Hypothyroidism and hyperthyroidism

Abstract

Congenital hypothyroidism is a condition in which the thyroid gland does not produce enough thyroid hormones. It occurs in 1:2000-4000 newborns. Common clinical features include decreased activity and increased sleep, feeding difficulty, constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment, congenital hypothyroidism leads to severe intellectual deficit and short stature. Congenital hyperthyroidism occurs when the thyroid gland produces too much of the hormone thyroxine, which can accelerate body metabolism, causing unintentional weight loss and a rapid or irregular heartbeat. Hyperthyroidism is very rare and its prevalence is unknown. Common clinical features include unintentional weight loss, tachycardia, arrhythmia, palpitations, anxiety, tremor and sweating. Here we summarize the genes involved in congenital hypo- and hyperthyroidism and the tests we use for genetic analysis. (www.actabiomedica.it)

Congenital hypothyroidism

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. It has a prevalence of 1:2000-4000 and is more frequent in females than in males (ratio of 2:1) (1). At birth, clinical features are mild or absent, becoming apparent a few months later. The disorder is characterized by reduced physical activity, increased sleeping periods, feeding difficulties, constipation, jaundice, myxedematous face, wide fontanels, macroglossia, abdominal distention with umbilical hernia, and hypotonia. Developmental and growth delay become evident 4-6 months after birth Without therapy, the disorder leads to intellectual disability and very short stature (1).

Congenital hypothyroidism can be caused by thyroid dysgenesis (85% of cases) or defects in thyroid hormone biosynthesis (10-15% of cases) (2). Secondary congenital hypothyroidism is caused by chronic low levels of thyroid stimulating hormone (TSH) and may be due to congenital hypopituitarism. Peripheral congenital hypothyroidism is caused by defects in the transport, metabolism and action of thyroid hormones, or peripheral resistance to thyroid hormones (3). Congenital hypothyroidism can also be syndromic.

Currently, neonatal screening mainly detects elevated levels of TSH that increase in response to the reduction in thyroid hormone. This screening identifies 90% of cases of CH. Most patients have normal development after treatment with thyroxine. Besides assay of TSH, triiodothyronine (T3) and thyroxine (T4), other diagnostic tests include thyroid scanning with radioactive iodine, thyroid echography, and assay of serum thyroglobulin. These exams can help determine the etiology of the disease and differentiate permanent and transient cases (1,4). Differential diagnosis should consider chronic fatigue syndrome, depression, dementia and heart failure (5).

Newborns diagnosed with CH should be treated with levothyroxine to ensure normal neurocognitive development. Serum levels of TSH, T4 and T3 should be measured frequently. When babies are treated soon after birth, their prognosis is excellent and their IQ normal (1). Congenital hypothyroidism is usually sporadic, but in 10% of cases it is inherited (6).

Generalized thyroid hormone resistance is a rare genetic disorder caused by a reduced peripheral response to thyroid hormones. The prevalence is 1:40000. In 85% of cases it is caused by mutations in THRB (7).

Twenty-five genes are currently known to be associated with congenital hypothyroidism or generalized thyroid hormone resistance (Table 1). Pathogenic variants may be missense, nonsense, splicing or small indels. We use a multi-gene NGS panel to detect nucleotide variations in coding exons and flanking introns of the above genes.

Table 1.

Genes associated with congenital hypothyroidism

Gene	OMIM gene	Disease	OMIM disease	Inheritance	Gene function
THRA	190120	CHNG6	614450	AD	Nuclear hormone receptor mediator of T3 biological activity
NKX2-1	600635	CAHTP	610978	AD	Transcription factor for expression of thyroid- specific genes
NKX2-5	600584	CHNG5	225250	AD	Transcription factor for thyroid organogenesis
PAX8	67415	CHNG2	218700	AD	Transcription factor for expression of thyroid- specific genes, maintenance of thyroid cell differentiation
POU1F1	173110	CPHD1	613038	AD, AR	Transcription factor involved in specification of lactotrope, somatotrope and thyrotrope phenotypes in developing anterior pituitary gland
GNAS	139320	PHP1A PHP1C	103580 612462	AD	Activation of adenylate cyclase that regulates thyroid activity
SECISBP2	607693	Abnormal thyroid hormone metabolism	609698	AR	Co-translational insertion of selenocysteine into selenoproteins like type II iodothyronine deiodinase
THRB	190160	GRTH PRTH	188570 274300 145650	AD AR AD	Nuclear hormone receptor for triiodothyronine. Mediation of thyroid hormone activity
TRHR	188545	Generalized thyrotropin-releasing hormone resistance	188545	AR	TRH receptor promoting TSH and prolactin release
KAT6B	605880	GTPTS SBBYSS	606170 603736	AD	Histone acetyltransferase transcriptional activator and repressor, also important for thyroid organogenesis
LHX4	602146	CPHD4	262700	AD	Early stages of pituitary development
TSHB	188540	CHNG4	275100	AR	Control of thyroid structure and metabolism
TSHR	603372	CHNG1	275200	AR	Major controller of thyroid cell metabolism. Receptor for thyrotropin and thyrostimulin
TPO	606765	TDH2A	274500	AR	Central role in thyroid gland function. Generation of thyroxine, T3
SLC5A5	601843	TDH1	274400	AR	Uptake of iodine by thyroid
DUOXA2	612772	TDH5	274900	AR	Thyroid hormone synthesis
DUOX2	606759	TDH6	607200	AR	Thyroid hormone synthesis
IYD	612025	TDH4	274800	AR	Hydrolysis of thyroglobulin to release iodide
PROP1	601538	CPHD2	262600	AR	Involved in ontogenesis of pituitary gonadotropes, somatotropes, lactotropes and caudomedial thyrotropes
SLC26A4	605646	PDS	274600	AR	Sodium-independent transporter of iodide
TG	188450	TDH3	274700	AR	Substrate for synthesis of T4 and T3, storage of inactive forms of thyroid hormone and iodine
FOXI1	601093	PDS	/	AR	Transcription factor for SLC26A4
FOXE1	602617	Athyroidal/ thyroidal hypothyroidism with spiky hair, cleft palate	241850	AR	Thyroid morphogenesis
UBR1	605981	JBS	243800	AR	Degradation of substrate proteins
SLC16A2	300095	AHDS	300523	XLR	Cell import of T4, T3, T2

AHDS = Allan-Herndon-Dudley syndrome; CAHTP = choreoathetosis and congenital hypothyroidism with/without pulmonary dysfunction; CHNG = congenital nongoitrous hypothyroidism; CPHD = combined pituitary hormone deficiency; GRTH = generalized thyroid hormone resistance; GTPTS = genitopatellar syndrome; JBS = Johanson-Blizzard syndrome; PDS = Pendred syndrome; PRTH = selective pituitary thyroid hormone resistance; SBBYSS = Ohdo syndrome, SBBYS variant; TDH = thyroid dyshormono- genesis; AD = autosomal dominant; AR = autosomal recessive; XLR = X-linked recessive.

Nonautoimmune hyperthyroidism

Nonautoimmune hyperthyroidism or hereditary hyperthyroidism is a rare form of hyperthyroidism, characterized by excessive thyroid activity. Major symptoms are hyperactivity, anxiety, weight loss, exophthalmos and tachycardia (8). Age of onset is highly variable. Clinical diagnosis is based on observation and measurement of plasma concentrations of thyroid hormone. Differential diagnosis is based on absence of exophthalmos and presence of myxedema, anti-TSH antibodies and lymphocyte infiltration of the thyroid (9). Hyperthyroidism can be treated with drugs that inhibit thyroid activity or with ablation therapy (surgery or radioiodine) (10).

The nonautoimmune hyperthyroidism has autosomal dominant inheritance and is caused by mutations in TSHR (OMIM gene: 603373; OMIM disease: 609152, 603373) (9). Prevalence is unknown: very few families (130 patients from 22 families) and some sporadic cases, especially in Caucasian subjects, have been described (9,11).

Pathogenic variants may be missense, nonsense, splicing or small indels. MAGI uses an NGS panel to detect nucleotide variations in coding exons and flanking introns of TSHR.

Conclusions

We created a NGS panel to detect nucleotide variations in coding exons and flanking regions of all the genes associated with hypo- and hyperthyroidism. When one of those suspects is present we perform the analysis of all the genes present in this short article.

In order to have a high diagnostic yield, we developed a NGS test that reaches an analytical sensitivity (proportion of true positives) and an analytical specificity (proportion of true negatives) of ≥99% (coverage depth ≥10x).

Conflict of interest:

Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article