Thyroid hypoplasia

Summary

Thyroid hypoplasia (MONDO:0019861) is a disease with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.5	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000158	Macroglossia	Very frequent (80-99%)
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000821	Hypothyroidism	Very frequent (80-99%)
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0005990	Thyroid hypoplasia	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	thyroid hypoplasia
Mondo ID	MONDO:0019861
Orphanet	95720
ICD-11	936952450
UMLS	C0151516
MedGen	57720
GARD	0008426
MedDRA	10065938
Is cancer (heuristic)	no

Data availability: 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › inherited thyroid metabolism disease › thyroid hormone resistance syndrome › generalized resistance to thyroid hormone › thyroid hypoplasia

Related subtypes (5): thyroid hormone resistance, generalized, autosomal dominant, thyroid hormone resistance, generalized, autosomal recessive, thyroid ectopia, athyreosis, thyroid hemiagenesis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PAX8	Supportive	Autosomal dominant	thyroid hypoplasia	5
SLC26A4	Supportive	Autosomal dominant	thyroid hypoplasia	10
TSHR	Supportive	Autosomal dominant	thyroid hypoplasia	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSHR	Orphanet:424	Familial hyperthyroidism due to mutations in TSH receptor
TSHR	Orphanet:90673	Hypothyroidism due to TSH receptor mutations
TSHR	Orphanet:95713	Athyreosis
TSHR	Orphanet:95720	Thyroid hypoplasia
TSHR	Orphanet:99819	Familial gestational hyperthyroidism
PAX8	Orphanet:146	Differentiated thyroid carcinoma
PAX8	Orphanet:95712	Thyroid ectopia
PAX8	Orphanet:95713	Athyreosis
PAX8	Orphanet:95720	Thyroid hypoplasia
SLC26A4	Orphanet:705	Pendred syndrome
SLC26A4	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC26A4	Orphanet:95713	Athyreosis
SLC26A4	Orphanet:95720	Thyroid hypoplasia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	gencc
PAX8	HGNC:8622	ENSG00000125618	Q06710	Paired box protein Pax-8	gencc
SLC26A4	HGNC:8818	ENSG00000091137	O43511	Pendrin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
PAX8	Paired box protein Pax-8	Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells.
SLC26A4	Pendrin	Sodium-independent transporter of chloride and iodide.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	25.9×	0.114
GPCR	1	8.0×	0.180
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
PAX8	Transcription factor	no		Paired_dom, Homeodomain-like_sf, Pax2_C
SLC26A4	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of thyroid gland	3
thyroid gland	3
left lobe of thyroid gland	2
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSHR	169	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
PAX8	242	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SLC26A4	190	tissue_specific	marker	palpebral conjunctiva, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX8	1,994
TSHR	1,672
SLC26A4	1,648

Intra-cohort edges

A	B	Sources
PAX8	TSHR	string_interaction
SLC26A4	TSHR	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSHR	P16473	9
PAX8	Q06710	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC26A4	O43511	82.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC26A4 causes Pendred syndrome (PDS)	1	3806.7×	0.003	SLC26A4
Formation of intermediate mesoderm	1	475.8×	0.009	PAX8
Inorganic anion exchange by SLC26 transporters	1	423.0×	0.009	SLC26A4
Hormone ligand-binding receptors	1	317.2×	0.009	TSHR
Formation of the nephric duct	1	211.5×	0.011	PAX8
SLC transporter disorders	1	68.0×	0.029	SLC26A4
Disorders of transmembrane transporters	1	46.4×	0.034	SLC26A4
R-HSA-425393	1	43.3×	0.034	SLC26A4
G alpha (s) signalling events	1	24.4×	0.054	TSHR
SLC-mediated transmembrane transport	1	19.7×	0.060	SLC26A4
Transport of small molecules	1	8.4×	0.125	SLC26A4
Disease	1	4.4×	0.212	SLC26A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thyroid-stimulating hormone signaling pathway	1	5617.3×	0.002	TSHR
cellular response to thyrotropin-releasing hormone	1	5617.3×	0.002	TSHR
regulation of thyroid-stimulating hormone secretion	1	5617.3×	0.002	PAX8
pronephric field specification	1	2808.7×	0.002	PAX8
metanephric comma-shaped body morphogenesis	1	2808.7×	0.002	PAX8
obsolete negative regulation of mesenchymal cell apoptotic process involved in metanephric nephron morphogenesis	1	2808.7×	0.002	PAX8
obsolete negative regulation of apoptotic process involved in metanephric collecting duct development	1	2808.7×	0.002	PAX8
obsolete negative regulation of apoptotic process involved in metanephric nephron tubule development	1	2808.7×	0.002	PAX8
positive regulation of metanephric DCT cell differentiation	1	2808.7×	0.002	PAX8
inorganic anion transport	1	1872.4×	0.002	SLC26A4
negative regulation of mesenchymal cell apoptotic process involved in metanephros development	1	1872.4×	0.002	PAX8
cellular response to glycoprotein	1	1872.4×	0.002	TSHR
metanephric distal convoluted tubule development	1	1404.3×	0.003	PAX8
metanephric S-shaped body morphogenesis	1	1404.3×	0.003	PAX8
positive regulation of thyroid hormone generation	1	1404.3×	0.003	PAX8
metanephric epithelium development	1	1123.5×	0.003	PAX8
metanephric nephron tubule formation	1	1123.5×	0.003	PAX8
regulation of metanephric nephron tubule epithelial cell differentiation	1	1123.5×	0.003	PAX8
cellular response to gonadotropin stimulus	1	936.2×	0.003	PAX8
otic vesicle development	1	936.2×	0.003	PAX8
positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	936.2×	0.003	PAX8
iodide transport	1	802.5×	0.003	SLC26A4
pronephros development	1	802.5×	0.003	PAX8
mesenchymal to epithelial transition involved in metanephros morphogenesis	1	702.2×	0.003	PAX8
mesonephros development	1	510.7×	0.004	PAX8
regulation of pH	1	468.1×	0.005	SLC26A4
sulfate transmembrane transport	1	401.2×	0.005	SLC26A4
urogenital system development	1	330.4×	0.006	PAX8
positive regulation of branching involved in ureteric bud morphogenesis	1	267.5×	0.007	PAX8
sensory organ development	1	224.7×	0.008	PAX8

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TSHR	LEVOSALBUTAMOL
PAX8	SORAFENIB TOSYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
PAX8	14	4
SLC26A4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR
CHLOROTRIANISENE	4	TSHR
PHENOXYBENZAMINE HYDROCHLORIDE	4	TSHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC26A4	37	Binding:37
TSHR	33	Functional:24, Binding:9
PAX8	3	Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR
CHLOROTRIANISENE	4	TSHR
PHENOXYBENZAMINE HYDROCHLORIDE	4	TSHR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TSHR, PAX8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC26A4
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC26A4	37	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.