestations in different age periods

0-2 years
Poor weight gain Steatorrhea Recurrent bronchitis / bronchiolitis Meconium ileus Rectal prolapse Hypoproteinemic edema	Pneumonia / empyema Salt Loss Syndrome Prolonged jaundice of newborns Increased bleeding associated with vitamin K deficiency
3-16 years old
Recurrent respiratory infection or asthma Idiopathic bronchiectasis Steatorrhea Acute or chronic pancreatitis	Sinusitis and nasal polyposis Chronic intestinal obstruction, intussusception Heatstroke with hyponatremia Family CF diagnosis

Diagnostic criteria for CF
To solve the problems of diagnosing CF, including its atypical forms, criteria were developed according to which the presence of a characteristic clinical syndrome plus proof of any dysfunction of the chlorine channel is mandatory for CF.

Taking into account all the scientific advances in understanding the nature of cystic fibrosis and CF-dependent diseases over the past 10 years, in 2013, a group of experts from the European Cystic Fibrosis Society, led by Carlo Castellani, prepared new diagnostic standards edited by Alan R. Smyth and Scott Bell ( scheme).

Scheme.

Diagnostic criteria for cystic fibrosis ECFS 2013

Neonatal screening
It is carried out on the basis of the Guidelines for neonatal screening in the Russian Federation using the European recommendations for neonatal screening. 90% of newborns without clinical manifestations of cystic fibrosis can be diagnosed by screening before 6 weeks of age. In 5-10% of cases, there are difficulties with the diagnosis of cystic fibrosis (Cystic Fibrosis Foundation Patient Registry, 2005 Annual Data Report to the Center Directors. Bethesda, MD: CFF).

Neonatal screening problems:

5-10 newborns out of 1000 have neonatal hypertrypsinogenemia.

Failure to comply with the timing of blood sampling leads to diagnostic errors. The test is on the 4-5th day, the retest is carried out no later than 8 weeks (optimally the 21-28th day of life).

IRT is not stable in blood samples during storage (max. 14 days).

Meconial ileus, hyperechoic intestine of the fetus in the second trimester requires examination for CF regardless of the screening program.

RTI increases in newborns not only with CF (trisomy 13 and 18, renal failure, intrauterine infection, intestinal atresia, renal diabetes insipidus, newborns of North African and African American descent, heterozygous carriers of CFTR mutations?).

False negative result for meconium ileus, prematurity, blood transfusions, viral infection.

There is a need to discuss the definition of a lower threshold for the diagnosis of neonatal hypertrypsinogenemia for each laboratory.

Sweat sample
Indications:

1. With a positive result of neonatal screening (a twofold increase in the level of immunoreactive trypsinogen in the blood during the first month of a child's life).
2. If the patient has any characteristic clinical manifestations of CF.
3. Family history of CF.

The sweat test is a reliable diagnostic tool for CF in 98% of patients. The test can be performed on all babies 48 hours after birth, although newborns may have trouble gaining sweat. Despite the fact that the "gold standard" for CF diagnostics is the quantitative determination of chlorides in sweat fluid (the classical Gibson - Cook method), the method for determining conductivity on the Macrodact and Nanodact devices (Vescor, USA) showed a good correlation with it. in numerous studies.

Result evaluation
If the sweat test is positive (chlorides> 60 mmol / L with the classical Gibson-Cook method and / or conductivity> 80 mmol / L NaCl), the diagnosis is confirmed.

Genetic research
Genetic testing is done after a sweat test. However, due to the limited possibilities of DNA diagnostics in Russia, this method is not mandatory, but it is used for research purposes and for the final confirmation of the diagnosis.

At the first stage of DNA examination, a panel is most often used, which includes 28 mutations, both the most frequent in the world and specific for Russia: F508del, CFTRdele2,3 (21kb), 3849 + 10kbC> T, W1282X, 2143delT, 2184insA, 1677delTA, N1303K, G542X, R334W, E92K, L138ins, 394delTT, 3821delT, S1196X, 2789 + 5G> A, G85E, 2183AA> G, 604insA, 621 + 1G> T, R117H, R347P, R553X, 36671insTCAA, G557del 1G> A, 2184delA. According to the laboratory of genetic epidemiology of the Federal State Budgetary Institution "Medical Genetic Research Center" (MGSC) of the Russian Academy of Medical Sciences, when using this panel, it is possible to detect only about 82.5% of mutant alleles in CF patients. In the event that a positive sweat test does not find any gene mutations (which in itself is unlikely), sequencing of the CF gene may be required to identify approximately 98% of mutations in the CFTR gene.

1. Based on the data of the national register of CF patients on DNA diagnostics of the CFTR gene, the characteristics of the nature and frequency of mutations in the regions of the country were established. On the basis of the register data, it is recommended to create regional recommendations for the identification of mutations with reference to the register ( latest version).
2. Absence of mutations without sequencing is not enough to exclude CF.
3. Several CFTR mutations (3849 + 10 kb C> T) are associated with normal or marginal sweat test results.
4. "Soft" mutations are characterized by a late onset of the disease, the borderline value of sweat samples, and are more often detected during sequencing.
5. Patients with borderline sweat test results (chlorides 30-60 mmol / l and / or conductivity 50-80 mmol / l), a single gene mutation present real difficulties for diagnosis.

To diagnose CF or exclude it with borderline test results, it is necessary:

the use of several methods for the determination of sweat chlorides;

advanced DNA analysis (gene sequencing);

clinical laboratory and instrumental examination: scatology and fecal elastase 1, sputum culture / smear from the posterior pharyngeal wall, consultation with an ENT doctor and andrologist, radiography chest, sinuses;

observation in the center of cystic fibrosis until the final decision is made.

In European countries, to confirm the defect of ion transport, the method of determining the difference in nasal potentials or the measurement of electric current in a biopsy specimen of the intestine is used, reflecting the dysfunction of the chlorine channel. Both methods are based on the electrical nature of ion transport and are highly informative for CF diagnostics.

Diagnosis of pancreatic insufficiency includes:

scatology (neutral fat);

fecal elastase 1 feces, followed by dynamic control once a year, regardless of the result;

fecal lipid profile;

Ultrasound of the pancreas;

DNA diagnostics of CFTR mutations.

In CF patients, the elastase index may decrease during the first years of life, therefore, it is determined over time. A low level of pancreatic elastase is one of the hallmarks of CF. Approximately 1% of CF patients have a borderline sweat test result in combination with intact pancreatic function and chronic bronchitis.

Diagnostics of the chronic bronchopulmonary process:

CT diagnostics (age in European consensus - 7 years and earlier according to indications, in some countries - from 3-4 years);

early X-ray examination (at birth and then once a year);

lung function - spirography (FEV1) (once every 3 months);

the regularity of sputum microflora testing (once every 3 months) and antibiotic sensitivity;

genotyping of microorganisms, PCR diagnostics;

indications for examination and the use of special media and methods for certain types of microorganisms (B. cepacia, NTMB, tuberculosis, aspergillosis, pulmonary candidiasis with reference to Russian and foreign consensus and recommendations).

As additional diagnostic markers can be used azoospermia in post-pubertal age, identification of CF-associated pathogens from the respiratory tract, radiological signs sinusitis.

Knowledge of the main symptoms of CF and the characteristics of its course at different age periods allows one to promptly suspect the presence of the disease and refer the patient for further examination. Frequent cases of late diagnosis of CF are associated both with the lack of sufficient knowledge of the disease among doctors and with the phenotypic diversity of its forms. The limited possibilities of DNA diagnosis of CF in Russia and its low availability complicate and delay the final verification of the disease.

LITERATURE

1. Cystic fibrosis. Ed. N.I. Kapranova, N.Yu. Kashirskaya. M .: ID "MEDPRACTICA-M", 2014, 672 p. ISBN 978-5-98803-314-1
2. Welsh M.J., Ramsey B.W., Accurso F.J., Cutting G.R. Cystic fibrosis. In: Scriver C.R., Beaudet A.L., Sly W.S., Valle D., eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, 2001: 5121-88.
3. European cystic fibrosis society standards of care working group. Best practice guidelines. Edited by Alan R. Smith and Scott Bell, 2014.
4. Farell P.M., Rosenstein B.J., White T.B. et al. Cystic fibrosis foundation. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report // J. Pediatr., 2008; 153 (2): S4-S14.
5. Krasovsky S.A., Kashirskaya N.Yu., Usacheva M.V., Amelina E.L., Chernyak A.V., Naumenko Zh.K. Influence of the age of diagnosis and initiation of specific therapy on the main clinical and laboratory manifestations of the disease in patients with cystic fibrosis // Questions of modern pediatrics, 2014, vol. 13, no. 2, p. 36-43.
6. de Boeck K., Wilschanski M., Castellani C. et al. Cystic fibrosis: terminology and diagnostic algorithms. Thorax, 2006; 61: 627-635.
7.de Oronzo M.A. Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome? // J. Prenat. Med., 2011 Jan-Mar; 5 (1): 9-13.
8. Bombieri C. et al. Recommendations for the classification of diseases as CFTR-related disorders // Journal of Cystic Fibrosis, 2011, vol. 10, suppl. 2; S86-S102.
9. Hall E., Lapworth R. Use of sweat conductivity measurements. Annals of Clinical Biochemistry, 2010; 47: 390-392.
10. Sands D., Oltarzewski M., Nowakowska A., Zybert K. Bilateral sweat tests with two different methods as a part of cystic fibrosis newborn screening (CF NBS) protocol and additional quality control. Folia Histochem Cystobiol., 2010 Sep 30; 48 (3): 358-65.
11. Sezer R.G., Aydemir G., Akcan A.B. et al. Nanoduct sweat conductivity measurements in 2664 patients: relationship to age, arterial blood gas, serum electrolyte profiles and clinical diagnosis // J. Clin. Med. Res., 2013 Feb; 5 (1): 34-41.
12. Petrova N.V. Molecular genetic and clinical genotypic features of cystic fibrosis in Russian populations. Abstract of thesis. diss. doct. biol. sciences. M., 2009, 42 p.
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14. Servidoni M.F., Sousa M., Vinagre A.M. et al. Rectal forceps biopsy procedure in cystic fibrosis: technical aspects and patients perspective for clinical trials feasibility. BMC Gastroenterol., 2013 May 20; 13 (1): 91.

Genetic damage to the exocrine glands occurs with cystic fibrosis. it dangerous pathology, at which the life expectancy is very short. Currently, this period has increased to 40 years with positive dynamics in the process of maintenance therapy. The basis for a favorable prognosis is a timely and reliable analysis of cystic fibrosis, which includes a number of complex examinations and tests.

More information about cystic fibrosis is

When is the diagnosis carried out

The disease occurs in an autosomal recessive mode of inheritance, occurs in a ratio of 1 to 25 (one sick infant out of 2500 children). In cystic fibrosis, the transfer of ionic protein compounds through epithelial cells is impaired, due to which the viscosity of the secretion increases in the exocrine glands. More than 2000 types of gene mutations have been identified, in which there is a difficulty in the outflow and evacuation of mucus.

As a result, the patient has complications - the excretory ducts expand, tissues atrophy, and fibrosis develops. The function of the intestines and pancreas decreases, and respiratory failure occurs. Sclerotic formations are formed in the organs, the ciliary layer is destroyed in the bronchi. Often the subsequent manifestations are atelectasis and emphysema.

With a constant accumulation of secretions, favorable conditions are created for the development and reproduction of bacterial colonies. Destruction is aggravated by exposure to pathogens. The walls of the organs are thickened, cysts develops in the ducts. The liver suffers from protein and fat deficiency, with further complications, the infection enters the bloodstream, resulting in the appearance of lymphocytic infiltrates.

The diagnosis in children under one year old is made on the basis of one of the following criteria:

Poor newborn weight gain with normal appetite
Chronic diarrhea or constipation with increased body fat and a characteristic fetid odor
Salty-tasting skin
Bowel obstruction due to accumulation of meconium masses
The presence of pancreatitis
Abnormal bloating
Wheezing, wheezing, and coughing without sputum discharge
Prolonged manifestation of jaundice in newborns
Malabsorption
Rectal prolapse
Intoxication
Vascular pattern on the abdomen
Heat.

In young children, the development of bronchiectasis, the formation of nasal polyps, sinusitis can be observed. In adolescents, extensive damage to the respiratory system is diagnosed, up to pneumothorax and bleeding. Diabetes, distal obstruction, cirrhotic manifestations are often connected. Men suffer from infertility. In the future, deformation of the fingertips occurs - the phalanges thicken.

Diagnostic techniques

If the family previously had cases of cystic fibrosis in one of the children or both parents are carriers of the mutated gene, a special test is performed for early stage pregnancy. It allows you to identify the defective gene even during intrauterine development.

Invasive diagnostics

There are several methods for obtaining fetal tissues and cells for research. The collection is performed if there is a suspicion of genetic abnormalities at the chromosomal level. Tests are divided into the following types:

Chorinobiopsy

Chorionic villus sampling to detect hereditary pathologies. Before diagnosis, it is necessary to undergo an ultrasound examination to clarify the duration of pregnancy. The procedure is performed for a period of 10-12 weeks. In addition, the doctor finds out data on the child's heartbeat, chorin localization, length and norm of the cervical canal.

The operating area undergoes standard processing. The test is performed without anesthesia.

To obtain optimal information, two types of access are chosen. The first is the transabdominal technique, which involves using a special adapter. This allows you to control the trajectory of the tool and the depth of its entry. Application of a single needle 0.2 mm in diameter is positioned along the chorionic membrane. The two-needle technique is more advanced, since the test is carried out with a guidewire and an intra-biopsy device.

If the chorion is localized on the posterior wall of the uterus and access to it is difficult, a transcervical method is required. During the procedure, a catheter with a flexible guide is used, which allows you to safely expand the walls. After the introduction nutrient medium material is being collected. For reliable results, about 5 g of chorinic villi are required. If the attempt fails the first time, repeat the test. The threat of termination of pregnancy may increase after the third procedure.

Every fourth patient may experience complications. Spotting is sometimes observed. Normally, they stop on their own after a few days. The increase in the level of phytoprotein compounds in the blood is insignificant, the indicator is restored by 16-18 weeks of pregnancy. The risk of developing infectious lesions is minimal, accounting for about 0.3% of cases.

Cytogenetic biopsy

Another examination method that allows you to find out the state of the organ that ensures the life of the unborn child. During placentocentesis, tissue is taken for a sample. The particle is processed in special conditions reagents to obtain information about the chromosome set. The test is carried out in the second trimester of pregnancy, manipulations last several minutes, pain at the same time are absent.

An ultrasound sensor is applied to the abdomen to read information. A thin needle is inserted into the uterine cavity. After removing the tissue, it is taken out. The risk of termination of pregnancy is negligible.

With the same manipulations, it is possible to conduct a test to determine the state of the amniotic fluid. For amnioreduction, an adapter is required to control the insertion depth and trajectory of the needle.

Cordocentesis test

The procedure is a method of obtaining blood from the umbilical cord region to identify hereditary pathologies. This examination provides reliable data, while the child does not feel the impact. Manipulations are carried out by puncturing a specific area of the abdomen and taking from 1 to 5 ml of blood. An accurate analysis helps not only to identify cystic fibrosis, but also provides information about metabolism, the chromosomal component. The operation is performed if it is necessary to confirm genetic abnormalities. Prenatal test methods can reduce the risk of pathologies and disabilities in children.

Newborn screening

This is one of the most important early diagnosis methods aimed at increasing the duration and quality of life of patients suffering from muviscidosis. The analysis can be taken even in the hospital, the blood test for neonatal screening is carried out in four stages:

The first is carried out in relation to all newborns, without exception. On days 4-5 or 6-7 (in premature babies), blood is taken. Dried smear for the content of immunoreactive trypsin elements. Normally, the indicator is 70 mg / ml.
If the level is increased, repeat the test from 21 to 28 days. In a healthy child, the parameter does not exceed 40 mg / ml. In patients with cystic fibrosis, this value is more than 70 mg / ml. It should be noted that the initial examination may give a negative result, which changes with repeated blood sampling.
The third stage is based on the results of the sweat test. Also carried out in the hospital.
The fourth step is DNA testing, which is required when borderline data are obtained.

If a positive result is obtained, the doctor prescribes immediate therapy. A relationship of trust between a parent and a pediatrician is extremely difficult to build. Therefore, experts try to do everything possible to avoid mistakes when detecting false indicators.

Sweat gland samples

After a twofold increase in the level of trypsnin substances detected during neonatal tests, the following diagnosis is carried out. One of the most reliable and reliable methods is the study of the contents of the sweat glands. The analysis can be taken from children starting from 2 days of age.

The method involves determining the level of sodium and chloride elements in sweat fluid. In patients with cystic fibrosis, the indicator is 3-4 times higher than normal. Since newborns are not yet able to secrete a sufficient amount of secretion, the test must be repeated.

The procedure takes 45-60 minutes. No specific preparation is required, the diagnosis is carried out in the morning, before feeding. The area to be examined is pre-cleaned and dried. The doctor must induce the release of fluid with a drug that is applied to the skin. Next, two gauze swabs are applied to this area, absorbing moisture. One of them is soaked in saline, the second in Pilocarpine. Both pads are connected to electrodes, through which low-frequency pulses are supplied. The sensations are usually painless, the patient can only feel tickling. If the child is restless, it means that the bandages are not applied correctly, there is a burning sensation.

After 10 minutes, the tampons are removed. Redness of the integument is a normal phenomenon that disappears within a few hours. A piece of paper or a test tube is applied to the test site, which the doctor fixes with a plaster or wax, which helps to avoid evaporation. After half an hour, the container with sweat liquid is placed in a sealed vessel.

For the study, it is necessary to find out the mass of the sample obtained, then a test for the level of chloride and sodium substances is already given. The indicator is normal - 40 mmol / l. With a positive result, it is more than 60 units. The conductivity parameter in healthy children is 60-75 mmol / l, in patients - above 80. If no abnormalities are found, but other tests show the presence of cystic fibrosis, the patient is under observation for a year.

Coprogram

The food mixture passes through the entire digestive system and is converted into feces in the intestines. Along the way, nutrients are released and absorbed. By the composition of the stool, one can judge about violations of the functionality of organs. It is not recommended to collect the contents from the diaper; it is better to use a film or oilcloth for these purposes. For constipation, a gas-evacuating tube is used.

Older children are placed in the pot, but it is important that no urine gets into it. For constipation, do not give the child laxatives or put candles. For a few days, it is important to follow a diet - do not introduce foods with a dye into the diet, you need to stop taking drugs and enzymes. It is better to take the analysis obtained during the morning bowel movement.

When examined in the feces, steatorrhea is found, which indicates an impaired secretion of the glands. In healthy children, the elastase index is normal, it is 500 μg / g, with cystic fibrosis this parameter is reduced by 80-90%. The activity of proteolytics is increased.

Examination of the nasal cavity

This is another test for detecting the concentration of chloride and sodium substances in the mucous membranes. It is required when it is necessary to confirm the data of sweat analysis and information about genetic abnormalities. Diagnostics is quite painful, it is rarely carried out. The patient receives sedatives before starting the procedure.

During the procedure, electrodes are inserted into the nasal openings, through which a low-frequency pulse is sent. There is a needle in the child's forearm, which is connected to the equipment. The result is an elucidation of the difference between the perspiration of the mucous membranes and the epidermis. Normally, the indicator varies between 5 and 35 mV, with cystic fibrosis it exceeds 40-90 mV.

Other techniques

Examination of patients implies the use of a number of diagnostic tests:

The X-ray shows the thickening of the bronchial walls, the presence of sclerotic formations and atelectasis. The gaps are blocked, the evacuation of sputum is difficult or impossible, which manifests itself in dark spots in the picture.
Spirometry is performed for patients from 5 years old. Diagnostics allows you to determine the volume and rate of breathing, vital capacity of the lungs. In addition, the body's response to the intake of dilators and the appropriateness of their appointment are being investigated.
Bronchoscopy is an additional technique that involves examination and assessment of the state of the mucous membranes of the respiratory system. Often performed with hemoptysis, it allows you to determine the degree of obstruction. In some cases, it is required for sputum collection.

Forecast and prevention

Scientific research is focused on the possibility of improving the quality of life and its prolongation for patients suffering from cystic fibrosis. New therapy regimens and techniques are being developed surgical intervention... The chance of a favorable forecast increases. But all healing procedures ineffective without full and reliable diagnostics. The earlier the disease is detected, its specificity, course and stage of development, the live longer a patient.

Preventive measures consist only in constant supervision and control of doctors, compliance with all recommendations. It is impossible to predict the development of pathology during pregnancy planning. If the family has had cases of the disease in children, or both parents are carriers of the mutated gene, the risk of cystic fibrosis in the unborn child increases many times.