Bannayan-Riley-Ruvalcaba syndrome

Summary

Bannayan-Riley-Ruvalcaba syndrome (MONDO:0007924) is a disease with 2 cohort genes and 2 clinical trials. Top therapeutic interventions include everolimus.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 11
• Phenotypes (HPO): 55
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

55 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0002250	Abnormal large intestine morphology	Very frequent (80-99%)
HP:0003764	Nevus	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004390	Hamartomatous polyposis	Very frequent (80-99%)
HP:0005306	Capillary hemangioma	Very frequent (80-99%)
HP:0007400	Irregular hyperpigmentation	Very frequent (80-99%)
HP:0012032	Lipoma	Very frequent (80-99%)
HP:0100013	Neoplasm of the breast	Very frequent (80-99%)
HP:0100026	Arteriovenous malformation	Very frequent (80-99%)
HP:0100761	Visceral angiomatosis	Very frequent (80-99%)
HP:0200008	Intestinal polyposis	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001482	Subcutaneous nodule	Frequent (30-79%)
HP:0001933	Subcutaneous hemorrhage	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000098	Tall stature	Occasional (5-29%)
HP:0000189	Narrow palate	Occasional (5-29%)
HP:0000268	Dolichocephaly	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000445	Wide nose	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000587	Abnormal optic nerve morphology	Occasional (5-29%)
HP:0000872	Hashimoto thyroiditis	Occasional (5-29%)
HP:0000965	Cutis marmorata	Occasional (5-29%)
HP:0001004	Lymphedema	Occasional (5-29%)
HP:0001009	Telangiectasia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001681	Angina pectoris	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0002858	Meningioma	Occasional (5-29%)
HP:0002890	Thyroid carcinoma	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0004942	Aortic aneurysm	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bannayan-Riley-Ruvalcaba syndrome
Mondo ID	MONDO:0007924
OMIM	153480
Orphanet	109
DOID	DOID:0050657
ICD-10-CM	E71.440
ICD-11	357383447
NCIT	C3939
SNOMED CT	21984008
UMLS	C0265326
MedGen	78554
GARD	0005887
NORD	1684
Is cancer (heuristic)	no

Also known as: Bannayan syndrome · Bannayan-Riley-Ruvalcaba syndrome · Bannayan-Zonana syndrome · BRRS · BZS · macrocephaly multiple lipomas and hemangiomata · macrocephaly pseudopapilledema and multiple hemangiomas · macrocephaly with multiple lipomas and hemangiomas · Myhre-Riley-Smith syndrome · RILEY-SMITH syndrome · RMSS · Ruvalcaba -Myhre-Smith syndrome · Ruvalcaba-MYHRE-SMITH syndrome

Data availability: 11 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › Bannayan-Riley-Ruvalcaba syndrome

Related subtypes (59): arterial disorder, ischemic colitis, thrombotic disease, capillary disorder, angiodysplasia, hepatic vascular disorder, vascular hemostatic disease, vein disorder, ischemic disease, peripheral vascular disease, venous thromboembolism, ocular vascular disorder, cholesterol embolism, thoracic outlet syndrome, idiopathic spontaneous coronary artery dissection, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, angioosteohypertrophic syndrome, arterial tortuosity syndrome, hereditary arterial and articular multiple calcification syndrome, pulmonary venoocclusive disease, multiple cutaneous and mucosal venous malformations, arterial dissection-lentiginosis syndrome, patent ductus arteriosus, multisystemic smooth muscle dysfunction syndrome, STING-associated vasculopathy with onset in infancy, capillary malformation, Ehlers-Danlos syndrome, vascular-like type, calciphylaxis, neonatal Marfan syndrome, Ehlers-Danlos syndrome, vascular type, lethal arteriopathy syndrome due to fibulin-4 deficiency, congenital portosystemic shunt, arterial calcification of infancy, vasculitis, Loeys-Dietz syndrome, skin vascular disease, lymphatic malformation, familial thoracic aortic aneurysm and aortic dissection, congenital anomaly of superior vena cava, congenital anomaly of the inferior vena cava, congenital anomaly of hepatic vein, congenital renal artery stenosis, internal carotid agenesis, coronary sinus stenosis, coronary sinus atresia, vascular occlusion disorder, vascular insufficiency disorder, blood vessel neoplasm, vascular ectasia, vascular disorder of penis, fibrocartilaginous embolism, vascular malformation, lymphatic vessel neoplasm, neurovascular disorder, superior vena cava syndrome, coronary microvascular disorder, segmental arterial mediolysis, bleeding disorder, vascular-type, arterial tortuosity-bone fragility syndrome

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

11 retrieved; paginated sample, class counts are floors:

3 pathogenic/likely pathogenic, 2 uncertain significance, 2 not provided, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
216987	NM_000314.8(PTEN):c.860C>G (p.Ser287Ter)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627548	NM_000314.8(PTEN):c.475delinsCTT (p.Arg159fs)	PTEN	Pathogenic	criteria provided, single submitter
428234	NM_000314.8(PTEN):c.377C>T (p.Ala126Val)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
439291	NM_000314.8(PTEN):c.548dup (p.Asn184fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
822660	NM_000314.8(PTEN):c.302T>C (p.Ile101Thr)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064566	NM_000314.8(PTEN):c.752G>A (p.Gly251Asp)	PTEN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127677	NM_000314.8(PTEN):c.-844T>C	MLDHR	Uncertain significance	criteria provided, multiple submitters, no conflicts
560622	NM_000314.8(PTEN):c.152_160dup (p.Asp51_Val53dup)	PTEN	Uncertain significance	criteria provided, single submitter
127695	NM_000314.8(PTEN):c.892C>G (p.Gln298Glu)	PTEN	Likely benign	reviewed by expert panel
1810292	NM_000314.8(PTEN):c.-687G>A	LOC130004274	not provided	no classification provided
2578336	NM_000314.8(PTEN):c.634+3_634+7delinsTCTCATCCTTGAATTT	PTEN	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 14 · 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
PTEN	Supportive	Autosomal dominant	Bannayan-Riley-Ruvalcaba syndrome	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	gencc,clinvar
MLDHR	HGNC:55481	ENSG00000289051	C0HLV8	PTEN upstream open reading frame MP31	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
MLDHR	PTEN upstream open reading frame MP31	Inhibits lactate dehydrogenase (LDH)-mediated conversion of lactate to pyruvate in mitochondria by competing with mitochondrial LDH for binding to NAD(+).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
MLDHR	Other/Unknown	no		MP31

Expression context

Cohort genes with no expression data: 1.

1 cohort gene 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)	1
unknown	1

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
endothelial cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
MLDHR

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTEN	11,626
MLDHR	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTEN	P60484	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MLDHR	C0HLV8	83.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 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
PTEN Loss of Function in Cancer	1	5710.0×	0.002	PTEN
Regulation of PTEN mRNA translation	1	1142.0×	0.004	PTEN
Regulation of PTEN localization	1	1038.2×	0.004	PTEN
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.007	PTEN
Transcriptional Regulation by MECP2	1	317.2×	0.007	PTEN
Negative regulation of the PI3K/AKT network	1	278.5×	0.007	PTEN
Ovarian tumor domain proteases	1	278.5×	0.007	PTEN
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PTEN
Regulation of PTEN stability and activity	1	184.2×	0.007	PTEN
Regulation of PTEN gene transcription	1	178.4×	0.007	PTEN
TP53 Regulates Metabolic Genes	1	129.8×	0.008	PTEN
Downstream TCR signaling	1	128.3×	0.008	PTEN
Ub-specific processing proteases	1	53.1×	0.019	PTEN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of synaptic vesicle clustering	1	4213.0×	0.005	PTEN
negative regulation of keratinocyte migration	1	2808.7×	0.005	PTEN
rhythmic synaptic transmission	1	2106.5×	0.005	PTEN
central nervous system myelin maintenance	1	1404.3×	0.005	PTEN
negative regulation of oxidative phosphorylation	1	1203.7×	0.005	MLDHR
negative regulation of cell cycle G1/S phase transition	1	1203.7×	0.005	PTEN
negative regulation of wound healing, spreading of epidermal cells	1	1203.7×	0.005	PTEN
spindle assembly involved in female meiosis	1	936.2×	0.005	PTEN
central nervous system neuron axonogenesis	1	936.2×	0.005	PTEN
postsynaptic density assembly	1	936.2×	0.005	PTEN
neuron-neuron synaptic transmission	1	842.6×	0.005	PTEN
negative regulation of peptidyl-serine phosphorylation	1	842.6×	0.005	PTEN
negative regulation of cell size	1	842.6×	0.005	PTEN
presynaptic membrane assembly	1	842.6×	0.005	PTEN
negative regulation of organ growth	1	702.2×	0.005	PTEN
forebrain morphogenesis	1	702.2×	0.005	PTEN
multicellular organismal response to stress	1	648.1×	0.005	PTEN
negative regulation of axonogenesis	1	648.1×	0.005	PTEN
cellular response to electrical stimulus	1	648.1×	0.005	PTEN
negative regulation of excitatory postsynaptic potential	1	648.1×	0.005	PTEN
maternal behavior	1	561.7×	0.005	PTEN
prepulse inhibition	1	561.7×	0.005	PTEN
locomotor rhythm	1	526.6×	0.005	PTEN
synapse maturation	1	468.1×	0.005	PTEN
dendritic spine morphogenesis	1	443.5×	0.005	PTEN
negative regulation of focal adhesion assembly	1	383.0×	0.006	PTEN
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	351.1×	0.006	PTEN
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.006	PTEN
phosphatidylinositol dephosphorylation	1	324.1×	0.006	PTEN
positive regulation of intracellular signal transduction	1	324.1×	0.006	PTEN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTEN	0	0
MLDHR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PTEN	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MLDHR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTEN	8	—
MLDHR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07218575	PHASE2/PHASE3	NOT_YET_RECRUITING	Double-Blind Trial of Everolimus for Improving Social Abilities in PTEN Germline Mutations
NCT04094675	PHASE2	COMPLETED	Sirolimus for Cowden Syndrome With Colon Polyposis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EVEROLIMUS	4	1