The Thyroid

4.1. DYSHORMONOGENESIS A variety of genetic defects could affect thyroid hormone synthesis, resulting in congenital hypothyroidism. Inability to transport iodide is caused by defects in the sodium-iodide symporter (NIS) (OMIM 601843) (70). In Pendred syndrome, characterized by congenital hypothyroidism with goiter and deafness, the defect lies in the step of organification of iodide, caused by mutations in the SLC26A4 gene (OMIM 605646) (71). Organification defects are also caused by mutations in thyroid peroxidase (TPO) (OMIM 606765) (72).

4.2. THYROID HORMONE RESISTANCE Generalized thyroid hormone resistance is characterized by a reduced effect of T4 and T3 because of mutations in the thyroid hormone receptor-P (THRP) (OMIM 190160). Patients typically have elevated levels of T4 and T3 with an inappropriately normal TSH. Most patients are clinically euthyroid, although some could have symptoms of hypothyroidism because of the lack of thyroid hormone effect. The majority of patients have autosomal dominant-negative inheritance because mutations affect ligand binding or interaction with cofactors while preserving DNA-binding activity. The defective receptors occupy DNA-binding sites but are unable to activate transcription; their presence on the binding site prevents action of the normal allele (73).



Albright's hereditary osteodystrophy (AHO), also called pseudohypoparathyroidism, is a clinical syndrome of short stature and short fourth and fifth metacarpals associated with hypocalcemia and ectopic calcification. It is caused by inactivating mutations in the GNAS1 gene (OMIM 139320), which leads to impaired parathyroid hormone action. The GNAS1 gene is paternally imprinted, meaning that normally only the maternal copy is expressed. Patients with AHO exhibit variable severity resulting from a combined effect of tissue-specific imprinting and haploinsufficiency. Thus, patients who inherit an abnormal GNAS1 gene from their mother are more severely affected (the normal paternal allele is imprinted and suppressed), and patients who inherit the gene from their father are less severely affected (the abnormal paternal allele is suppressed, and the normal maternal allele is expressed). Figure 2 shows an example pedigree showing the effect of imprinting on the severity of the clinical expression of AHO (74,75).

5.2. CALCIUM-SENSING RECEPTOR MUTATIONS The calcium-sensing receptor (CASR) (OMIM 601199) is a plasma membrane G-protein-coupled receptor expressed in the parathyroid glands and kidneys (76). Inactivating mutations in this receptor result in decreased calcium sensing with an altered "set point" for calcium, causing mild hypercalcemia (77). This autosomal dominant syndrome is called familial hypocalciuric hypercalcemia (FHH). Infants with homozygous-inactivating mutations have neonatal severe hyperparathyroidism (NSPT), a more severe disorder with marked hypercalcemia (77). Activating mutations have been described and lead to autosomal dominant hypocalcemia (78,79).


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