Thyroid & parathyroid

Congenital / metabolic anomalies

Aplasia / hypoplasia

Last author update: 1 July 2016
Last staff update: 15 August 2023

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PubMed Search: Thyroid aplasia / hypoplasia

See also: Congenital hypothyroidism, Dyshormonogenetic goiter, Ectopic thyroid, Lingual thyroid, Screening - neonatal hypothyroidism

Andrey Bychkov, M.D., Ph.D.
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Cite this page: Bychkov A. Aplasia / hypoplasia. website. Accessed April 14th, 2024.
Definition / general
  • Total or partial absence of thyroid gland
  • Most common cause of congenital hypothyroidism
  • First well documented cases of absent thyroid as a cause of cretinism were presented by Curling in 1850 (Med Chir Trans 1850;33:303); thyroid hemiagenesis and hypoplasia were first described by Jones in 1852 (The Cyclopaedia of Anatomy and Physiology, Vol 4)
  • 400+ cases of thyroid hemiagenesis have been reported to date
  • Thyroid aplasia is the total absence of thyroid gland in orthotopic (normal place) and ectopic locations
    • Synonyms: athyreosis / athyrosis, thyroid agenesis
      • Outdated: athyreotic cretinism, cryptothyroidism
    • True athyreosis is diagnosed only if serum thyroglobulin is undetectable
    • Term "apparent athyrosis" describes patients with no functional thyroid tissue on thyroid scans, but demonstration of a thyroid gland remnant (ectopia or severe hypoplasia) by ultrasound or serum thyroglobulin
  • Hemiagenesis is a failure in the formation of one lobe of the thyroid (i.e. hemiaplasia)
  • Hypoplasia is incomplete development of orthotopic thyroid
  • Thyroid dysgenesis (dysthyroidosis, thyroid dysgenetic disorder) is a collective term for various anomalies in the anatomic development of the thyroid, including thyroid gland proper abnormalities (agenesis, hemiagenesis and hypoplasia) and ectopic thyroid tissue
  • Most cases of hemiagenesis show absence of the left lobe with a left:right ratio of 4:1 (J Clin Endocrinol Metab 1981;52:247)
  • Thyroid hemiagenesis has several variations: absent lobe, absent lobe and isthmus, absent isthmus, absent both lateral lobes with remaining isthmus
  • The absence of thyroid tissue may reflect failure of thyroid follicular cell precursors to survive due to defective expression of main thyroid transcription factors (TTF1, TTF2, PAX8), which results in inability to initiate formation of the medial anlage or maintain it during growth and migration (Endocrinol Metab Clin North Am 2016;45:243)
  • Genes associated with thyroid gland dysgenesis include those causing nonsyndromic congenital hypothyroidism (mutations of TSHR are the most common genetic cause of dysgenesis and hypothyroidism) and those causing syndromic / multiorgan congenital hypothyroidism (NKX2.1, FOXE1, PAX8, NKX2.5) (J Med Genet 2005;42:379)
  • Most cases of thyroid dysgenesis are explained by non Mendelian mechanisms, such as epigenetic modifications, somatic mutations occurring early in embryogenesis in the thyroid bud, or stochastic developmental events (Best Pract Res Clin Endocrinol Metab 2014;28:133)
  • A two hit model combining germline and somatic (epi)genetic variation has been proposed (Endocr Dev 2007;10:29)
  • Familial cases are caused by germline mutations in genes involved in thyroid development (NKX2.1, FOXE1, PAX8, GLIS3) and growth (TSH receptor):
    • Bamforth-Lazarus syndrome, characterized by thyroid agenesis, spiky hair and choanal atresia, is associated with mutation of FOXE1 gene encoding TTF2 (Nat Genet 1998;19:399)
    • No specific gene defect has clearly emerged yet as the cause of familial cases of thyroid hemiagenesis (Pediatr Res 2005;57:908)
    • Defects of any gene which controls thyroid development and function can result in hypoplasia
    • Familial cases show dominant inheritance with variable penetrance (N Engl J Med 2000;343:441)
  • Hypothyroid state develops gradually from the "in utero" period, when it is partially compensated by transplacental transfer of maternal thyroid hormones, to the postnatal period, when infants are completely dependent on their own thyroid function (Best Pract Res Clin Endocrinol Metab 2014;28:133)
  • The risk of congenital hypothyroidism is 0.5% to 1% for subsequent siblings and for the offspring of the affected child (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012)
Diagrams / tables

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PAX8 mutation in thyroid hypoplasia

Clinical features
  • Athyreosis and severe hypoplasia manifest as congenital hypothyroidism:
    • Jaundice, lethargy, macroglossia
    • Signs are often subtle and not present at birth (> 90% infants)
    • Growth and developmental delay are usually apparent by 4 - 6 months
  • The biochemical severity of the hypothyroidism tends to be greater in infants with true athyreosis than in those with thyroid hypoplasia or ectopy
  • Hemiagenesis rarely causes hypothyroidism and is usually detected incidentally:
  • Use thyroid function tests, scintigraphy and ultrasound
  • Screening for neonatal hypothyroidism was established on a worldwide basis in 1970s, now it is acclaimed as the most successful pediatric screening test
  • Serum TSH and free T4 should be measured in all newborns with abnormal screening results or suspected clinically to have hypothyroidism
  • Scintigraphy in pediatric practice is more sensitive than ultrasound, but both imaging techniques are recommended to complement each other (Eur J Endocrinol 2012;166:43)
  • If thyroid gland is not found on pediatric autopsy, serial sectioning along thyroglossal duct (especially in the posterior lingual-sublingual region) is warranted to identify ectopic thyroid tissue (Khong, Malcomson: Keeling's Fetal and Neonatal Pathology, 5th Edition, 2015)
  • Hypothyroidism: elevated TSH (> 50 mU/L), low T4, T3
  • Traces of serum thyroglobulin found in infants with radiologically undetectable thyroid help to differentiate ectopic or severely hypoplastic thyroid from true athyreosis (Clin Biochem 2004;37:818)
Radiology description
  • Thyroid scintigraphy is performed to distinguish different types of thyroid dysgenesis; it shows the isotope uptake, position and rough anatomic structure of the thyroid gland, although it is less helpful in assessing thyroid size and morphology (Eur J Endocrinol 2012;166:43)
  • In infants, scintigraphy with 99m Tc pertechnetate is favored over 123I (Pediatrics 2004;114:e683)
  • Thyroid sonography is noninvasive and no radioactivity is given, but it is less sensitive than scintigraphy in identifying small amounts of ectopic thyroid tissue; ultimobranchial remnants constitute a diagnostic trap, being often reported as small thyroid lobes (Pediatr Radiol 2010;40:725)
  • The onset of hypothyroidism can be estimated from an anteroposterior Xray of the knee; the absence of both the femoral and tibial epiphyseal centers in a term newborn suggests hypothyroidism of prenatal onset (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012)
Prognostic factors
  • Early diagnosis and treatment (not later than 3 months of age) of hypothyroidism are critical to prevent neurological damage
  • Untreated congenital hypothyroidism inevitably progresses to severe neurodevelopmental impairment and infertility
Case reports
  • Lifelong thyroid hormone replacement therapy for correction of hypothyroidism - the treatment of choice is T4
  • Treatment of presumed congenital hypothyroidism should be started immediately, regardless of imaging or confirmatory lab results, because every day of delay may result in loss of IQ (J Pediatr 2000;136:273)
  • If replacement therapy is commenced within the first 2 weeks of life, intellectual disability can be prevented in > 90% of children with congenital hypothyroidism (Nat Rev Endocrinol 2011;8:104)
Clinical images

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Phenotype of congenital hypothyroidism

Hemiagenesis on CT

Hemiagenesis on scintiscan

Hemiagenesis on sonography

Gross description
  • Agenesis: absence of thyroid gland in proper place or at any ectopic location
  • Hemiagenesis:
    • Absence of single lobe, absence of lobe + isthmus or bilobar agenesis with hypertrophied isthmus
    • Remaining lobe is often hypertrophied
  • Hypoplasia: reduced size and weight of one or both thyroid lobes
Microscopic (histologic) description
Microscopic (histologic) images

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Hashimoto thyroiditis in
thyroid hemiagenesis

Cytology description
Molecular / cytogenetics description
  • Currently molecular genetic analyses are only performed on a research basis and could probably be restricted to patients with positive family history or suggestive associations (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012)
  • Typical suggestive associations (Endocrinol Metab Clin North Am 2016;45:243):
    • Isolated thyroid hypoplasia or apparent athyreosis with a family history and recessive inheritance suggests TSH receptor mutation
    • Thyroid dysgenesis combined with kidney anomalies, or isolated thyroid hypoplasia / apparent athyreosis with a family history and dominant inheritance points to PAX8 mutation
    • Associated cleft palate and spiky hair should prompt the search for FOXE1 mutations
    • Anomalies of lungs (unexplained respiratory distress) and brain (hypotonia, choreoathetosis) suggest NKX2.1 mutation; these mutations are heterozygous and generally sporadic
    • Neonatal diabetes, polycystic kidneys, glaucoma, hepatic fibrosis and exocrine pancreatic deficiency should lead to GLIS3 analysis; transmission is autosomal recessive
Differential diagnosis
  • True athyreosis should be differentiated from severe hypoplasia and ectopic thyroid either clinically (by scintiscan) or postmortem
  • Thyroid dysgenesis is often being a part of complex syndrome with extrathyroid comorbidities, which needs further diagnostic workup to establish full phenotype
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