Congenital hypothyroidism is one of the common pediatric endocrine disorders that cause mental and physical developmental delays in children, and it is also preventable and treatable. Since congenital hypothyroidism may have no specific clinical symptoms or mild symptoms in the neonatal period, group screening of newborns is the main method for early detection of congenital hypothyroidism. Since 1981, screening for congenital hypothyroidism in newborns has been conducted in China, and the national screening coverage rate has exceeded 60%, with an incidence rate of about 1/2050. In order to standardize the diagnosis and treatment of the disease, the Ministry of Health promulgated the Technical Specification for Neonatal Disease Screening (2010 version) in 2010. Based on the framework of this specification, this paper proposes further operational consensus on newborn screening for congenital hypothyroidism, analysis of screening results, diagnosis and management, and follow-up. Definition and etiological classification Congenital hypothyroidism is a congenital disorder caused by insufficient production of thyroid hormones or defects in their receptors. If left untreated after birth, congenital hypothyroidism will lead to growth retardation and mental retardation. The classification of congenital hypothyroidism can be divided into primary and secondary according to the part of the lesion. Primary hypothyroidism is the result of a disease of the thyroid gland itself. It is characterized by elevated blood thyrotropin (TSH) and reduced free thyroid hormone (FT4), with congenital abnormalities of the thyroid gland being the most common cause; secondary hypothyroidism, also known as central hypothyroidism, is characterized by reduced FT4 and normal or decreased TSH, and is less common. There is also a peripheral hypothyroidism, which is caused by defective thyroid hormone receptor function and is relatively rare. Congenital hypothyroidism is divided into persistent hypothyroidism and transient hypothyroidism according to disease regression. Persistent hypothyroidism refers to a persistent deficiency of thyroid hormones that requires lifelong replacement therapy; transient hypothyroidism refers to a temporary lack of thyroid hormone secretion at birth due to various reasons such as the mother or the biological child, and thyroid function can be restored to normal. The etiology and classification of congenital hypothyroidism are detailed in Table 1. In newborn screening and clinical practice, some children with elevated blood TSH and normal FT4 levels are referred to as hyper TSHemia. The clinical course of hyperTSHemia may be a return to normal TSH, persistence of hyperTSHemia, and further elevation of TSH with a decrease in FT4 levels and progression to a hypothyroid state. Clinical manifestations I. Most children with congenital hypothyroidism have no specific clinical symptoms or mild symptoms at birth, but careful history and physical examination can often reveal suspicious clues, such as low fetal movement during maternal pregnancy, overdue delivery, huge babies, and after birth, they may present with heavy jaundice or delayed resolution of jaundice, drowsiness, little crying, low cry, nasal dullness, poor sucking power, skin pattern (poor peripheral blood circulation), bloated face, large anterior and posterior halos, constipation, abdominal distention, umbilical hernia, slow heart rate, and low heart sounds. If central hypothyroidism is combined with other pituitary hormone deficiencies, it may manifest as hypoglycemia, small penis, cryptorchidism and facial midline abnormalities such as cleft lip, cleft palate and optic nerve dysplasia. The main clinical manifestations in infancy and childhood are mental retardation and physical retardation. Children often have severe short stature and may have special facial features (wide eye spacing, collapsed nose, thick lips and large tongue, pale yellow face), rough skin, mucous edema, unresponsiveness, umbilical hernia, abdominal distention, constipation, low heart function and digestive function, anemia, etc. Diagnosis I. Neonatal screening for congenital hypothyroidism has a high incidence and is mostly non-specific in the neonatal period. If treatment is started after the clinical onset, it will affect the intellectual and physical development of the affected children. Therefore, group screening of newborns is necessary for early detection and early diagnosis. The Ministry of Health specifies that the screening method for congenital hypothyroidism in newborns is to take blood from the heel of a full-term newborn within 7 d after 72 h of birth and with adequate breastfeeding, and to determine the TSH value of the dried blood filter by dropping it on a special filter paper sheet. This method can only detect primary hypothyroidism and hyper-TSHemia, but not central hypothyroidism or delayed TSH elevation in children. Some international countries use the method of simultaneous screening of T4+TSH, but the screening cost is high. Due to technical and individual differences, about 5% of children with congenital hypothyroidism cannot be detected by the newborn screening system. Therefore, in cases of negative screening for hypothyroidism, clinicians should still take blood to recheck thyroid function if there are suspicious symptoms. Critically ill newborns or newborns treated with blood transfusions may have false-negative results and should be re-tested if necessary. Low or very low birth weight infants may have delayed elevation of TSH due to delayed establishment of the hypothalamic-pituitary-thyroid axis feedback. To prevent false negative screening in newborns, blood may be retrieved 2-4 weeks after birth or when weight exceeds 2500g to determine TSH and FT4. Confirmatory tests are performed to determine serum FT4 and TSH. The concentration of FT4 is not affected by the level of thyroid binding globulin (TBG). If TSH is increased and FT4 is decreased, the diagnosis is congenital hypothyroidism. If TSH is elevated and FT4 is normal, the diagnosis is hyper TSHemia. If TSH is normal or reduced and FT4 is reduced, the diagnosis is secondary or central hypothyroidism. Other ancillary tests 1. Ultrasound of the thyroid gland: can assess the development of the thyroid gland, but is not as sensitive as ectopic thyroid gland as emitting nuclear imaging, and goiter often indicates impaired thyroid hormone synthesis or iodine deficiency. 2. Thyroid emitting nuclide uptake and imaging: Iodine 123 (I-123) or technetium 99m (Tc99m) is commonly used for thyroid nuclide imaging in newborns due to low reflexivity. Care should be taken not to delay the start of treatment because of this test. Thyroid radionuclide imaging is used to determine the location, size, development and uptake of the thyroid gland. A lack of thyroid uptake combined with ultrasound can identify a thyroid deficiency. A lack of thyroid uptake may also be due to TSHβ gene deficiency or receptor defects, iodine transport disorders, or the presence of maternal TRB-Ab. Combining thyroid ultrasound with serum thyroglobulin and TRB-Ab testing can further analyze and determine the cause of congenital hypothyroidism. If the nuclear scan suggests an enlarged thyroid gland it is necessary to exclude thyroid synthesis disorders, combined with further perchlorate excretion tests to clarify the defects in oxidation and organicization of thyroid iodine. 3. Radiographs: Delayed ossification of the distal femur in the orthopantomogram of the knee in newborns suggests possible intrauterine hypothyroidism. Wrist radiographs in toddlers and children may show marked delay in bone maturation. 4. Thyroglobulin (Tg) measurement: Tg reflects the presence and activity of thyroid tissue and is significantly lower in children with thyroid dysplasia than in normal controls. A lack of iodine uptake in the thyroid gland with elevated Tg suggests the presence of a thyroid gland and requires consideration of TSH receptor mutations, iodine transport disorders, or the presence of maternal TRB-Ab, rather than thyroid dysplasia. 5. Anti-thyroid antibodies: TSH receptor blocking antibodies produced by mothers with autoimmune thyroid disease can affect fetal thyroid development and function through the placenta. 5% of women of gestational age with autoimmune thyroid disease may have thyroglobulin or peroxidase antibodies, but TRB-Ab positivity is rare. TRB-Ab can cause transient hypothyroidism. 6. genetic tests: only performed when there is a family history or other tests suggesting some kind of defective hypothyroidism. only 2% of thyroid dysplasia is reported to be due to mutations in TTF-1, TTF-2, PAX8 and other genes, and the cause is unknown in most children. 7. Other tests: routine blood tests, liver biochemistry, cardiac enzyme profile, and lipids are required for children with delayed diagnosis and treatment; hypothalamic-pituitary partial MRI and other pituitary hormone tests should be done for secondary hypothyroidism. Treatment of either primary or secondary congenital hypothyroidism should be done as soon as the diagnosis is established. For initial newborn screening results showing a TSH value of more than 40 mU/L on dried blood filter paper, along with ultrasound showing thyroid agenesis or hypoplasia, or with clinical signs and symptoms of congenital hypothyroidism, levothyroxine sodium (L-T4 therapy) may be started immediately without waiting for venous blood test results. Screening-positive newborns who do not meet the above criteria should wait for the results of venous blood tests before deciding whether to give treatment. L-T4 is the treatment of choice. The initial treatment dose for congenital hypothyroidism in the neonatal period is 10-15ug/(kg*d) given orally once daily to normalize FT4 and TSH as soon as possible, preferably within two weeks of treatment for FT4 and within four weeks of treatment for TSH. For children with severe congenital heart disease, the initial treatment dose should be reduced. Blood is drawn and retested 2 weeks after treatment, and the treatment dose is adjusted according to blood FT4 and TSH concentrations. At subsequent follow-up, the thyroid hormone maintenance dose needs to be individualized. The dose of L-T4 treatment should be adjusted according to the venous blood FT4 and TSH values, usually 5-10ug/(kg*d) in infancy, 5-6ug/(kg*d) in 1-5 years old, 4-5 ug/(kg*d) in 5-12 years old, and premature closure of cranial suture and hyperthyroidism in children with overdose. Children with overdose may have premature craniosynostosis and hyperthyroidism, such as irritability and excessive sweating, etc. The dosage should be reduced promptly and rechecked after 4 weeks. For small infants, L-T4 tablets should be crushed and taken in a spoon with a little water or milk, not in a bottle. For hyper TSHemia with TSH greater than 10mU/L and normal FT4, treatment should be given to those whose TSH remains elevated after review. The starting therapeutic dose of L-T4 can be reduced as appropriate and adjusted according to TSH levels after 4 weeks. The management plan for infants with TSH consistently maintained at 6 to 10 mU/L is still controversial. TSH can be physiologically elevated during the first months of life. Infants with this condition need to be closely followed for thyroid function. For those with normal FT4 and TSH measurements and reduced total T4, treatment is generally not required. It is most often seen in TBG deficiency, premature infants, or when the newborn has an infection. In young and older children with hypothalamic-pituitary hypothyroidism, L-T4 therapy needs to be started at low doses. If adrenal glucocortical insufficiency is present, physiologically required corticosteroids should be administered to prevent sudden adrenocortical failure. If other endocrine hormone deficiencies are found, replacement therapy should be given accordingly. Regular follow-up is required to review the blood FT4 and TSH concentrations in order to adjust the dose of L-T4 therapy. The first recheck is performed 2 weeks after treatment. If there is any abnormality, adjust the L-T4 dose to review 1 month. review every 2-3 months within 1 year of age, 3-4 months above 1 year of age, 6 months above 3 years of age, and after dose change should be reviewed after 1 month, and physical developmental assessment should be performed at the same time. Some children with hyper-TSHemia can be found to have increased FT4 during follow-up, and the dose of L-T4 taken needs to be gradually reduced until it is discontinued for observation. Children with congenital hypothyroidism with abnormal thyroid development need lifelong treatment. Other children may try to stop taking the drug for 1 month after 2 to 3 years of regular treatment and have their thyroid function, thyroid ultrasound or thyroid radionuclide imaging reviewed. Children on higher doses of treatment can be checked by halving the dose and rechecking after 1 month if they stop the medication. If TSH is increased or if FT4 is decreased, lifelong thyroid treatment should be given. If the thyroid function is normal for temporary hypothyroidism, continue to discontinue the medication and follow up regularly for more than 1 year, noting that TSH will rise again in some children. The prognosis is that factors such as early or late initiation of treatment, initial dose of L-T4 and compliance with maintenance therapy up to 3 years of age are closely related to the final intelligence level of the child. Newborn screened children should start treatment as early as possible to correct the hypothyroid state in time to avoid central nervous system damage. Most children with congenital hypothyroidism have near normal neurological and intellectual development if treatment is started within 2 weeks of birth. Most children with hypothyroidism detected by neonatal screening have a good prognosis after early treatment. The physical development of children with late detection and treatment may gradually catch up with children of the same age, but the neurological and mental developmental delays are irreversible. In children with severe congenital hypothyroidism, neurological sequelae may still occur even in those treated early. Some of those with delayed treatment may have varying degrees of deficits in listening, speaking, manipulation, and cognitive responses, even if their mental development is not significantly delayed.