Thyroid gland
Hyperplasia / goiter
Dyshormonogenetic goiter

Author: Andrey Bychkov, M.D. (see Authors page)

Revised: 7 August 2016, last major update August 2016

Copyright: (c) 2003-2016, PathologyOutlines.com, Inc.

PubMed Search: Thyroid Gland Dyshormonogenetic Goiter

See also: Aplasia / hypoplasia, Congenital hypothyroidism, Screening-neonatal hypothyroidism
Cite this page: Dyshormonogenetic goiter. PathologyOutlines.com website. http://pathologyoutlines.com/topic/thyroiddyshormono.html. Accessed December 7th, 2016.
Definition / General
  • Thyroid enlargement due to various inherited defects in thyroid hormone synthesis
  • Lack of circulating thyroid hormone activates TSH secretion, which causes overstimulation and hyperplasia of defective thyroid gland
  • Important cause of congenital hypothyroidism often found during neonatal screening or otherwise manifested around puberty
  • Sporadic goitrous cretinism was known before 20th century (for example, documented by Pendred and Osler), however biochemical defects and causative mutations of different entities began to be identified only after 1950 and 1990, respectively (Thyroid 2003 Aug;13:771)
  • Less than 200 cases with detailed morphology have been reported (series and case reports), including around 30 cases with cancer
Terminology
  • Dyshormonogenetic goiter = Thyroid dyshormonogenesis
  • Also known as inherited congenital/familial goiter and congenital/sporadic goitrous cretinism (more vague terms)
Epidemiology
  • Rare inherited disorder with incidence of 1 per 30-50K live births in Europe and North America
  • Second most common cause of congenital hypothyroidism (accounts for 10-15%) after thyroid dysgenesis
  • F > M (2:1)
  • Mean age at surgery is 16 years (range varies from neonates to sixth decade), with 80% cases occur before 25 years
  • No racial or ethnic predilection (Thyroid 2011 Jan;21:13)
Pathophysiology / Etiology
  • Mutations in genes encoding enzymes, which participate in thyroid hormone synthesis
    • There are 7 genes involved in thyroid hormonogenesis and all related steps may be impaired: thyroglobulin synthesis (TG), iodide transport via basal (NIS/SLC5A5) and apical (PDS/SLC26A4) membranes of follicular cell, generation of H2O2 (DUOX2, DUOXA2), iodide organification (TPO), coupling of mono- and diiodotyrosine (TPO), proteolytic breakdown of thyroglobulin and iodide recycling (IYD/DEHAL1)
    • TPO (OMIM 274500) and TG (OMIM 274700) are the most frequent responsible genes (Thyroid Res 2015 Apr 11:5)
    • Mostly due to single gene mutation, multiple mutations is more uncommon
    • The earlier the enzyme abnormality occurs in pathway of hormone synthesis, the more severe the clinical presentation (Endocr Rev 1983 Summer;4:213)
  • Mode of inheritance of all forms of thyroid dyshormonogenesis is autosomal recessive, with the exception of DUOX2 mutations, which may be autosomal dominant (Endocr Dev 2014;26:60)
  • Mechanism: impaired T3/T4 synthesis => deficient circulating thyroid hormone => loss of negative feedback loop => normal physiologic response to increased thyrotropin releasing hormone production in hypothalamus => increased TSH secretion in anterior pituitary => chronic TSH stimulation => hyperplasia of thyroid gland
Diagrams / Tables
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Thyroid hormone synthesis

Mechanism of dyshormonogenesis

Congenital hypothyroidism

Genetic causes of
dyshormonogenesis

     

Pedigrees

Thyroid imaging in congenital hypothyroidism

Scintigraphic classification of dyshormonogenesis

Clinical Features
  • Various degrees of hypothyroidism and goiter are seen
  • Clinical presentation depends on severity of the metabolic error (Wenig: Atlas of Head and Neck Pathology, 2015)
    • Early presentation in neonatal period with evident goiter and congenital hypothyroidism complicated by growth and mental retardation (cretinism) suggests severe defect
    • Presentation in puberty or adult life with goiter and minimal evidence of thyroid dysfunction (euthyroidism, subclinical hypothyroidism) implies mild defect
    • Some metabolic defects may be masked by a high dietary iodine intake, evident from Japanese series (Endocr Dev 2014;26:60)
  • Familial recurrence of congenital hypothyroidism due to dyshormonogenesis is 25% (J Clin Endocrinol Metab 2014 Feb;99:363)
  • Most cases manifest before third decade
  • Very rarely a diagnosis is made only at autopsy
  • Pendred syndrome (Pendred Syndrome/DFNB4, J Med Genet 1996 Dec;33:1037)
    • Familial association of congenital goiter with deaf-mutism (most patients presents with severe deafness rather than with hypothyroidism)
    • Caused by mutations (150+ variants) in PDS/SLC26A4 gene encoding pendrin (OMIM 274600)
    • Occurs in 7.5 to 20 per 100,000 individuals
    • Accounts for 10% of patients with hereditary deafness
    • With sufficient dietary iodide, 90% are clinically and biochemically euthyroid (Curr Opin Pediatr 2011 Aug;23:421)
  • No associated malformations are present in dyshormonogenetic goiter except Pendred syndrome (J Clin Endocrinol Metab 2014 Feb;99:363)
  • Tumors may develop in dyshormonogenetic goiter (see Case Reports)
    • Most common are follicular carcinoma and incidental papillary microcarcinoma
    • Also papillary carcinoma and rarely follicular adenoma
    • Dyshormonogenesis may predispose to follicular carcinoma by increasing chance of mutation in dividing follicular cells under chronic TSH stimulation (Clin Endocrinol Metab 1979 Mar;8:193)
Diagnosis
  • History of congenital or familial goiter in a young individual (often diagnosed due to routine screening of newborns for congenital hypothyroidism)
  • Radiologic evaluation includes thyroid ultrasound and scintiscan
  • Correlation of clinical signs with laboratory and ancillary tests
  • Laboratory workup is complex - goal is identifying impaired step of thyroid hormone synthesis
  • Prenatal diagnosis can be made in utero by sonography and measurement of TSH in amniotic fluid (J Obstet Gynaecol Res 2013 Mar;39:720)
Laboratory
  • Hypothyroidism (if present): elevated TSH, low serum T4, T3 and thyroglobulin
  • Additional tests (J Med Genet 2005 May;42:379): thyroxine binding globulin, thyrotropin releasing hormone (to evaluate hypothalamic-pituitary axis), thyroglobulin antibodies (to rule out autoimmune thyroiditis), urinary mono- and diiodotyrosine, oral radioiodine test (to measure iodide trapping via saliva to plasma ratio)
Radiology Description
  • Ultrasound reveals enlarged, orthotropic thyroid (Korean J Radiol 2015 Mar-Apr;16:419)
    • Solid hypoechoic nodules
    • Lobes develop a convex appearance laterally, and isthmus is readily visualized, in contrast to a normal gland
    • Thyroid gland size in children varies with age and should be correlated with height, weight and body surface area
    • Ultrasound scans at 20 to 22 weeks gestation are able to detect fetal thyroid hypertrophy (J Clin Endocrinol Metab 2014 Feb;99:363)
  • Scintigraphy (Endocr Dev 2014;26:60, Pediatr Radiol 2013 Oct;43:1244)
    • In iodide trapping defect (NIS), patients show no or very low radioiodine uptake in the thyroid; further, in contrast to athyreosis, salivary glands and the gastric mucosa lack uptake (“white scintigraphy”)
    • In iodide organification defect (TPO, DUOX2, PDS), radioiodine uptake is normal, but perchlorate discharge test is positive - most radioisotope is washed out into the bloodstream instead of accumulating in thyroid
    • Patients with TG and DEHAL1 defects show normal radioiodine uptake and normal perchlorate test
Case Reports

Cancers in dyshormonogenetic goiter
Treatment
  • T4 replacement therapy until the serum TSH becomes normalized
  • Some disorders can be treated with iodine supplementation, e.g. all SLC26A4, DUOX2, DUOXA2 and IYD defects, and partial defects in SLC5A5 (Curr Opin Pediatr 2011 Aug;23:421)
  • Surgery is considered in patients with very large goiters (compressive or cosmetic reasons) or when malignancy is suspected
  • Fetal goiter detected by ultrasound with confirmed hypothyroidism (high amniotic TSH) can be treated by intra-amniotic injections of thyroxine (J Obstet Gynaecol Res 2013 Mar;39:720)
Clinical Images
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Ultrasound of fetal goiter

Ultrasound 26 year old man

Pendred syndrome

Various defects
on scintigraphy
(NIS, TPO and PDS)

 

Scintigraphy

Gross Description
Gross Images
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Marked nodular
hyperplastic changes (AFIP)



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Enlarged multinodular thyroid

Excision

Follicular adenoma
in a goiter

Micro Description
  • Diffuse process with prominent nodularity and no normal appearing thyroid tissue (Wenig: Atlas of Head and Neck Pathology, 2015)
  • Nodules and internodular thyroid parenchyma are markedly cellular/hyperplastic (Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology)
    • Predominant pattern of nodules is solid or microfollicular, also trabecular, insular and macrofollicular/microcystic
    • Papillary hyperplasia prominent within the nodules; papillae are mainly simple (without fibrovascular cores and branching) and broad
    • Marked nuclear atypia with bizarre nuclei (enlarged, irregularly shaped, hyperchromatic), more evident in internodular tissue than in the nodules; also random vesicular nuclei, occasional mitotic figures
    • No / minimal colloid (“empty follicles”) within the entire gland; when present, it is usually pale, filamentous and found in apparent nodules
    • “Kaleidoscopic” pattern of nodules is remarkable: different nodules show different degrees of cellularity and architecture (Am J Pathol 1955 Nov-Dec;31:997), and any one nodule is not uniform in structure (J Pathol 1969 Nov;99:251)
    • Internodular background is uniform in structure
  • Associated changes
    • Extensive bridging fibrosis of internodular tissue; sometimes may circumscribe nodules and cause irregularities at the border simulating capsular invasion
    • Cytoplasmic oxyphilia (sign of functional exhaustion) and focal clear cell metaplasia (sign of hormone overproduction) (Int J Surg Pathol 1999 July;7:3 )
    • Myxoid change
    • Absent or rare focal mild thyroiditis
  • Important considerations
    • Histologic features of the background thyroid are as important as the appearance of the nodules (Int J Surg Pathol 1999 July;7:3 )
    • Histologic changes in newborns are not as prominent as in older patients, who develop variation of patterns and secondary changes over the course of disease (J Pathol 1969 Nov;99:251)
    • Severity of microscopic appearance depends on degree and duration of TSH stimulation, and is modulated by therapy (hormone replacement or iodine supplementation)
    • Dyshormonogenetic goiter should be suspected in a child or young adult with diffuse follicular hyperplasia, nodularity, scant colloid and nuclear atypia
    • Several studies (J Pathol 1969 Nov;99:251, Endocrine Pathology 1994 March;5:49) found that structural changes in the gland may correlate with particular defects (e.g. microcystic/alveolar pattern in cases with formation of abnormal iodoprotein, or severe atypia and solid pattern in organification defects), however most modern authors believe that morphology is independent of the biochemical abnormality (Sternberg's Diagnostic Surgical Pathology, Wenig: Atlas of Head and Neck Pathology, 2015)
  • Cancer in dyshormonogenetic goiter
    • Nuclear and architectural features typical for dyshormonogenesis often mimic malignancy
    • In one study almost every fifth case was considered as follicular, papillary, medullary, or undifferentiated carcinoma (Endocr Pathol 1997 Winter;8:283)
    • Some previously reported cases of congenital thyroid carcinoma were actually examples of thyroid dyshormonogenesis (Clin Endocrinol Metab 1981 Jul;10:317)
    • Only strict criteria for diagnosing malignancy should be applied, e.g. true capsular or vascular invasion in case of follicular carcinoma
Micro Images
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Resembles nodular hyperplasia

Hyperplastic nodules showing solid growth pattern

Marked fibrosis causes apparent increased lobularity

 

Contributed by Dr. Mark R. Wick



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Multinodularity

   

Fibrosis

     

Hypercellular nodule

 

Papillarity

   

Hyperplastic nodule

     

Scant colloid

       

Atypia

IHC in Pendred syndrome

     

Follicular adenoma in dyshormonogenetic goiter

 

Papillary microcarcinoma in dyshormonogenetic goiter

   

Papillary carcinoma in goiter

Cytology Description
Positive Stains
Negative Stains
Electron Microscopy Description
Molecular / Cytogenetics Description
Molecular / Cytogenetics Images
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Structure of TPO mutations

DUOXA2 mutation

Differential Diagnosis
  • Multinodular endemic goiter (Endocrine Pathology March 1994, 5:49)
    • Similar: identical gross appearance, extensive hyperplasia
    • Difference: abundant colloid, hyperplasia confined by nodules (not throughout the entire gland), normal thyroid tissue present between nodules, frequent secondary degenerative changes (hemorrhage, foamy and hemosiderin-laden macrophages, dystrophic calcification, fibrosis and cyst formation)
    • Ancillary studies: euthyroidism, rarely toxic goiter
  • Radiation thyroiditis: diffuse cytologic atypia through gland, history of thyroid radiation
  • Iatrogenic goiter caused by antithyroid drugs: similar histology, history of thionamides treatment of patient or mother (in case of fetal goiter)
  • Graves disease (especially untreated): diffuse hyperplasia without nodularity, no solid or related patterns, columnar epithelium present without nuclear atypia, hyperthyroidism clinically
  • Follicular adenoma: unilocular lesion
  • Follicular thyroid carcinoma with capsular invasion
    • Localized lesion with otherwise uninvolved thyroid parenchyma
    • Clear cut capsular or vascular invasion must be present; capsule is often vascularized
    • In widely invasive carcinoma, multiple satellite nodules display similar morphology
    • Laboratory tests show absence of hypothyroidism
    • It is proposed that dyshormonogenetic goiter be excluded in every case of follicular carcinoma diagnosed in a patient < 20 years (Int J Surg Pathol July 1999;7:125)
  • Multifocal papillary thyroid carcinoma: cytologic, architectural (true papillae) and other (extrathyroidal extension, cervical or distant metastasis) features of cancer (Int J Surg Pathol July 1999;7:125)
  • Poorly differentiated (insular) carcinoma: mitotic activity, necrosis, invasive growth
  • Medullary thyroid carcinoma may resemble goiter with prominent myxomatosis and hyalinosis, but is calcitonin+