| disease | Sporadic Cretinism |
| alias | Cretinism, Sporadic Cretinism |
Sporadic cretinism, or cretinism, is a disease caused by congenital factors leading to reduced thyroid hormone secretion, resulting in slowed growth and development and intellectual disability, and is found in non-goiter endemic areas. Many countries around the world have made neonatal hypothyroidism screening mandatory by law. The incidence varies by country: the United States reported a rate of 1/6,179 in 1987; 12 European countries reported rates ranging from 1/3,000 to 1/7,900 in 1978; Australia reported a rate of 1/4,678 in 1981; Japan reported the same rate of 1/7,900 that year; Shanghai, China, reported a rate of 1/6,873 in 1984; and Tianjin reported a rate of 1/7,900 in 1987.
bubble_chart Etiology
90% of cases are due to thyroid dysplasia or ectopia, while the rest result from congenital enzyme deficiencies leading to insufficient thyroid hormone synthesis, hypothalamic-pituitary hypothyroidism, and transient thyroid dysfunction.
1. Undeveloped, dysplastic, or ectopic thyroid tissue
(1) Maternal exposure to radioactive 131I therapy (contraindicated for pregnant and lactating women). (2) Autoimmune diseases (maternal thyroid disorders cause certain thyroid components to enter the bloodstream, producing antibodies that damage the fetal thyroid). (3) Exposure to toxic substances during fetal development causing developmental defects. (4) Reduced TSH secretion in early fetal stages, leading to thyroid dysplasia. (5) Thyroid tissue remaining at the base of the tongue or ectopically located in front of the larynx, within the thorax, or in the trachea during embryonic development, with lingual ectopic thyroid being the most common.
2. Maternal intake of goitrogenic drugs during pregnancy, such as propylthiouracil, methimazole (Tapazole), and iodides.3. Thyroid hormone synthesis and functional disorders, presenting as familial goiter types, seen in non-endemic goiter regions. There are eight common defects: (1) Impaired iodine uptake or transport by the thyroid; (2) Peroxidase deficiency leading to defective tyrosine iodination; (3) Defective iodotyrosine coupling; (4) Deiodinase deficiency; (5) Production of abnormal iodinated proteins; (6) Thyroid unresponsiveness to TSH; (7) Difficulty in thyroid hormone secretion; (8) Peripheral tissue unresponsiveness to thyroid hormone.
bubble_chart Clinical Manifestations
There are three main characteristics: intellectual disability, delayed growth and development, and low basal metabolic rate.
1. Neonatal and Infant Period Reduced fetal movement, approximately 20% of cases involve intrauterine survival beyond 42 weeks. Birth weight often exceeds the 90th percentile. The anterior fontanelle may be as large as 4×4 cm, and the posterior fontanelle may exceed 0.5×0.5 cm. Body length and head circumference may be normal. Delayed passage of meconium, frequent constipation, drowsiness, poor feeding, prolonged physiological jaundice, hoarse and low-pitched crying, abdominal distension and fullness, lethargy, hypothermia (often below 35°C), mottled, cool, and moist skin, forehead wrinkles resembling an elderly appearance, broad and thick tongue, and mucous edema in the respiratory tract leading to stuffy nose and increased secretions. The face appears puffy, with a low nasal bridge and wide-set eyes. Those with hyperlipidemia may exhibit white sebaceous gland papules on the face. The anterior and posterior hairlines are low, heart rate is slow, and umbilical hernia may be present. Since breast milk contains thyroid hormones, some symptoms may be masked, leading to delayed manifestation.
1. Serum T4 Normal range: 45～130μg/L (4.5～13μg/dl). During the neonatal period, levels <60μg/L (6μg/dl) indicate a decrease, excluding cases where reduced TBG causes low serum T4. Regular monitoring during treatment is necessary.
2. Serum T3 Normal range: 800～200ng/L (80～200ng/dl). In mild hypothyroidism, T3 often remains normal, decreasing only in severe cases. In endemic cretinism, serum T3 may increase. Certain chronic sexually transmitted diseases or liver diseases can reduce serum T3, but rT3 increases while thyroid function remains normal. Therefore, thyroid function should be assessed in conjunction with serum T3 and TSH levels.
3. Serum TSH Normal range: <10mu/L (10μu/ml). In this condition, levels often exceed 20mu/L (20μu/ml). Levels between 10～20mu/L (10～20μu/ml) indicate reduced thyroid reserve function. If both serum TSH and T4 are low, it suggests hypothyroidism secondary to hypothalamic or pituitary dysfunction, requiring a TRH stimulation test for differentiation. During hypothyroidism treatment, TSH should be monitored regularly to adjust the dose.
4. Serum thyroglobulin A negative result indicates the absence of thyroid tissue or abnormal thyroglobulin synthesis. A positive result with low serum T4 and T3, and elevated TSH suggests residual thyroid tissue.
5. 131I uptake In hypothyroidism, the 24-hour 131I uptake is <12% (normal: 45%). A value <2% indicates congenital absence of the thyroid.
6. Others Findings may include low blood glucose, elevated serum cholesterol and triglycerides, increased CPK and LDH levels, and reduced basal metabolic rate.
Typical cretinism can be diagnosed based on clinical manifestations. After treatment, the appearance may change drastically compared to the original state, so pre-treatment photographs should be taken as clinical evidence. Early diagnosis and treatment should be pursued. For atypical cases, laboratory tests and X-ray examinations should be combined, and diagnostic treatment may be necessary for confirmation.
1. Prenatal diagnosis: Measure TSH and rT3 in amniotic fluid, along with maternal blood TSH. If maternal blood TSH is normal but amniotic fluid TSH is elevated and rT3 is decreased, a preliminary diagnosis can be made. rT3 (amniotic fluid) normal values: <20 weeks 330±31 ng/dl; 20–30 weeks 323±91 ng/dl; ~35 weeks 91±3 ng/dl; ~42 weeks 93±5 ng/dl.
2. Newborn screening: Neonatal blood TSH peaks at 20–60 minutes after birth and gradually declines over 1–4 days. Therefore, umbilical bleeding TSH within 30 minutes after birth or heel blood T4 and TSH at 4–7 days should be tested. Filter paper dry blood spot samples can be used, mailed to the testing center for analysis. Positive cases should be rechecked with venous blood for T4, TSH, and, if necessary, blood TBG, FT4I, and RT3U.
Early differentiation should be made from Hirschsprung's disease, malnutrition, and Beckwith-Wiedemann syndrome (macroglossia-omphalocele-visceromegaly-hypoglycemia syndrome). Hirschsprung's disease, though associated with constipation, often involves vomiting, abdominal distension and fullness, visible intestinal loops, large foul-smelling stools, and normal BMR. Barium enema reveals spastic and dilated colon segments, with normal blood T4 and TSH. Malnutrition often includes diarrhea, abdominal distension and fullness, emaciation, hypokalemia, high-pitched crying, and a thin, pointed tongue, with normal blood T4 and TSH. B-W syndrome shows normal serum T4. Differentiation should also be made from transient TSH elevation, transient blood T4 reduction in premature infants, and low T3 syndrome. If necessary, observe or treat for a period and combine with laboratory tests for diagnosis.
3. Diagnosis of atypical cases: For cases with irregular treatment and atypical laboratory or clinical findings, discontinue medication and observe for 3–3 weeks to monitor the reappearance of hypothyroidism symptoms and signs, as well as abnormal lab results. Then resume medication and observe clinical and laboratory improvements for confirmation.
4. Diagnosis of familial thyroid hormone synthesis and dysfunction cretinism.
(1) Iodide uptake defect: Possibly due to a malfunction of the "iodine pump" that transports iodide into cells. Check 24-hour 131I uptake <12%, or saliva iodine/plasma iodine <10 (normal >10).
(2) Iodine organification defect (peroxidase defect): Most common. Iodine is rapidly displaced after perchlorate administration. Method: Measure thyroid radioactive iodine concentration 1.5–2 hours after administering 131I (1 µCi), then give potassium perchlorate (10 mg/kg) and recheck thyroid 131I concentration after 2 hours. A drop >10% is positive. Differentiate from Pendred syndrome (see section on simple goiter diagnosis).
(3) Iodotyrosine coupling defect (conjugation enzyme defect):
Suspect this condition when urinary excretion of 131I exceeds 1% of the oral dose for 5 consecutive days, or when urinary 131I excretion doubles after methimazole-perchlorate administration.
(4) Deiodinase Deficiency Administer 131I-labeled DIT, and measure the chemical properties of radioactive substances in urine after 6 hours. In normal individuals, 90% of the urinary radioactivity is inorganic iodine, whereas in affected children, it is 131I-DIT.
(5) Abnormal Thyroglobulin Metabolism Impaired thyroglobulin synthesis leads to abnormal iodinated proteins in the child's blood. These proteins cannot undergo deiodination and are excreted in large amounts through urine. Increased levels of iodinated histidine in urine should raise suspicion of this condition. Alternatively, plasma chromatography can be used to detect abnormal proteins.
(6) Thyroid Unresponsiveness to TSH A case was reported of a boy born to consanguineous parents, presenting with congenital non-goitrous cretinism. The 131I uptake test was normal, with elevated and biologically active blood TSH levels, but the child's body showed no response to TSH. In vitro metabolic tests on thyroid tissue also demonstrated no response to TSH.
(7) Impaired Thyroid Hormone Secretion A defect in macrophage cytoplasmic proteolytic enzymes prevents the digestion of thyroglobulin and the subsequent release of T3 and T4 into the bloodstream.
(8) Peripheral Tissue Resistance to Thyroid Hormones The defect lies in abnormal nuclear receptors, preventing thyroid hormones from exerting their physiological effects. Clinically, this may manifest as deafness and dumbness, goiter, and thyroid function that is either normal or reduced. TSH levels are normal or slightly elevated, while T3 and T4 levels are also normal or slightly elevated, with normal RT3U. Cases of partial peripheral tissue resistance to thyroid hormones have also been reported.
Conditions 1–7 above are all autosomal recessive, while condition 8 is autosomal dominant.
bubble_chart Treatment Measures
1. General Treatment It is essential to establish confidence and adhere to lifelong treatment without interruption, as discontinuation would nullify previous efforts. Additionally, strengthening guidance and regularly educating the affected child can help improve intellectual development. The diet should be rich in calories, proteins, vitamins, and minerals such as calcium and iron.
2. Drug Therapy
(1) Thyroid Tablets The initial dosage should start small and gradually increase, especially for those with a long-standing condition and low basal metabolic rate, to prevent heart failure. The content of T3 and T4 in desiccated thyroid tablets is unstable, and the amounts vary among different products. Therefore, regular blood tests for T4, TSH, and clinical observation of therapeutic effects are necessary to determine whether the dose is adequate. The general dosage can be referenced in the following table:
Table: Dosage of Thyroid Tablets for Treating Cretinism
| Age | Initial Dose (mg/day) | Maintenance Dose (mg/day) |
| Under 2 months | 5–10 | 10–20 |
| ~6 months | 10–20 | 20–40 |
| ~1 year | 20 | 40–60 |
| ~3 years | 40 | 60–80 |
| ~7 years | 60 | 80–120 |
| ~14 years | 80 | 120–200 (maximum 240) |
Individual needs may vary slightly, and the dose can be gradually increased every 5–7 days. Too small a dose may impair intellectual and physical development, while excessive doses may induce artificial hyperthyroidism, disrupt nitrogen balance, and hinder growth. The optimal dose should maintain normal blood TSH levels and T4 at the upper normal range to allow partial conversion of T4 to T3. Clinical indicators include: normal bowel movements once daily, improved appetite, heart rate maintained at around 110/min for children and 140/min for infants, disappearance of abdominal distension and fullness, and intellectual progress. During long-term medication, the dose should be adjusted with age to meet the body's needs. Side Effects: Overdose may cause diarrhea, palpitations, vomiting, profuse sweating, dysphoria, restlessness, and fever. Long-term excessive use may lead to weight loss, and in rare cases, allergic reactions or frequent premature contractions. In such cases, the dose should be divided into multiple administrations.
For pericardial effusion without symptoms of cardiac tamponade, pericardial puncture is unnecessary, as the effusion may resolve with oral thyroid tablet treatment.
Premature and low-birth-weight infants with transient hypothyroidism should also receive treatment to prevent impaired brain development, with observation continuing until a definitive diagnosis is made.
(2) Triiodothyronine (T3) acts quickly and dissipates rapidly, making it suitable for young infants or cases with thyroid gland compression symptoms. A dose of 20μg is equivalent to 40mg of desiccated thyroid tablets.
(3) Vitamins A, B, C, and D vitamins should be supplemented long-term according to clinical needs, especially for those prone to angular cheilitis, who should be provided with riboflavin. The dose can be determined based on specific circumstances.
(4) Minerals Calcium tablets should also be taken long-term to support growth and development. Those with anemia should additionally take iron supplements.
(5) Iodine In cases of familial goiter with cretinism due to iodine uptake and deiodinase deficiency, iodine should be supplied to compensate for the loss and facilitate hormone synthesis. For those with deiodinase deficiency, goiter may disappear after iodine supplementation.
In the latter half of fetal development and the first six months after birth, the brain cells are in a critical stage of growth. Therefore, if the disease occurs during this period, it can severely affect intelligence. Early diagnosis and treatment are essential, with 90% of those treated within three months after birth achieving normal intelligence. For those who develop the condition after the age of three, intelligence is mostly unaffected. Prognosis is also related to the cause of the disease: in cases of absent thyroid, 41% have an IQ > 85; for those with hormone synthesis disorders, 44% have an IQ > 85; and for those with ectopic thyroid, 78% have an IQ > 85.
It is often necessary to differentiate from the following:
1. Down syndrome: Distinctive facial features, upward slanting of the outer corners of the eyes, epicanthal folds, protruding tongue, fine skin, soft and sparse hair, joint laxity, obvious separation between the big toe and the other toes, shortened middle phalanx of the little finger, incomplete calcification visible on X-ray, often with a simian crease, frequently accompanied by congenital heart disease, karyotype mostly trisomy 21, blood T4 mostly normal.
2. Cerebral hypoplasia: Dull gaze, often with exotropia, normal body proportions, fine skin, no mucous edema, BMR not decreased, blood T4 normal.
3. Pituitary dwarfism: Normal intelligence, normal body proportions, normal facial features, fine skin, rare mucous edema and constipation, decreased growth hormone in blood, low TSH.
4. Chondrodystrophy: Normal intelligence, disproportionate body, short and thick limbs, upper body longer than lower body, characteristic shortening of the diaphysis visible on X-ray of long bones, widened metaphysis with irregular edges, blood T4 normal.
5. Renal rickets: Normal intelligence, signs of rickets, low blood calcium, increased blood phosphorus, rickets-like changes on X-ray of long bones, some cases may show changes in urine and renal function.
6. Mucopolysaccharidosis type I: Intellectual disability, hirsutism, hyperactivity, thick hair, bushy eyebrows and large eyes, flat nasal bridge, broad nasal wings, corneal clouding, hepatosplenomegaly, claw-like hands, X-ray of the skull may show a violin or shoe-shaped sella turcica, chest X-ray may show ribbon-like ribs, pointed distal phalanges and proximal metacarpals, fish or bird beak-like changes in the anterior edges of the 12th thoracic and 1st–2nd lumbar vertebrae. Positive for acidic mucopolysaccharides in urine.
7. Phenylketonuria: Intellectual disability, urine with a musty or mouse-like odor, yellow hair, fair skin, eczema, possible seizures, blood phenylalanine often >1.22 mmol/L (20 mg/dL), normal range 0.06–0.18 mmol/L (1–3 mg/dL), urine FeCl3 test may be positive.
8. Familial TBG deficiency: A sex-linked inherited disorder, blood T4 decreased, RT3U increased, TSH and FT4 normal, thyroid function also normal, no treatment required. Male patients are homozygous with nearly complete TBG deficiency, females are heterozygous with moderate TBG deficiency, male:female ratio = 9:1. Occurs in 1/10,000–1/14,000 newborns.
