Cretinism

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Cretinism is a condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormones (hypothyroidism). The term cretin refers to a person so affected. Cretinism is an old name used for congenital hypothyroidism. It includes sporadic cretinism and endemic cretinism. Sporadic cretinism is caused by gene mutations, radiation, drugs and so on. Usual symptoms are neurological impairment, low metabolism conditions and infertility. Thyroid hormone replacement is the main treatment. Endemic cretinism results from a diet deficient in iodine. Iodine deficiency results in enlargement of the thyroid gland, physical development, hypo-evolution and mental development impairment. As a public health problem, many countries have established the policy of iodine administration.

Cretinism was first described by ancient Roman writers. Cretinism was described by physicians and travelers in the 19th century and some areas in Europe and North America were named as “goiter belts”.

Cretinism may be classified into two groups which are transient and permanent cretinism. Permanent cretinism can be more classified into primary and secondary subtypes.

Cretinism is believed to be the result of a congenital anomaly in the thyroid gland. Cretinism can be caused by thyroid dysgenesis which is the most common cause of cretinism. Thyroid dysgenesis may be due to the absence of the thyroid gland, ectopic growth of the gland, or hypoplastic gland. Thyroid dysgenesis can be also due to mutations in genes as the TSH receptor gene, PAX8 gene, and NK2 homeobox 1. It is thought also that cretinism may be due to thyroid dyshormonogenesis. The decrease of thyroid hormone synthesis and secretion is due to impairment of thyroid peroxidase enzyme. Cretinism may be associated with some congenital anomalies like horseshoe kidney, ureterocele, hydrocele, and undescended testes. 

Cretinism may be caused by congenital causes like thyroid dysgenesis and ectopic thyroid. Cretinism can be caused by other causes like anti-thyroid medications and iodine deficiency.

Cretinism must be differentiated from other diseases that cause a failure to pass meconium or abdominal distension in infants, including meconium plug syndrome, small left colon syndrome, and Hirschsprung’s disease.

The incidence of cretinism is estimated to be 31.5 per 100,000 individuals in the United States. Cretinism is more in the Asian and Hispanic races more than the White and Black races. Cretinism affects the females more than males.

Common risk factors in the development of cretinism include post-dating delivery, macrosomia, mothers with anemia or goiter, and smoking parents. Other risk factors include cesarean section delivery and jaundice at the birth.

According to the Endocrine Society and the European Society for Pediatric Endocrinology, screening for cretinism is recommended in all neonates. Screening is important as early detection of cretinism will help in preventing the disease consequences as the mental retardation.

If left untreated, patients with cretinism may progress to develop mental retardation and neurological manifestations. Common complications of cretinism include growth retardation and cardiovascular problems. Prognosis is usually good with treatment with levothyroxine.

The majority of patients with cretinism are asymptomatic. A positive history of a family member had the disease before and maternal history of thyroid problems is suggestive of cretinism. The most common symptoms of cretinism include lethargy, hoarse cry, constipation, and umbilical hernia. Less common symptoms of cretinism include palpable goiter.

Patients with cretinism usually appear asymptomatic at the beginning of the disease. Physical examination of patients with cretinism is usually remarkable for jaundice, dry skin, large fontanelles, macroglossia, umbilical hernia, bradycardia, delayed puberty, and hypotonia.

Laboratory findings consistent with the diagnosis of cretinism include abnormal levels of thyroid hormones and thyroid stimulating hormone. High TSH and low T4 levels are consistent with primary cretinism. High TSH and normal T4 levels are consistent with sub-clinical cretinism.

There are no ECG findings associated with cretinism.

There are no x-ray findings associated with cretinism. However, knee x-ray may be helpful in evaluating the severity of cretinism. Knee x ray may show wide sagittal suture which indicates delayed bone maturation. 

There are no CT scan findings associated with cretinism.

There are no MRI findings associated with cretinism.

The thyroid gland ultrasonography may be helpful in the diagnosis of cretinism. Findings on an ultrasound suggestive of cretinism include a thyroid gland in an ectopic location or a large gland which is suggestive of thyroid dyshormonogenesis.

Thyroid radionuclide uptake and scanning may be helpful in the diagnosis of cretinism. The absence of the radionuclide uptake is consistent with somethyroid gland anomalies like ectopic thyroid gland, thyroid gland hypoplasia, and thyroid aplasia.

There are no additional diagnostic studies for cretinism.

Surgical intervention is not recommended for the management of cretinism.

The mainstay of treatment for cretinism is thyroid hormone replacement therapy. Levothyroxine (L-T4) is administrated orally to patients with cretinism.

Effective measures for the primary prevention of cretinism include iodide supply in the diet and screening of the newborns. 

There are no established measures for the secondary prevention of cretinism.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Cretinism was first described by ancient Roman writers. In the 19th century, cretinism was described by physicians and travelers and some areas in Europe and North America were named as “goiter belts”.

• Cretinism was described by ancient Roman writers and they declared Southern Europe around the Alps as endemic areas.^[1]
• In 1848, the first study of goiter and cretinism was held in Italy to detect the goiter cases in the population.
• In the 19th century, cretinism was described by physicians and travelers. They did not know the cause of cretinism and linked it to polluted air and water in the Alps mountains.
• In the 19th century, some areas in Europe and North America were named as “goiter belts”.
• In the 20th century, the relationships of sporadic cretinism with congenital hypothyroidism and of endemic cretinism with hypothyroidism due to iodine deficiency were discovered.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Cretinism may be classified into two groups which include transient and permanent cretinism. Permanent cretinism may classified into two subgroups including primary and secondary cretinism.

• Cretinism may be classified based on the duration of thyroid hormones deficiency into two groups:^[1]
  • Transient cretinism: Transient deficiency of the thyroid hormones which may be discovered at birth. Thyroid hormone levels returns back to normal after a period of time.
  • Permanent cretinism: Permanent deficiency of the thyroid hormones which requires life long hormonal replacement. Permanent cretinism can be classified into two subgroups based on the location of the etiology:
    • Primary permanent cretinism
    • Secondary (central) permanent cretinism

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Cretinism is believed to be the result of a congenital anomaly in the thyroid gland. Cretinism can be caused by thyroid dysgenesis which is the most common cause of cretinism. Thyroid dysgenesis may be due to the absence of the thyroid gland, ectopic growth of the gland, or hypoplastic gland. Thyroid dysgenesis can be also due to mutations in genes as the TSH receptor gene, PAX8 gene, and NK2 homeobox 1. It is thought also that cretinism may be due to thyroid dyshormonogenesis. The decrease of thyroid hormone synthesis and secretion is due to impairment of thyroid peroxidase enzyme. Cretinism may be associated with some congenital anomalies like horseshoe kidney, ureterocele, hydrocele, and undescended testes.

• Cretinism is believed to be caused by a congenital anomaly in the thyroid gland.
• Different mechanisms causing congenital hypothyroidism include:
  • Thyroid dysgenesis:^[1]
    • Thyroid dysgenesis is the most common cause of congenital hypothyroidism. It is due to the absence of the thyroid gland, ectopic growth of the thyroid gland, or hypoplastic gland.
    • It is believed that thyroid dysgenesis may be caused by a mutation in some genes responsible for thyroid formation and function. These genes include the following:
      • Mutation in the TSH receptor is responsible for the hypoplastic thyroid gland.
      • Mutations in the paired box 8 (PAX8) gene leads to thyroid dysgenesis.
      • Mutations in the transcription factors NK2 homeobox 1, transcription factor-2, and NK2 homeobox 5 genes also lead to thyroid dysgenesis.
  • Thyroid dyshormonogenesis:
    • It is believed that the defect in the synthesis of the thyroid hormone is another mechanism for pathogenesis of cretinism.
    • The most common mechanism involved in decreased thyroid hormone synthesis and secretion is the impairment of thyroid peroxidase enzyme. This impairment leads to defect in the iodide oxidation and organification.

• Cretinism can occur due to genetic defects. ^[2]
• Mutation in sodium-iodide symporter gene can impede the iodine transportation into the thyroid follicles. This mutation decreases the synthesis of the thyroid hormone.^[3]

• Cretinism may be associated with the following conditions: ^[4]
  • Horseshoe kidney
  • Ureterocele
  • Undescended testes
  • Hydrocele
  • Cleft palate
  • Bilateral choanal atresia
  • Neurologic manifestations (ataxia)

• There are no gross findings associated with cases of cretinism.

• There are no microscopic findings associated with cases of cretinism.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Cretinism may be caused by congenital causes like thyroid dysgenesis and ectopic thyroid gland. Cretinism may be caused by other causes like antithyroid medications and iodine deficiency.

Primary Cretinism may be caused by:^[1][2]

• Congenital causes:
  • Thyroid dysgenesis
  • Thyroid dyshormonogenesis
  • Ectopic thyroid gland
• Acquired causes:
  • Autoimmune diseases
  • Antibodies pass placenta cause hypothyroidism
  • Antithyroid medications usage that can cross the placenta
  • Iodine deficiency
  • Inability to uptake iodide

Central hypothyroidism is caused by:^[3]

• Inflammation or infection of pituitary gland and hypothalamus
• Trauma
• Structural changes
• Untreated maternal hypothyroidism during pregnancy

• Cretinism is caused by a mutation in the TTF-2 gene.
• Cretinism is caused by a mutation in the genes responsible for the thyroid hormone secretion. These genes include the following:^[4][5]
  • Dual oxidase 2 gene (DUOX 2)
  • Thyroglobulin gene (TG)
  • Thyroid peroxidase gene (TPO)
  • Thyroid stimulating hormone receptor gene (TSHR) 

List the causes of the disease in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Cretinism must be differentiated from other diseases that cause a failure to pass meconium or abdominal distension in infants, including meconium plug syndrome, small left colon syndrome, and Hirschsprung’s disease.

Cretinism must be differentiated from other diseases that cause a failure to pass meconium or abdominal distension in infants, including meconium plug syndrome, small left colon syndrome, and Hirschsprung’s disease.

Disease	Prominent clinical features	Radiological findings
Cretinism (Congenital hypothyroidism)	Most infants are born asymptomatic.[1] Symptoms, if present, may include, but not limited to: Macroglossia Hoarse cry Umbilical hernia Puffy facies Increased head circumference Hypothermia
Meconium plug syndrome	Transient intestinal obstruction for 1-2 days after birth. Obstruction is functional due to dilated colon and delayed passage of feces. Usually seen in premature infants.[2]
Small left colon syndrome	Reduced caliber of the colon starting from splenic flexure and going down, causing intestinal obstruction. Characterized by a sudden change of the colon diameter. Usually associated with gestational diabetes.[3]
Distal small intestine/colon atresia	Failure to pass meconium due to failure of intestine recanalization. Proximal lesions have an earlier onset of symptoms than distal lesions. Colonic atresia may affect normal children or may be associated with other abnormalities as Hirschsprung’s disease or gastroschisis.[4]
Meconium ileus	Intestinal obstruction due to inspissation of meconium in the distal ileum. Most cases of meconium ileus are secondary to cystic fibrosis. Typically presents with failure to pass meconium and abdominal distension with or without vomiting. Meconium ileus may first present with complications, including perforation and volvulus.[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

The incidence of cretinism is estimated to be 31.5 per 100,000 individuals in the United States. Cretinism is more in the Asian and Hispanic races more than the White and Black races. Cretinism affects the females more than males.

• The incidence of cretinism is estimated to be 31.5 per 100,000 individuals in the United States.^[1]

• Cretinism affects the new borns.

• Cretinism usually affects individuals of the Hispanic and Asian races more the White and Black races.
• The incidence of cretinism in the different races as the following:^[1]
  • Asian race: The incidence of cretinism is 98.4 per 100,000 Asian individuals.
  • Hispanic race: The incidence of cretinism is 64.1 per 100,000 Hispanic individuals.
  • White race: The incidence of cretinism is 55.1 per 100,000 White individuals.
  • Black race: The incidence of cretinism is 52.6 per 100,000 Black individuals.

• Females are more commonly affected by cretinism than males. The female to male ratio is approximately 2:1. ^[2]

• Between 1978 and 2005, the incidence of cretinism was estimated to be 48.3 cases per 100,000 individuals in the New York state. Between 1981 and 2002, the incidence of cretinism was estimated to be 25 cases per 100,000 individuals in France.^[3]

• Between 2006 and 2012, the incidence of cretinism was estimated to be 170 cases per 100,000 individuals in Iran.^[4]
• The incidence of cretinism was estimated to be 55 cases per 100,000 individuals in Greece.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Common risk factors in the development of cretinism include post-date delivery, macrosomia, mothers with anemia or goiter, and smoking parents. Other risk factors include cesarian section delivery and jaundice at the birth.

• Common risk factors in the development of cretinism include:^[1][2][3]
  • Twins
  • Postdate delivery
  • Macrosomia
  • Low birth weight
  • Mother with anemia or goiter
  • Smoking parents

• Less common risk factors in the development of cretinism include:
  • Cesarian section delivery
  • Jaundice at birth

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

According to the Endocrine Society and the European Society for Pediatric Endocrinology, screening for cretinism is recommended in all neonates. Screening is important as early detection of cretinism will help in preventing the disease consequences as the mental retardation.

• According to the Endocrine Society and the European Society for Pediatric Endocrinology, screening for congenital hypothyroidism (cretinism) is recommended in all neonates. Screening is recommended because early detection of cretinism and early treatment will prevent the consequences of the disease which may be mental retardation.^[1]
• In a worldwide view of strategies, screening of cretinism is been held in many countries including the United States. The screening helped in detecting the newborn with hypothyroidism. These cases are around 2000 annually in the united states and 12,000 worldwide.^[2]
• The screening of cretinism can be performed through the following laboratory tests:^[3][4]
  • Measuring the level of thyroxine hormone (T4)
  • Blood TSH assay
  • Both thyroxine and TSH levels

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

If left untreated, patients with cretinism may progress to develop mental retardation and neurological manifestations. Common complications of cretinism include growth retardation and cardiovascular problems. Prognosis is usually good after treatment with levothyroxine.

• The symptoms of cretinism usually develop in the first months after birth and start with symptoms such as jaundice, large fontanelles, and umbilical hernia.
• If left untreated, patients with cretinism may progress to develop mental retardation and neurological manifestations like ataxia and poor motor coordination.^[1]

• Common complications of cretinism include:^[2]
  • Mental retardation
  • Growth retardation
  • Cardiovascular problems

• Prognosis is generally good after appropriate treatment with levothyroxine.^[3]

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