Isolated thyroid-stimulating hormone deficiency

Summary

Isolated thyroid-stimulating hormone deficiency (MONDO:0010139) is a disease caused by TSHB (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: TSHB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18
• Phenotypes (HPO): 42
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0005990	Thyroid hypoplasia	Very frequent (80-99%)
HP:0008245	Pituitary hypothyroidism	Very frequent (80-99%)
HP:0025483	Abnormal circulating thyroglobulin concentration	Very frequent (80-99%)
HP:0031098	Decreased thyroid-stimulating hormone level	Very frequent (80-99%)
HP:0031208	Increased pituitary glycoprotein hormone alpha subunit level	Very frequent (80-99%)
HP:0031219	Reduced radioactive iodine uptake	Very frequent (80-99%)
HP:0031507	Decreased circulating thyroxine level	Very frequent (80-99%)
HP:0000053	Macroorchidism	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000282	Facial edema	Frequent (30-79%)
HP:0000870	Increased circulating prolactin concentration	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0001615	Hoarse cry	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002045	Hypothermia	Frequent (30-79%)
HP:0002690	Large sella turcica	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0003265	Neonatal hyperbilirubinemia	Frequent (30-79%)
HP:0004491	Large posterior fontanelle	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0008828	Delayed proximal femoral epiphyseal ossification	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001662	Bradycardia	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0011437	Maternal autoimmune disease	Excluded (0%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)
HP:0000716	Depression	Very rare (<1-4%)
HP:0000853	Goiter	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated thyroid-stimulating hormone deficiency
Mondo ID	MONDO:0010139
OMIM	275100
Orphanet	90674
DOID	DOID:0070123
UMLS	C0271789
MedGen	78786
GARD	0010129
Is cancer (heuristic)	no

Also known as: CHNG4 · hypothyroidism, congenital, nongoitrous 4 · hypothyroidism, congenital, nongoitrous, 4 · hypothyroidism, congenital, nongoitrous, type 4 · isolated thyrotropin deficiency · isolated TSH deficiency · pituitary cretinism · thyroid-stimulating hormone, deficiency of

Data availability: 18 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hypothyroidism, congenital, nongoitrous › isolated thyroid-stimulating hormone deficiency

Related subtypes (8): hypothyroidism, congenital, nongoitrous, 5, hypothyroidism due to TSH receptor mutations, congenital nongoitrous hypothyroidism 3, congenital nongoitrous hypothyroidism 6, hypothyroidism, congenital, nongoitrous, 2, hypothyroidism, congenital, nongoitrous, 8, hypothyroidism, congenital, nongoitrous, 9, hypothyroidism, congenital, nongoitrous, 7

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

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 likely pathogenic, 3 pathogenic/likely pathogenic, 3 pathogenic, 1 benign, 1 likely benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
12684	NM_000549.5(TSHB):c.145G>A (p.Gly49Arg)	TSHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12685	NM_000549.5(TSHB):c.94G>T (p.Glu32Ter)	TSHB	Pathogenic	no assertion criteria provided
12687	NM_000549.5(TSHB):c.205C>T (p.Gln69Ter)	TSHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12688	NM_000549.5(TSHB):c.162+5G>A	TSHB	Pathogenic	criteria provided, multiple submitters, no conflicts
2733969	NM_000549.5(TSHB):c.230del (p.Phe77fs)	TSHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437070	NM_000549.5(TSHB):c.373del (p.Cys125fs)	TSHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1048762	NM_000549.5(TSHB):c.108_109del (p.Ala37fs)	TSHB	Likely pathogenic	criteria provided, single submitter
3574752	NM_000549.5(TSHB):c.-1_5del (p.Met1_Thr2del)	TSHB	Likely pathogenic	criteria provided, single submitter
3574990	NM_000549.5(TSHB):c.315T>A (p.Cys105Ter)	TSHB	Likely pathogenic	criteria provided, single submitter
875322	NM_000549.5(TSHB):c.*64T>C	TSHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291985	NM_000549.5(TSHB):c.256G>A (p.Gly86Arg)	TSHB	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892743	NM_000549.5(TSHB):c.298G>A (p.Ala100Thr)	TSHB	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892744	NM_000549.5(TSHB):c.43T>C (p.Cys15Arg)	TSHB	Uncertain significance	criteria provided, single submitter
4533274	NM_000549.5(TSHB):c.373T>C (p.Cys125Arg)	TSHB	Uncertain significance	criteria provided, single submitter
976259	NM_000549.5(TSHB):c.374G>A (p.Cys125Tyr)	TSHB	Uncertain significance	criteria provided, single submitter
256640	NM_000549.5(TSHB):c.40A>G (p.Thr14Ala)	TSHB	Benign	criteria provided, multiple submitters, no conflicts
291984	NM_000549.5(TSHB):c.-13A>G	TSHB	Likely benign	criteria provided, single submitter
764732	NM_000549.5(TSHB):c.223A>G (p.Arg75Gly)	TSHB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
TSHB	Definitive	Autosomal recessive	isolated thyroid-stimulating hormone deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSHB	Orphanet:90674	Isolated thyroid-stimulating hormone deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSHB	HGNC:12372	ENSG00000134200	P01222	Thyrotropin subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSHB	Thyrotropin subunit beta	Indispensable for the control of thyroid structure and metabolism.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSHB	Other/Unknown	no		Gonadotropin_bsu, Glyco_hormone_CN, Gonadotropin_bsu_CS

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSHB	150	tissue_specific	yes	adenohypophysis, pituitary gland, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSHB	908

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSHB	P01222	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycoprotein hormones	1	951.7×	0.002	TSHB
Hormone ligand-binding receptors	1	951.7×	0.002	TSHB
Thyroxine biosynthesis	1	815.7×	0.002	TSHB
G alpha (s) signalling events	1	73.2×	0.014	TSHB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
anatomical structure morphogenesis	1	139.3×	0.022	TSHB
cell-cell signaling	1	69.6×	0.022	TSHB
G protein-coupled receptor signaling pathway	1	36.2×	0.028	TSHB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

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

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)
TSHB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns