Disease Information

General Information of the Disease (ID: DIS00236)

• Name: Hypothyroidism
• ICD: ICD-11: 5A00

Type(s) of Resistant Mechanism of This Disease

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Investigative Drug(s) 1 drug(s) in total

Thyrotropin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NK2 homeobox 1 (NKX2-1) [1]

• Resistant Disease: Subclinical hypothyroidism [ICD-11: 5A00.22]
• Molecule Alteration: Missense mutation; p.G2626T
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Haploinsufficiency for NKX2-1, due to either chromosomal deletions encompassing the gene locus [94] or deleterious gene mutations, produces a "brain-thyroid-lung" syndrome. The severity of the individual components of the syndrome is very variable, and includes: 1) RTSH (70% of patients), 2) "benign hereditary chorea" (90% of patients) manifesting as neonatal hypotonia preceding the development of juvenile choreoathetosis and ataxia, 3) respiratory distress (55% of patients) due to lung hypoplasia causing significantly increased mortality.

Key Molecule: NK2 homeobox 1 (NKX2-1) [1]

• Resistant Disease: Subclinical hypothyroidism [ICD-11: 5A00.22]
• Molecule Alteration: Missense mutation; p.C2519A
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Haploinsufficiency for NKX2-1, due to either chromosomal deletions encompassing the gene locus [94] or deleterious gene mutations, produces a "brain-thyroid-lung" syndrome. The severity of the individual components of the syndrome is very variable, and includes: 1) RTSH (70% of patients), 2) "benign hereditary chorea" (90% of patients) manifesting as neonatal hypotonia preceding the development of juvenile choreoathetosis and ataxia, 3) respiratory distress (55% of patients) due to lung hypoplasia causing significantly increased mortality.

Key Molecule: NK2 homeobox 1 (NKX2-1) [1]

• Resistant Disease: Subclinical hypothyroidism [ICD-11: 5A00.22]
• Molecule Alteration: Missense mutation; p.C1302A
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Haploinsufficiency for NKX2-1, due to either chromosomal deletions encompassing the gene locus [94] or deleterious gene mutations, produces a "brain-thyroid-lung" syndrome. The severity of the individual components of the syndrome is very variable, and includes: 1) RTSH (70% of patients), 2) "benign hereditary chorea" (90% of patients) manifesting as neonatal hypotonia preceding the development of juvenile choreoathetosis and ataxia, 3) respiratory distress (55% of patients) due to lung hypoplasia causing significantly increased mortality.

Key Molecule: NK2 homeobox 1 (NKX2-1) [1]

• Resistant Disease: Congenital hypothyroidism [ICD-11: 5A00.0]
• Molecule Alteration: Missense mutation; p.G2626T
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Haploinsufficiency for NKX2-1, due to either chromosomal deletions encompassing the gene locus [94] or deleterious gene mutations, produces a "brain-thyroid-lung" syndrome. The severity of the individual components of the syndrome is very variable, and includes: 1) RTSH (70% of patients), 2) "benign hereditary chorea" (90% of patients) manifesting as neonatal hypotonia preceding the development of juvenile choreoathetosis and ataxia, 3) respiratory distress (55% of patients) due to lung hypoplasia causing significantly increased mortality.

Key Molecule: NK2 homeobox 1 (NKX2-1) [1]

• Resistant Disease: Congenital hypothyroidism [ICD-11: 5A00.0]
• Molecule Alteration: Missense mutation; p.C2519A
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Haploinsufficiency for NKX2-1, due to either chromosomal deletions encompassing the gene locus [94] or deleterious gene mutations, produces a "brain-thyroid-lung" syndrome. The severity of the individual components of the syndrome is very variable, and includes: 1) RTSH (70% of patients), 2) "benign hereditary chorea" (90% of patients) manifesting as neonatal hypotonia preceding the development of juvenile choreoathetosis and ataxia, 3) respiratory distress (55% of patients) due to lung hypoplasia causing significantly increased mortality.

Key Molecule: NK2 homeobox 1 (NKX2-1) [1]

• Resistant Disease: Congenital hypothyroidism [ICD-11: 5A00.0]
• Molecule Alteration: Missense mutation; p.C1302A
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Haploinsufficiency for NKX2-1, due to either chromosomal deletions encompassing the gene locus [94] or deleterious gene mutations, produces a "brain-thyroid-lung" syndrome. The severity of the individual components of the syndrome is very variable, and includes: 1) RTSH (70% of patients), 2) "benign hereditary chorea" (90% of patients) manifesting as neonatal hypotonia preceding the development of juvenile choreoathetosis and ataxia, 3) respiratory distress (55% of patients) due to lung hypoplasia causing significantly increased mortality.

Key Molecule: Paired box 8 (PAX8) [1]

• Resistant Disease: Subclinical hypothyroidism [ICD-11: 5A00.22]
• Molecule Alteration: Missense mutation; p.L16P
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: PAX8 mutations are not a relevant cause of sporadic thyroid ectopy or genuine agenesis but found in a minority of cases (e.g. 1/28 German, 1/16 Chinese) within the normotopic hypoplasia subgroup. More generally, heterozygous PAX8 LOF mutations have to be considered as another cause of RTSH that is clinically and by thyroid function tests indistinguishable from that caused by TSHR mutations. The clinical severity can thus range from subclinical hypothyroidism with normal-sized gland to overt hypothyroidism with severe thyroid gland hypoplasia.

Key Molecule: Paired box 8 (PAX8) [1]

• Resistant Disease: Subclinical hypothyroidism [ICD-11: 5A00.22]
• Molecule Alteration: Missense mutation; p.F20S
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: PAX8 mutations are not a relevant cause of sporadic thyroid ectopy or genuine agenesis but found in a minority of cases (e.g. 1/28 German, 1/16 Chinese) within the normotopic hypoplasia subgroup. More generally, heterozygous PAX8 LOF mutations have to be considered as another cause of RTSH that is clinically and by thyroid function tests indistinguishable from that caused by TSHR mutations. The clinical severity can thus range from subclinical hypothyroidism with normal-sized gland to overt hypothyroidism with severe thyroid gland hypoplasia.

Key Molecule: Paired box 8 (PAX8) [1]

• Resistant Disease: Subclinical hypothyroidism [ICD-11: 5A00.22]
• Molecule Alteration: Missense mutation; p.R133Q
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: PAX8 mutations are not a relevant cause of sporadic thyroid ectopy or genuine agenesis but found in a minority of cases (e.g. 1/28 German, 1/16 Chinese) within the normotopic hypoplasia subgroup. More generally, heterozygous PAX8 LOF mutations have to be considered as another cause of RTSH that is clinically and by thyroid function tests indistinguishable from that caused by TSHR mutations. The clinical severity can thus range from subclinical hypothyroidism with normal-sized gland to overt hypothyroidism with severe thyroid gland hypoplasia.

Key Molecule: Paired box 8 (PAX8) [1]

• Resistant Disease: Congenital hypothyroidism [ICD-11: 5A00.0]
• Molecule Alteration: Missense mutation; p.L16P
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: PAX8 mutations are not a relevant cause of sporadic thyroid ectopy or genuine agenesis but found in a minority of cases (e.g. 1/28 German, 1/16 Chinese) within the normotopic hypoplasia subgroup. More generally, heterozygous PAX8 LOF mutations have to be considered as another cause of RTSH that is clinically and by thyroid function tests indistinguishable from that caused by TSHR mutations. The clinical severity can thus range from subclinical hypothyroidism with normal-sized gland to overt hypothyroidism with severe thyroid gland hypoplasia.

Key Molecule: Paired box 8 (PAX8) [1]

• Resistant Disease: Congenital hypothyroidism [ICD-11: 5A00.0]
• Molecule Alteration: Missense mutation; p.F20S
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: PAX8 mutations are not a relevant cause of sporadic thyroid ectopy or genuine agenesis but found in a minority of cases (e.g. 1/28 German, 1/16 Chinese) within the normotopic hypoplasia subgroup. More generally, heterozygous PAX8 LOF mutations have to be considered as another cause of RTSH that is clinically and by thyroid function tests indistinguishable from that caused by TSHR mutations. The clinical severity can thus range from subclinical hypothyroidism with normal-sized gland to overt hypothyroidism with severe thyroid gland hypoplasia.

Key Molecule: Paired box 8 (PAX8) [1]

• Resistant Disease: Congenital hypothyroidism [ICD-11: 5A00.0]
• Molecule Alteration: Missense mutation; p.R133Q
• Resistant Drug: Thyrotropin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: PAX8 mutations are not a relevant cause of sporadic thyroid ectopy or genuine agenesis but found in a minority of cases (e.g. 1/28 German, 1/16 Chinese) within the normotopic hypoplasia subgroup. More generally, heterozygous PAX8 LOF mutations have to be considered as another cause of RTSH that is clinically and by thyroid function tests indistinguishable from that caused by TSHR mutations. The clinical severity can thus range from subclinical hypothyroidism with normal-sized gland to overt hypothyroidism with severe thyroid gland hypoplasia.

References

• Ref 1: Resistance to thyrotropin .Best Pract Res Clin Endocrinol Metab. 2017 Mar;31(2):183-194. doi: 10.1016/j.beem.2017.03.004. Epub 2017 Mar 30. 10.1016/j.beem.2017.03.004