Congenital hypothyroidism in children: clinical guidelines

List of Abbreviations

CH — congenital hypothyroidism

HPS – hypothalamo-pituitary system

HP — hypopituitarism

BMI – body mass index

LH — luteinizing hormone

MRI — magnetic resonance imaging

CPP — precocious puberty

RPH - radiopharmaceutical

TG — thyroglobulin

TRH — thyrotropin-releasing hormone

TSH — thyroid-stimulating hormone

FNA – fine-needle aspiration biopsy

US — ultrasound examination

FSH — follicle-stimulating hormone

HR — heart rate

TG — thyroid gland

ECG — electrocardiography

EchoCG — echocardiography

EEG — electroencephalography

SD — standard deviation

SDS — standard deviation score

T₃ — triiodothyronine

T₄ — thyroxine

CNS – central nervous system

IQ – intelligence quotient

WISC - Wechsler Intelligence Scale for Children

Terms and Definitions

Hypothyroxinemia is a deficiency of thyroid hormones.

Neonatal screening is a mass screening of all newborns for hypothyroidism by measuring TSH in capillary blood, which allows for the detection of the majority of cases at the preclinical stage and the timely prescription of replacement therapy

Thyroid dysgenesis is a structural disorder of the thyroid gland associated with a defect in the embryonic development of thyroid tissue, manifested by aplasia, hemiagenesis, hypoplasia, or ectopia (dystopia).

Dyshormonogenesis is a disorder of the production or transport of thyroid hormones resulting from enzymatic defects (iodine transport, peroxidase system, thyroglobulin synthesis, deiodination).

Primary hypothyroidism is a clinical syndrome developing as a result of inadequate production of thyroid hormones due to primary pathology within the thyroid gland itself.

Secondary hypothyroidism is a clinical syndrome developing as a result of inadequate TSH production in the absence of primary pathology of the thyroid gland itself leading to a decrease in its function.

Transient hypothyroidism is a state of temporary hypothyroxinemia accompanied by elevated TSH.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital hypothyroidism (CH) is one of the most common congenital thyroid disorders in children, based on complete or partial deficiency of thyroid hormones, leading to delayed development of all organs and systems of the body in the absence of timely initiated treatment [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

CH is a group of diseases heterogeneous in etiology, caused by pathology of the thyroid gland, the hypothalamo-pituitary system, or the peripheral action of thyroid hormones.

Hypothyroxinemia leads to the development of metabolic disorders, a decrease in the rate of oxidative processes and enzyme system activity, an increase in transmembrane cell permeability, and the accumulation of underoxidized metabolic products in tissues. Thyroid hormone deficiency severely disrupts the processes of growth and differentiation of all tissues and systems of the body.

The central nervous system suffers more than others from thyroid hormone deficiency in a child. Low levels of thyroid hormones, especially in the first months of life, lead to delayed myelination of nerve fibers, reduced accumulation of lipids and glycoproteins in nervous tissue, which ultimately causes morphofunctional disorders in the membranes of brain conduction pathway neurons.

The irreversibility of CNS damage in congenital hypothyroidism in the absence of treatment is associated with the growth and maturation features of the newborn's brain.

During the period of maximum growth and active neurogenesis, which occurs in the first 6 months of a child's life, the brain is particularly sensitive to adverse influences, including thyroxine deficiency. Therefore, thyroid deficiency during the critical period of fastest CNS development delays its maturation, leading to irreversible intellectual disability [2,3,4,5,6].

1.3 Epidemiology of the Disease or Condition

The incidence of congenital primary hypothyroidism ranges from 1:3000–4000 newborns in Europe and North America to 1:6000–7000 newborns in Japan. In individuals of Negroid descent, the disease is quite rare (approximately 1:30,000), whereas in Hispanics, by contrast, it is frequent (1:2000). The disease is 2–2.5 times more common in girls than in boys. The prevalence of CH in the Russian Federation according to neonatal screening results is 1 case per 3600 newborns (1997–2015) [7-9].

1.4 Features of Coding the Disease or Condition

E03.0

Congenital hypothyroidism with diffuse goiter. Congenital parenchymatous goiter (non-toxic).

E03.1

Congenital hypothyroidism without goiter. Thyroid aplasia (with myxedema). Congenital thyroid atrophy.

E07.1

Dyshormonal goiter. Familial dyshormonal goiter. Pendred syndrome.

E07.8

Other specified disorders of the thyroid gland. Thyroxine-binding globulin defect. Thyroid hemorrhage. Thyroid infarction. Euthyroid sick syndrome.

ICD-11: 5A00.0

ORPHAcode: ORPHA: 442

1.5 Classification of the disease or condition

Below is the combined classification of CH, based on the level of lesion, severity, and degree of disease compensation [10].

I. By etiology.

1. Primary hypothyroidism.

A. Thyroid dysgenesis.

- Agenesis (aplasia);

- Hypoplasia;

- Dystopia (ectopia);

- Hemiagenesis;

- Thyroid dysgenesis associated with mutations in genes NKX2-1, FOXE1, PAX-8, JAG1 and others.

B. Dyshormonogenesis.

- Iodine transport defect (SLC5A5, SLC26A4 gene mutations);

- Peroxidase system defect (DUOX2, DUOXA2, TPO gene mutations);

- Thyroglobulin synthesis defect (TG gene mutation);

- Deiodination defect (IYD gene mutation);

2. Central hypothyroidism (secondary, tertiary hypothyroidism).

- Hypothyroidism caused by a deficiency of transcription factors involved in pituitary development or function (HESX1, LH3, LH4, Pit1, PROP1 gene mutations);

- Isolated TSH deficiency (mutations in the gene encoding the TSH $\alpha$-subunit);

- TRH deficiency (isolated, pituitary stalk interruption syndrome, hypothalamic damage);

- TRH resistance (TRH receptor gene mutations);

3. Peripheral resistance to thyroid hormones.

- Resistance to thyroid hormones (THRA and THRB gene mutations);

- Impaired thyroid hormone transport (MCT8 gene mutation);

- TSH receptor gene defect (TSHR gene mutation);

- Pseudohypoparathyroidism type 1a (GNAS gene mutation);

4. Syndromic forms of hypothyroidism.

- Pendred syndrome (hypothyroidism, deafness, goiter) – SLC26A4 gene mutation;

- Bamforth-Lazarus syndrome (hypothyroidism, cleft soft palate, spiked hair) – FOXE1 (TTF2) gene mutations;

- Kocher-Debré-Semelaigne syndrome (muscular pseudohypertrophy, hypothyroidism);

- Ectodermal dysplasia, hypohidrosis, hypothyroidism, ciliary dyskinesia;

- Choreoathetosis, hypothyroidism, respiratory distress syndrome – NKX2-1 (TTF1) gene mutations;

- Obesity, colitis, hypothyroidism, myocardial hypertrophy, intellectual disability;

- Neonatal diabetes mellitus, congenital hypothyroidism, congenital glaucoma, hepatic fibrosis – GLIS3 gene mutations.

5. Transient hypothyroidism.

- Maternal intake of antithyroid drugs;

- Transplacental transfer of TSH receptor-blocking antibodies;

- Iodine deficiency or excess in the mother or newborn;

- Homozygous / compound heterozygous DUOX2 gene mutations;

- Heterozygous DUOXA2 gene mutations;

- Congenital hepatic hemangioma or hemangioendothelioma.

The prevalence of various forms and possible molecular genetic defects is presented in Appendix A3.

II. By severity.

· latent (subclinical) — elevated TSH levels with normal free T₄ levels;

· manifest — TSH hypersecretion with reduced free T₄ levels, presence of clinical manifestations;

· complicated, which may present with cretinism, heart failure, serous cavity effusion, secondary pituitary adenoma.

III. By degree of compensation.

· Compensated;

· Decompensated.

Complicated hypothyroidism (typically unrecognized, neglected cases of the disease) without timely prescribed and properly selected replacement pharmacotherapy can lead to the development of hypothyroid (myxedematous) coma.

In the vast majority of cases (85–90%), primary congenital hypothyroidism occurs. Among primary hypothyroidism, 85% of cases are sporadic, and the majority of these are due to thyroid dysgenesis (embryopathy). According to various authors, thyroid agenesis occurs in 22–42% of cases, thyroid tissue is ectopic in 35–42%, and thyroid hypoplasia is present in 24–36% [11–13].

Secondary or tertiary congenital hypothyroidism, manifesting as isolated TSH deficiency or hypopituitarism, is much rarer (5–10%) [14].

A special form of CH is transient neonatal hypothyroidism. This form of the disease is most frequently observed in iodine-deficient regions. Transient hypothyroidism may also result from immaturity of the iodine organification system, especially in premature, immature newborns. Transient hypothyroidism in a newborn can be caused by the mother's intake of antithyroid and other drugs during pregnancy that disrupt thyroid hormone synthesis by the fetal thyroid gland. Transplacental transfer of maternal TSH receptor-blocking antibodies has been described [2].

With the development of molecular genetic analysis methods, views on the etiology of congenital hypothyroidism have changed significantly in recent years. To date, a number of genes have been identified whose mutations lead to disruptions in thyroid formation, migration, and differentiation, defects in thyroid hormone synthesis, and hypothalamic-pituitary axis abnormalities. The absence of specific symptoms characteristic of a particular genetic defect does not allow for isolated single-gene diagnostics to identify the mutation. The variants of thyroid dysgenesis have been most widely studied, but it has been shown that malformation of this vital organ is associated with gene mutations in only 2% of cases; in the remaining cases, the cause remains unknown. In the structure of hereditary forms of the disease, defects of dyshormonogenesis genes are the predominant causes of CH development, as evidenced by the results of molecular genetic analyses (detailed information on gene defects leading to congenital hypothyroidism is presented in Appendix A3) [15–19].

1.6 Clinical presentation of the disease or condition

1.6.1. Clinical manifestations of hypothyroidism.

The clinical manifestations of primary hypothyroidism in the absence of replacement therapy are described by the following main syndromes [1, 2, 20, 21].

1.6.1.1. Metabolic-hypothermic syndrome:

· constant feeling of chilliness;

· lowered body temperature;

· moderate weight gain (due to decreased lipolysis and water retention).

1.6.1.2. Trophic disorders of the skin and its appendages.

The development of this syndrome is associated with impaired glycosaminoglycan metabolism under conditions of thyroid hormone deficiency, resulting in increased tissue hydrophilicity.

Characteristic features:

· myxedematous firm edema of the face and extremities;

· large lips and tongue with dental impressions on the lateral margins;

· "facies senilis" with coarsened facial features;

· thick, dry, cold, pale skin with a yellowish tint that cannot be gathered into folds; peeling on the elbows;

· slowly growing, dull, brittle hair, increased hair loss on the head, eyebrows, and extremities, up to the development of total alopecia;

· thin nails with longitudinal or transverse ridging.

1.6.1.3. Disorders of the nervous system and sensory organs.

The development of this syndrome is associated with the suppression of higher nervous activity and unconditioned reflexes under conditions of thyroid hormone deficiency. Characteristic features:

· lethargy;

· somnolence;

· memory impairment;

· hypomimia.

Symptoms of peripheral nervous system damage include:

· paresthesias;

· sluggish tendon reflexes.

Sensory organ dysfunction:

· hearing loss (edema of the auditory tubes and middle ear);

· olfactory impairment (due to swelling of the nasal mucosa);

· nasal congestion;

· lowering of pitch and coarsening of the voice (due to edema and thickening of the vocal cords).

1.6.1.4. Cardiovascular system involvement.

Cardiovascular changes in hypothyroidism are associated with a decreased effect of thyroid hormones and catecholamines on the heart, as well as the development of dystrophic changes in the myocardium.

Characteristic features:

· bradycardia;

· muffled heart sounds;

· low blood pressure;

· decreased pulse pressure.

On ECG:

· sinus bradycardia;

· low QRS voltage;

· ST-segment depression;

· flattened, biphasic, or inverted T wave.

Arrhythmias in hypothyroidism are very rare, but may occur during thyroid hormone replacement therapy.

On Echocardiography:

· decreased left ventricular systolic and diastolic function;

· reduced myocardial contractility (ejection fraction);

· decreased cardiac output;

· decreased stroke volume.

1.6.1.5. Gastrointestinal changes.

Characteristic features:

· constipation;

· biliary dyskinesia;

· decreased appetite.

1.6.1.6. Hematopoietic disorders (anemic syndrome).

Hematopoietic disorders should be considered one of the characteristic manifestations of hypothyroidism.

The following are observed:

· iron-deficiency anemia;

· vitamin B₁₂-deficiency anemia (rare).

Platelet function disorders are characteristic:

· decreased platelet adhesion and aggregation;

· normal platelet count.

1.6.1.7. Renal function impairment:

· decreased renal blood flow (frequent);

· decreased glomerular filtration rate;

· appearance of mild proteinuria (possible).

1.6.1.8. Reproductive system dysfunction.

In long-standing decompensated hypothyroidism, delayed puberty is noted.

In girls:

· menstrual irregularities such as oligomenorrhea, opsomenorrhea, or amenorrhea are possible;

· anovulatory cycles.

In most cases, these disorders are combined with galactorrhea and are caused by elevated prolactin levels (hyperprolactinemic hypogonadism syndrome, or persistent galactorrhea-amenorrhea syndrome). The presence of this syndrome in patients with primary hypothyroidism is known as Van Wyk—Grumbach—Rosssyndrome. Hyperprolactinemia leads to disruptions in the cyclic release of LH and gonadotropin reception in the gonads. Long-standing hyperprolactinemia contributes to the development of secondary polycystic ovary syndrome.

Van Wyk—Grumbach syndrome (J. Van Wyk and M. Grubach) is a variant of precocious puberty in children with primary decompensated hypothyroidism [1,2].

Signs of precocious puberty in girls are:

· breast development, sometimes with galactorrhea, and menarche;

· high TSH and prolactin levels;

· moderately elevated LH and FSH concentrations;

· ultrasound signs of cystic ovaries.

In boys, this syndrome is characterized by:

· macroorchidism in the absence or mild manifestation of androgenization symptoms;

· significantly elevated concentrations of TSH, prolactin, and gonadotropic hormones;

· prepubertal testosterone levels (as a rule) [1,2].

1.6.1.9. Musculoskeletal system involvement.

Marked (2-3-fold) slowing of bone remodeling processes:

· suppression of bone resorption;

· suppression of bone formation;

· delayed bone tissue differentiation.

Hypothyroidism can lead to the development of myopathies, presenting with either muscle hypertrophy or atrophy.

1.6.2. Clinical features of congenital primary hypothyroidism at different ages.

Clinical manifestations and course of hypothyroidism vary significantly across different age groups [1,2,20,21]. In childhood, they depend on the period of disease onset, duration of the hypothyroidism syndrome, and the timing of initiation of replacement therapy. In the first month of a child's life, when early diagnosis is crucial, the typical clinical picture of congenital hypothyroidism is observed in only 10–15% of cases.

1.6.2.1. Symptoms of primary congenital hypothyroidism in newborns and infants.

Congenital hypothyroidism in newborns manifests with the following symptoms:

· edematous face, lips, eyelids, half-open mouth with a wide, "flattened" tongue;

· localized edema in the form of dense "pads" in the supraclavicular fossae, dorsum of the hands and feet;

· signs of immaturity despite full-term pregnancy;

· low, coarse voice when crying or screaming;

· delayed passage of meconium;

· delayed detachment of the umbilical cord,

· poor epithelialization of the umbilical wound;

· prolonged jaundice.

Children are often born from a post-term pregnancy (more than 40 weeks) with a high birth weight (more than 3500 g).

1.6.2.2. Clinical picture of primary congenital hypothyroidism in infants and young children.

In older children (after 5–6 months), the clinical manifestations of hypothyroidism are similar to those in adults. In addition, in the absence of treatment in children with congenital hypothyroidism, progressive delay in psychomotor, physical, and subsequently sexual development comes to the forefront.

Delayed motor development:

· children are lethargic, can lie quietly for hours without showing distress when hungry;

· show no interest in toys;

· late in sitting and walking.

Skin:

· dry, yellowish, flaky due to decreased secretion of sweat and sebaceous glands, mottled ("marbled") pattern, cold to the touch;

· dry, brittle, lusterless hair with increased hair loss. Seborrhea of the scalp, forehead, and eyelids is characteristic;

· brittle nails with cracks;

· slow hair and nail growth.

A complex of respiratory symptoms is characteristic:

· difficult nasal breathing;

· stridor;

· cyanosis of the nasolabial triangle;

· low, coarse voice;

· frequent colds.

Pronounced:

· adynamia;

· muscle hypotonia: protruding abdomen with an umbilical hernia, diastasis of the rectus abdominis muscles;

· posture with lumbar lordosis, protruding buttocks, and semi-flexed knees;

· frequent constipation, flatulence.

Characteristic features:

· postnatal growth retardation;

· progressive deceleration of growth rate (growth rate more than 1 SD below the mean (at chronological age > 1 year) for the corresponding chronological age and sex);

· pronounced short stature (height below the 3rd percentile or below 2 standard deviations (< -2.0 SDS) from the population mean for the corresponding chronological age and sex);

· body proportions close to chondrodysplastic ("upper/lower segment" ratio greater than normal values).

Characteristic features:

· underdevelopment of facial bones with satisfactory cranial bone growth;

· broad, depressed nasal bridge;

· hypertelorism;

· delayed closure of the anterior and posterior fontanelles;

· delayed tooth eruption and delayed shedding.

Characteristic features:

· muffled heart sounds;

· bradycardia;

· functional murmur;

· enlarged heart borders;

· decreased blood pressure and pulse pressure;

· delayed puberty [1].

1.6.3. Transient neonatal hypothyroidism.

Transient neonatal hypothyroidism is a condition of temporary (transient) hypothyroxinemia accompanied by elevated blood TSH levels. The transient elevation of TSH levels is in most cases associated with functional immaturity of the hypothalamic-pituitary system in the postnatal period.

This condition most frequently occurs in the following cases:

• in newborns whose mothers experienced iodine deficiency or excess during pregnancy;

• in newborns with low birth weight (<1500 g) and preterm infants (gestational age < 37 weeks);

• in children with intrauterine (and postnatal) growth restriction;

• in children born to mothers with autoimmune thyroid diseases (possible transplacental transfer of TSH receptor-blocking antibodies);

• in children whose mothers received high doses of antithyroid drugs for Graves' disease during pregnancy. Such children typically present with a goiter at birth, which tends to decrease in size as the drugs are eliminated from the child's blood;

• in children with intrauterine viral and bacterial infections.

At the primary screening stage, it is virtually impossible to differentiate between congenital and transient hypothyroidism. Differentiation of these conditions must be performed at stage II of screening, i.e., in outpatient settings, by repeat determination of serum TSH and free T₄ concentrations after discontinuation of replacement therapy.

Maternal iodine deficiency is the most frequent cause of neonatal hypothyroidism in areas with endemic goiter caused by insufficient iodine in water and food [2].

Predictors of transient hypothyroidism:

• initially normal free T₄ level;

• capillary blood TSH less than 30 mIU/L at the screening stage;

• low dose of #levothyroxine sodium** during the first year of life [22].

GCR BLOCE 2Level of recommendation validity B (Level of evidence – 2).

1.6.4. Secondary hypothyroidism.

Secondary hypothyroidism is most commonly a consequence of hypopituitarism (HP); therefore, the presence of other typical symptoms of HP (brain and skull malformations; hypoglycemia; micropenis, cryptorchidism in boys) allows for a suspected correct diagnosis. Secondary hypothyroidism caused by impaired function of the adenohypophysis or hypothalamus (Pit-1, PROP-1 gene mutations) is accompanied by a deficiency not only of TSH, but also of other pituitary trophic hormones. Congenital isolated TSH deficiency is an extremely rare autosomal recessive disorder caused by mutations in the TSH α- and β-subunit genes. [23-28]

Compared to primary hypothyroidism, secondary hypothyroidism is characterized by a milder and more subtle clinical presentation.

In secondary hypothyroidism, total and free T₄ concentrations are decreased, while the TSH level may be moderately elevated, normal, or decreased.

Transient secondary hypothyroidism is more frequently detected in preterm and low-birth-weight neonates. It may be due to immaturity of the hypothalamic-pituitary-thyroid axis or hypopituitarism.

Distinguishing true secondary hypothyroidism from transient secondary hypothyroidism is very difficult. Decreased T₄ and T₃ levels in preterm neonates reflect their adaptation to stress and are not an indication for thyroid hormone replacement therapy. By the first to second month of life, serum T₄ and T₃ levels gradually increase and reach normal values characteristic of term infants of the same age. True thyroid dysfunction in such infants can be detected after normalization of their weight and development [27,28].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria. Laboratory diagnostic tests.

In the Russian Federation, neonatal screening is performed exclusively for congenital primary hypothyroidism.

Criteria for diagnosing congenital primary hypothyroidism:

• TSH level above normal

The main goal of CH screening is the earliest possible detection of all newborns with elevated blood TSH levels. Children with abnormally high TSH levels require further in-depth evaluation for accurate diagnosis of the disease [1,20, 21, 29-35].

Comments. Screening allows the diagnosis to be made in the first days of a child's life before the full clinical picture of the disease develops and, thus, avoids severe consequences of the disease, primarily delayed mental and physical development of the child. Due to the relatively high incidence of hypothyroidism, the subtle nature of its clinical manifestations in the first days and weeks of life, and the serious consequences of late diagnosis, a state system of neonatal screening for congenital hypothyroidism has been introduced in many developed countries worldwide since the mid-1970s. Despite substantial costs, the neonatal screening program is cost-effective. Neonatal screening for CH is a mass screening of all newborns for hypothyroidism by determining TSH in capillary blood, which allows the detection of most cases of the disease at the preclinical stage and the timely initiation of replacement therapy.

Comments.

▪ Stage I — maternity hospital, inpatient facility, pediatric outpatient clinic

▪ Stage II — medical genetic counseling center,

▪ Stage III — pediatric outpatient clinic or medical genetic counseling center.

Stage I (pre-analytical stage) — maternity hospital, inpatient facility, pediatric outpatient clinic.

In all term newborns, the screening blood test (capillary blood from the heel) is taken no later than the second day of life, and in preterm infants on the 7th day of life; drops (6–8 drops) are applied to a special porous filter paper (filter card).

All blood samples are sent to a specialized medical genetic laboratory daily or every 1–2 days.

Stage II (analytical stage) — pediatric outpatient clinic or medical genetic counseling center

The laboratory determines the TSH concentration in dried blood spots.

Mass determination of TSH in capillary blood is used to diagnose CH (e.g., AutoDELFIA Neo-TSH kit, Perkin Elmer, immunofluorometric assay method). Threshold TSH values are determined by the test systems used in each laboratory. The assay is performed within 72 hours after the test card is received in the laboratory.

1. Capillary blood TSH less than 9 mIU/L in a term infant aged 4–14 days of life and less than 11 mIU/L at age under 3 days of life is considered normal

2. Capillary blood TSH above 9 mIU/L in a term infant aged 4–14 days of life and above 11 mIU/L at age under 3 days of life requires re-determination of TSH from the same blood sample; if a similar result is obtained, the healthcare facility is urgently notified for a repeat blood draw (retest) and delivery of the sample to the neonatal screening laboratory to determine the TSH level.

3. Capillary blood TSH from 9.0 (in a term infant aged 4–14 days of life) to 11 mIU/L (in a term infant aged under 3 days of life) up to 40.0 mIU/L: the laboratory re-determines TSH from the same blood sample; if a similar result is obtained, the outpatient clinic is urgently notified, and a venous blood sample is drawn to determine TSH and free T₄ in serum, or retesting (repeat capillary blood draw) is performed.

Interpretation of capillary blood retesting results:

· Capillary blood TSH less than 11 mIU/L (for an infant under 3 days of life), less than 9 mIU/L (from 4 to 14 days of life), and less than 5 mIU/L (older than 14 days of life) - child is healthy;

· Capillary blood TSH greater than 11 mIU/L (for an infant under 3 days of life), greater than 9 mIU/L (from 4 to 14 days of life), and greater than 5 mIU/L (for infants older than 14 days) - confirmatory diagnostics.

Interpretation of venous blood test results (confirmatory diagnostics):

· Serum TSH less than 6 mIU/L, free T₄ within normal limits: child is healthy;

· Serum TSH from 6 to 20 mIU/L with a normal free T₄ level for the corresponding age in a child older than 3 weeks (21 days):

a) performing diagnostic imaging studies of the thyroid gland, or

b) discussing two management options with the family:

1) immediate initiation of levothyroxine sodium therapy followed by retesting of thyroid function (determination of serum TSH and free T₄) at an older age after discontinuation of treatment, or

2) withholding therapy until the results of repeat serum TSH and free T₄ determinations are obtained, which should be performed in 2 weeks.

· Serum TSH less than 20 mIU/L, free T₄ below the normal range for age (less than 10 pmol/L): levothyroxine sodium treatment should be initiated immediately;

· Serum TSH greater than 20 mIU/L, even with normal free T₄ values, levothyroxine sodium therapy is prescribed immediately. 

4. TSH capillary blood greater than 40.0 mIU/L: the laboratory re-tests TSH from the same blood sample; if a similar result is obtained, the outpatient clinic is urgently notified and venous blood is drawn to determine serum TSH and free T₄.Without waiting for the results, levothyroxine sodium replacement therapy is prescribed, if it is impossible to obtain the results on the day of blood sampling. If the obtained results turn out to be within normal limits, the therapy will be discontinued [1,2, 20].

Stage III — pediatric outpatient clinic / medical genetic consultation (center)

At this stage, children with congenital hypothyroidism detected through neonatal screening are monitored dynamically by a pediatric endocrinologist [1,2,20, 36].

2.1 Complaints and Anamnesis

2.1.1. Neonatal period.

Complaints of:

· facial puffiness;

· macroglossia;

· low-pitched voice when crying and screaming;

· prolonged jaundice;

· delayed detachment of the umbilical cord;

· poor epithelialization of the umbilical wound.

History: post-term pregnancy, high birth weight.

2.1.2. 1st year of life.

Complaints of:

· lethargy;

· adynamia;

· absence of restlessness when wet and hungry;

· lack of interest in toys;

· delayed motor development: children are late in sitting and walking;

· constipation;

· dryness and peeling of the skin;

· slow hair and nail growth.

2.1.3. Preschool and early school age.

Complaints of:

· dryness and peeling of the skin;

· "mottled" skin pattern;

· hypothermia;

· dry, brittle, and increased hair loss;

· slow hair and nail growth;

· constipation;

· delayed psychomotor development;

· growth retardation.

2.1.4. Older age.

Complaints of:

· See 2.1.3.

· delayed puberty [1,2,10,20].

2.2 Physical Examination

Congenital hypothyroidism in newborns manifests with the following symptoms:

· high birth weight (> 3500 g);

· puffiness of the face, lips, eyelids, semi-open mouth with a wide, "flattened" tongue;

· localized edema in the form of dense "pads" on the supraclavicular fossae, dorsal surfaces of the hands and feet;

· signs of immaturity despite full-term pregnancy;

· low, rough voice when crying and screaming;

· delayed passage of meconium;

· delayed detachment of the umbilical cord, poor epithelialization of the umbilical wound;

· prolonged jaundice.

Comments.

For the diagnosis of congenital hypothyroidism in newborns, pediatricians, neonatologists, and endocrinologists can use the Apgar score to suspect the disease at an early stage. With a score of more than 5, congenital hypothyroidism should be suspected (Appendix A3, Table 4) [1].

Later, at the age of 3–4 months, the following symptoms appear:

· decreased appetite, swallowing difficulties;

· poor weight gain;

· flatulence, constipation;

· dry, pale, peeling skin;

· hypothermia (cold hands and feet);

· brittle, dry, dull hair;

· muscle hypotonia.

In older children (after 5–6 months), clinical manifestations of hypothyroidism are similar to those in adults.

In the absence of treatment in children with congenital hypothyroidism, progressive delay in psychomotor, physical, and subsequently sexual development comes to the fore.

Children with hypothyroidism are characterized by postnatal growth retardation, progressive deceleration of growth rate (growth velocity more than 1 SD below (at chronological age > 1 year) the velocity for the corresponding chronological age and sex), marked short stature (height below the 3rd percentile or below 2 standard deviations (< –2.0 SDS) from the population mean for the corresponding chronological age and sex). Body proportions in children with hypothyroidism approach chondrodystrophic ones (the upper-to-lower segment ratio is higher than normal values). With significant delay in bone maturation, when assessing body proportion, one must rely on the child's bone age.

Children with congenital hypothyroidism are characterized by underdevelopment of the facial skeleton bones with satisfactory growth of the cranial bones, a wide depressed nasal bridge, hypertelorism, late closure of the large and small fontanelles, delayed tooth eruption, and delayed tooth replacement.

Pubertal delay is noted.

Comments. Examination, measurement of height, weight, and body proportions make it possible to suspect the disease [1].

2.3 Laboratory Diagnostics

2.3.1. Hormonal studies.

· blood levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) should be measured in all patients with congenital hypothyroidism to assess the adequacy of the administered levothyroxine sodium** dose at 2 weeks and 1.5 months after the initiation of treatment;

· blood levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) should be measured in all patients with congenital hypothyroidism to assess the adequacy of the administered levothyroxine sodium** dose during the first year of life at least once every 2–3 months;

· blood levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) should be measured in all patients with congenital hypothyroidism to assess the adequacy of the administered levothyroxine sodium** dose after the first year of life at least twice a year;

· blood levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) should be measured in all patients with congenital hypothyroidism to assess the adequacy of the administered levothyroxine sodium** dose 2 months after each dose adjustment [1,20].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments.

In newborns with compensated primary hypothyroidism against the background of a normal free ₄T concentration, TSH levels may remain elevated due to immaturity of the hypothalamopituitary axis.

In cases of transient primary hypothyroidism, thyroid function normalizes within a few weeks or months after birth, which is detected during repeat TSH and free ₄T tests.

In secondary hypothyroidism, the concentration of free ₄T is decreased, and the TSH level is usually normal, but may be slightly elevated or decreased.

2.3.2. Additional hormonal tests.

Comments.

Thyroglobulin (Tg) concentration is significantly decreased in thyroid aplasia, normal or moderately decreased in its ectopic location, and increased in disorders of ₄T and ₃T synthesis (except for Tg synthesis defects). Determination of Tg in most cases does not allow for a precise establishment of the cause of hypothyroidism, since the Tg level only approximately corresponds to the mass of functioning thyroid tissue.

2.4 Instrumental Diagnostics

2.4.1

Comments.

This study detects: sinus bradycardia; prolonged systole; decreased amplitude of QRS complexes; slowed intraatrial, atrioventricular, and intraventricular conduction.

2.4.2.

Comments.

Radiography of the hands and wrist joints (determination of bone age) reveals delayed appearance of ossification centers and their asymmetry, as well as abnormal sequence of maturation.

Radiography of the knee joints and feet reveals delayed bone maturation (the dominant method for determining delayed bone maturation in newborns and young children in the USA and EU countries). The study reveals the absence of ossification centers (epiphyseal dysgenesis) in the distal femurs, proximal tibias, and cuboid bones.

Determination of bone age is used not only for diagnosis, but also to assess the adequacy of ongoing treatment for congenital hypothyroidism. Knee and foot radiography helps establish the duration of intrauterine hypothyroidism. Hand radiography allows for establishing the duration of postnatal hypothyroidism.

2.4.3. Ultrasound examination of the thyroid and parathyroid glands.

Comments.

For the diagnosis of thyroid ectopia, ultrasound results have low informative value. The diagnostic value of ultrasound in congenital hypothyroidism is increased by using color and power Doppler mapping and evaluating potential sites of ectopia [13,37]. If the ultrasound shows the thyroid gland in its typical location, congenital hypothyroidism may be caused either by defects in T4 and T3 synthesis or by transplacental transfer of maternal thyroid-blocking antibodies.

2.5 Other Procedures

2.5.1. Thyroid scintigraphy (sodium pertechnetate [99mTc])

Comments.

Thyroid scintigraphy can be performed in all children with congenital hypothyroidism, regardless of age, including newborns

If the thyroid gland is not visualized during radioisotope scanning, the diagnosis is unquestionable. This research method (unlike ultrasound) makes it possible to identify dystopically (ectopically) located thyroid tissue. Performing this procedure should not interfere with the timely initiation of treatment with levothyroxine sodium**. It is carried out shortly before the start or within 7 days after the initiation of hormone replacement therapy, or against the background of therapy discontinuation for 2-3 weeks. The use of the radiopharmaceutical diagnostic agent sodium pertechnetate [99mTc] from an extraction generator is justified by the property of thyroid cells to accumulate this radiopharmaceutical diagnostic agent (the observed maximum uptake is from 10 to 30 minutes after administration); sodium pertechnetate [99mTc] is not involved in the synthesis of thyroid hormones since it does not undergo organification. Sodium pertechnetate [99mTc] from an extraction generator has a short half-life (~6 hours) and, accordingly, is eliminated from the body quite quickly. Currently, there is a long-standing experience (since the 1960s) of using sodium pertechnetate [99mTc] in pediatric practice for many nosologies, and its safety has been proven. It has been established that rudimentary thyroid tissue during its dystopia (ectopia) is capable of producing thyroid hormones for a fairly long time, and its functional activity significantly decreases after the age of ten. In these cases, congenital hypothyroidism with late manifestations (late form of congenital hypothyroidism) can be diagnosed. There are various variants of thyroid dystopia (ectopia): at the root of the tongue or along the thyroglossal duct, and the severity of congenital hypothyroidism can vary widely [1,2,10,13, 20,37,38].

2.5.2. Molecular genetic diagnostics.

Comments.

High-throughput parallel sequencing of candidate genes responsible for the development of congenital hypothyroidism (PAX8, NKX2-5, TSHR, JAG1, FOXE1, NKX2-1, TG, DUOX2, DOUXA2, TPO, SLC5A5, IYD, SLC26A4, etc.) may be used.

Molecular genetic testing has been shown to be of high importance for establishing an accurate etiological diagnosis, the results of which can be used in prenatal diagnostics when biallelic mutations are confirmed or when dominant inheritance of the disease is proven (PAX8, NKX 2-1, DUOXA2). The study can help in predicting the risk of congenital hypothyroidism recurrence in a family and identifying associated pathology, including among family members, and in personalizing treatment to prevent goiter formation (in patients with mutations in the TPO, TG, DUOX2, DUOXA2 genes).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Conservative treatment.

Comments.

In children during the first year of life, administration of the drug crushed and diluted with water or breast milk during the morning feeding is considered acceptable.

Comments.

Table 1. Estimated calculated doses of levothyroxine sodium** in children with congenital hypothyroidism.

· free ₄T level within reference ranges (normalizes 1-2 weeks after treatment initiation);

· TSH level within reference ranges (normalizes 3–4 weeks after initiation of treatment);

· physical development parameters within normal ranges (height SDS, height velocity SDS);

· psychomotor development of the child appropriate for age;

· normal bone maturation parameters (bone age matching chronological age) [1,20,21,49]

GRL CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) Level C (Level of Evidence – 5).

Comments.

Transient hypothyroidism may resolve spontaneously upon disappearance of the underlying cause. In doubtful cases, the diagnosis is verified at an age older than 1 year. Levothyroxine sodium** is discontinued for 3–4 weeks, and serum TSH and free T4 levels are determined on a "washout" baseline. If TSH and free T4 levels are within reference ranges, treatment is not resumed; follow-up examinations with determination of serum TSH and free T4 concentrations are performed at 2 weeks, 1 month, and 6 months after discontinuation of treatment. If the diagnosis of congenital hypothyroidism is confirmed, treatment with levothyroxine sodium** is continued with ongoing monitoring of therapy adequacy.

In cases where an elevated TSH level was observed during levothyroxine sodium** therapy (due to an insufficient dose of levothyroxine sodium** or non-compliance with the regimen), interrupting treatment to clarify the diagnosis is not required. In this case, the diagnosis of congenital hypothyroidism is beyond doubt [1, 20, 21].

3.2. Surgical treatment

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments.

Children with congenital hypothyroidism and hearing loss require early audiological and speech therapy support (during the period of speech skill acquisition) and individual pedagogical assistance in case of difficulties with learning, memorization, or mastering new material [20, 51].

No contraindications identified.

5. Prevention and Dispensary Observation

5.1. Dispensary observation and prognosis

Table 2. Clinical follow-up of children with congenital hypothyroidism.

Comment.

The prognosis for neuropsychiatric development in congenital hypothyroidism depends on multiple factors. Researchers worldwide agree that the timing of initiating levothyroxine sodium replacement therapy is undoubtedly the decisive factor for a favorable intellectual development prognosis in a child with congenital hypothyroidism, although some authors note that even with early treatment, a small proportion of children still retain certain intellectual impairments. Treatment adequacy during the first year of life is an extremely crucial factor. Thus, with few exceptions, all children with congenital hypothyroidism who receive early and adequate treatment are able to achieve optimal intellectual development [1, 20, 21].

6. Organization of Medical Care

Comments.

If compensation can be achieved in an outpatient setting, hospitalization is not indicated for the patient.

Indications for discharging the patient from a medical organization are: achievement of the target free thyroxine blood level and successful elective surgical intervention [1, 20, 21].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Valentina A. Peterkova – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Supervisor of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Russian Ministry of Health.

Olga B. Bezlepkina – Doctor of Medical Sciences, Deputy Director of the Center – Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

TEXT AUTHORS:

Elena V. Nagaeva – Doctor of Medical Sciences, Head of the Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Tatiana Yu. Shiryaeva – Candidate of Medical Sciences, Associate Professor, Leading Researcher at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Olga A. Chikulaeva – Candidate of Medical Sciences, Leading Researcher at the Department of Thyroidology, Somatic and Reproductive Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Tatiana A. Vadina – Candidate of Medical Sciences, Pediatric Endocrinologist at the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Ekaterina V. Schröder – Pediatric Endocrinologist at the Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

EXPERTS:

Bashnina Elena Borisovna — Doctor of Medical Sciences, Professor at the Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov, Chief freelance pediatric endocrinologist of the North-Western Federal District.

Belyashova Elena Yurievna — Head of the Medical Genetic Center, Orenburg Regional Clinical Hospital No. 2, Chief freelance specialist in medical genetics in the Volga Federal District.

Bolotova Nina Viktorovna — Doctor of Medical Sciences, Professor at the Department of Propaedeutics of Childhood Diseases, Pediatric Endocrinology, and Diabetology, Saratov State Medical University named after V.I. Razumovsky of the Russian Ministry of Health.

Vasyukova Olga Vladimirovna — Candidate of Medical Sciences, Leading Researcher at the Institute of Pediatric Endocrinology and Head of the Center for Treatment and Prevention of Metabolic Diseases and Obesity, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Galkina Galina Aleksandrovna — Doctor of Medical Sciences, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Rostov Region, Chief freelance pediatric endocrinologist of the Southern Federal District.

Degtyarev Mikhail Vladimirovich — Radiologist, Head of the Radionuclide Diagnostics Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Kiyaev Alexey Vasilievich — Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief freelance pediatric endocrinologist of the Sverdlovsk Region, Chief freelance pediatric endocrinologist of the Ural Federal District.

Konyukhova Marina Borisovna — Pediatric Endocrinologist, Candidate of Medical Sciences, Medical Genetics Department, Morozov City Children's Clinical Hospital of the Moscow Healthcare Department.

Kolodkina Anna Aleksandrovna — Head of the Department of Hereditary Diseases and Early-Onset Endocrinopathies, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Candidate of Medical Sciences.

Kostrova Irina Borisovna — Head of the Pediatric Endocrinology Department, Children's Republican Clinical Hospital named after N.M. Kuraev, Chief freelance pediatric endocrinologist of the Republic of Dagestan, Chief freelance pediatric endocrinologist of the North Caucasian Federal District.

Malievsky Oleg Arturovich, Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Volga Federal District.

Mitkina Valentina Borisovna — Laboratory Geneticist, Medical Genetics Department, Morozov City Children's Clinical Hospital of the Moscow Healthcare Department.

Petryaikina Elena Efimovna — Doctor of Medical Sciences, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of Moscow, Chief freelance pediatric endocrinologist of the Central Federal District.

Samsonova Lyubov Nikolaevna — Doctor of Medical Sciences, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Svetlova Galina Nikolaevna — Deputy Chief Physician, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Pediatric Endocrinologist, Candidate of Medical Sciences.

Taranushenko Tatyana Evgenievna — Doctor of Medical Sciences, Head of the Department of Pediatrics, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of the Krasnoyarsk Territory, Chief freelance pediatric endocrinologist of the Siberian Federal District.

Sheremeta Marina Sergeevna — Candidate of Medical Sciences, Head of the Department of Radionuclide Diagnostics and Therapy, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Associate Professor at the Department of Endocrinology, Institute of Higher and Additional Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Shestopalova Elena Andreevna — Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Chugunov Igor Sergeevich — Head of the Pediatric Endocrine Tumor Department, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Candidate of Medical Sciences

Conflict of interest: the authors of the clinical guidelines declare no conflict of interest.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Pediatrician.

2. Pediatric endocrinologist.

Table 1. Scale for evaluating levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for evaluating levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions).

Table 3. Scale for grading levels of recommendation evidence (LRE) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Table 1. Gene defects leading to congenital hypothyroidism [3, 20, 21].

Table 2. Apgar score for diagnosing congenital hypothyroidism in newborns [1].

A diagnosis of congenital hypothyroidism (CH) is established when the total score exceeds 5.

Table 3. Assessment of intellectual development (IQ) in children and adolescents (Wechsler test, adapted by A.Yu. Panasyuk and revised by Yu.I. Filimonenko).

Comments. For each subtest, the patient receives a specific raw score, which is subsequently converted into a scaled score based on age. The testing determines Full-Scale IQ – an integral indicator that serves as a measure of general intelligence, Verbal IQ – a substructure of general intelligence functioning in a verbal-logical form with a primary reliance on knowledge. Performance IQ – is also a substructure of general intelligence; successful performance on this part of the test is related to the examinee's skills and the specific features of their psychophysical, sensorimotor, and perceptual characteristics [2].

Table 5. Levels of intellectual development.

Appendix B. Physician Action Algorithms

1. Diagnostic algorithm for congenital hypothyroidism (neonatal screening)

2. Diagnostic algorithm for congenital hypothyroidism (confirmatory diagnostics, venous blood)

Appendix C. Patient Information

What is congenital hypothyroidism? Congenital hypothyroidism is a condition in which the thyroid gland produces an insufficient amount of hormones from birth. These hormones are essential for the proper growth and development of the child.

How common is congenital hypothyroidism and how is it detected? Congenital hypothyroidism occurs in 1 out of every 3,000 to 4,000 newborns. The condition is detected through neonatal screening. Blood sampling from the newborn's heel is performed on the 2nd day of life. In premature infants, blood sampling is carried out on the 7th day. If TSH levels are elevated, a repeat evaluation is performed and a decision regarding treatment is made.

What are the causes of congenital hypothyroidism? In most cases, the disease occurs sporadically, and the exact cause is unclear. In rare cases, there is a genetic cause for the condition.

How does congenital hypothyroidism manifest and why is it dangerous? If treatment is not initiated in a timely manner, the child may develop manifestations of hypothyroidism (prolonged neonatal jaundice, delayed umbilical cord healing, constipation, subsequent motor and mental developmental delay, and decreased growth rate). A delayed start of treatment is dangerous due to the risk of intellectual disability.

How is congenital hypothyroidism treated? Upon establishing the diagnosis of CH, levothyroxine sodium is prescribed. This medication is safe and has proven efficacy.

How long does treatment need to be continued? Treatment for CH is lifelong. It is critically necessary for the proper growth and development of the child.

How often do you need to see a doctor? Once treatment is prescribed, the child is under continuous follow-up by a pediatric endocrinologist. Blood hormone levels (TSH, free T4) are monitored regularly as prescribed by the specialist. Additionally, throughout life at various stages, the child needs to be evaluated by specialists: an audiologist, speech therapist, neurologist, psychologist (neuropsychologist), and psychiatrist.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable