Hyperplastic Pituitary Gland, High Serum Glycoprotein Hormone -Subunit, and Variable Circulating Thyrotropin (TSH) Levels as Hallmark of Central Hypothyroidism due to Mutations of the TSH Gene
Abstract
Inheritable isolated central hypothyroidism (ICH) due to mutations of TSH beta gene has been reported in few patients. For this reason the diagnostic criteria are vague. The disorder is usually characterized by undetectable TSH levels, although low/normal serum TSH, depending on TSH measurement methods, has been documented in some patients. Here we report an Egyptian girl with ICH due to a novel nonsense mutation of the TSH beta gene (Q49X). She was referred at 75 days of age for severe clinical signs of hypothyroidism, whose central origin was documented by normal serum TSH, low free T(4) and free T(3) levels, impaired TSH response to TRH, absence of (99)Tc thyroidal uptake, and antithyroid autoantibodies. Ultrasound revealed a hypoplastic thyroid, whereas magnetic resonance imaging showed a hyperplastic pituitary. All other pituitary hormones, including PRL, were normally secreted. A diagnosis of idiopathic ICH was made, and substitutive L-T(4) treatment was started at 81 days of age. At the age of 7 yr the patient had normal thyroid hormone levels, but was severely mentally retarded. Interestingly, the sella computed tomography scan had completely normalized. At 8 yr of age the patient was reinvestigated after 6-week L-T(4) withdrawal. TSH values were highly variable depending on the measurement method used, whereas extremely high levels of circulating free glycoprotein alpha-subunit were recorded. Despite the fact that mutant TSH beta lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity. In conclusion, high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and, possibly, hyperplastic pituitary gland are the hallmark of ICH due to mutations of the TSH beta gene.
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If untreated within a few weeks of postnatal life, patients with biallelic TSHβ mutations develop cretinism comparable to patients with severe primary congenital hypothyroidism.
“If untreated within a few weeks of postnatal life, these patients develop cretinism comparable to patients with severe primary congenital hypothyroidism [26, 27].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [26]
Heritable forms of central hypothyroidism due to biallelic TSHβ mutations are associated with severe neonatal onset and characterized by typical manifestations of congenital primary hypothyroidism.
“Heritable forms of CeH due to biallelic TSHβ mutations are associated with severe neonatal onset and characterized by the typical manifestations of congenital primary hypothyroidism (e.g., jaundice, macroglossia, hoarse cry, failure to thrive and retarded growth, umbilical hernia, hypotonia).”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [26]
If left untreated, patients with isolated central congenital hypothyroidism due to biallelic TSHβ gene mutations develop cretinism comparable with patients with severe primary congenital hypothyroidism.
“If left untreated, these patients develop cretinism comparable with patients with severe primary CH (230–232).”
Isolated central congenital hypothyroidism due to biallelic TSHβ gene mutations is associated with severe hypothyroidism and characterized by typical manifestations of congenital hypothyroidism.
“Isolated central CH due to biallelic TSHβ gene mutations is associated with severe hypothyroidism and characterized by the typical manifestations of CH (hypotonia, jaundice, umbilical hernia, macroglossia, etc.).”
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References 27 · Cited by 71
- Authors
- Bonomi, M.
- Affiliations
- University of Milan (IT)
- Corresponding author
- Bonomi, M.
- ORCID
- Bonomi, M.
- Venue
- Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2001-04-01
- Volume
- 86
- Issue
- 4
- Pages
- 1600-1604
- ISSN
- 0021-972X (ISSN-L)
- OpenAlex
- W2090387340
- Cited by
- 71
- References
- 27
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 2 · 2014: 5 · 2013: 5 · 2012: 2
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- central hypothyroidism, TRH stimulation test, antithyroid autoantibodies, levothyroxine therapy, intellectual disability
- MeSH terms
- Base Sequence, Female, Humans, Hyperplasia, Hypothyroidism, Infant, Pedigree, Pituitary Gland, Thyrotropin, Glycoprotein Hormones, alpha Subunit, Mutation, Missense
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