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ISSN: 2157-7412
Journal of Genetic Syndromes & Gene Therapy
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Genetically Determined Central Hypothyroidism

Antonis Voutetakis, Nikolaos Settas and Catherine Dacou-Voutetakis*

First Department of Pediatrics, Division of Endocrinology Diabetes and Metabolism, University of Athens, Medical School, “Aghia Sophia” Children’s Hospital, Athens, Greece

*Corresponding Author:
Catherine Dacou-Voutetakis
First Department of Pediatrics
Division of Endocrinology Diabetes and Metabolism
University of Athens, Medical School
“Aghia Sophia” Children’s Hospital
Thivon & Livadeias, 11527, Athens, Greece
Tel: 00302107237257
Fax: 00302107237257
E-mail: [email protected]

Received date: July 20, 2013; Accepted date:August 19, 2013; Published date: August 21, 2013

Citation: Voutetakis A, Settas N, Dacou-Voutetakis C (2013) Genetically Determined Central Hypothyroidism. J Genet Syndr Gene Ther 4:172. doi:10.4172/2157-7412.1000172

Copyright: © 2013 Voutetakis A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Central, secondary or low TSH hypothyroidism can be congenital or acquired. Congenital Central hypothyroidism (CH-C), either isolated or (unlike primary hypothyroidism) combined with deficiency of other pituitary hormones, is usually caused by mutations in genes related either to TSH synthesis or pituitary ontogenesis. The prevalence of CH-C is higher than previously considered, ranging from 1:16000 to 1:20000 live births. Isolated CH-C is most frequently caused by mutations in the TSΗβ-subunit and in rare cases by TRHR gene mutations. Either one of these mutations are inherited as a recessive trait. In patients with multiple pituitary hormone deficiency, molecular defects have been detected in the following genes: IGSF1, PROP1, POU1F1, LHX3, LHX4, HESX1, SHH, TGIF, GLI2. The resulting phenotype varies and the mode of inheritance could be autosomal dominant, autosomal recessive or X-linked, depending on the specific gene involved. In patients with CH-C, the timely identification of the underlying genetic defect is crucial because it leads to early and appropriate management that improves prognosis and determines genetic counseling.


Pituitary; Thyroid; TSHβ-subunit; Central hypothyroidism; PROP1; SHH; TGIF; TRHR


Central hypothyroidism (CH) refers to hypothyroidism that is not caused by anatomical or functional defects of the thyroid gland per se (primary hypothyroidism) but by inefficient synthesis of TSH (secondary hypothyroidism) [1,2]. Central hypothyroidism might be congenital (CH-C) or acquired. The TSH values in individuals with central hypothyroidism would be expected to be subnormal. Although that is usually the case, normal or mildly elevated TSH values can also be detected in certain cases, leading to an erroneous diagnosis of primary hypothyroidism. This phenomenon has been attributed to an aberrant TSH molecule, which is measurable by applied methodology but is biologically inactive [3-5]. Regardless of the mechanism involved one should be aware of this phenomenon in order to avoid misinterpretation and diagnose primary instead of secondary (central) hypothyroidism.

A distinction between primary and secondary hypothyroidism is also important because in many CH-C cases TSH deficiency is accompanied by deficiency of other pituitary hormones (multiple pituitary hormone deficiency - MPHD). In such cases the concomitant deficiency of growth hormone (GH) and/or cortisol may cause hypoglycemia with adverse effects on brain function. One should also consider that in most screening programs for congenital hypothyroidism, only TSH is determined and hence CH-C escapes detection. Importantly, even if the neonatal screening procedure is enriched with T4 determination, not all cases will be identified because in a significant number of CH-C cases the thyroid function at birth is normal. Consequently, the screening results can be falsely normal or falsely re-assuring [6]. In such cases, only a high index of suspicion will lead to prompt identification of affected individuals.

Prevalence of CH-C

A more precise estimate of the prevalence of CH-C has been obtained in recent years based on the application of more efficient neonatal screening tests, which are also supplemented by an adequate follow-up period. The initial estimates of the prevalence of CH-C in the United States and Canada ranged from 1:106304 to 1:29.000 [7,8]. In a more recent study from The Netherlands, a CH-C prevalence of 1:20263 was reported [9]; 78% of these subjects had MPHD, 53% had a pituitary malformation on magnetic resonance imaging (MRI). In this particular report, it was also mentioned that delay in the detection of MPHD resulted in significant morbidity, and a mortality rate of 14%, possibly accounted for by the co-existence of GH and/or cortisol deficiency. Moreover, the CH-C cases constituted 13.5% of all cases of permanent congenital primary and secondary hypothyroidism [9]. Analogous were the results of a study by Kempers et al. [10] in which a prevalence of CH-C of 1:21.000 was estimated. In another study by Lanting et al. [11] the prevalence of CH-C, based on T4, TSH and T4/ TBG ratio determination was 1:16404. Thus, current data indicate that the prevalence of CH-C is higher than previously considered and ranges from 1:16400 to 1:20.000 live births, most of the cases having besides central CH, deficiency of other pituitary hormones (MPHD). Herein, we will review the molecular defects causing CH-C, isolated or in the context of MPHD (Table 1).

Isolated CH-C

This form of CH-C can be caused by mutations in the TSH β- subunit, or thyrotropin releasing hormone receptor (TRHR) genes.

Forms of central congenital hypothyroidism
A) Isolated CH-C
B) CH-C caused by IGSF1 gene
C) CH-C as part of MPHD1
I. Genes related to pituitary organogenesis
1. PROP1
2. POU1F1/PIT1
3. LHX3
4. LHX4
5. HESX1
II. Genes related to PSIS2 or isolated pituitary hypoplasia
1. SHH
3. GLI2

Table 1: Synopsis of genes related to central congenital hypothyroidism (CH-C).

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