PTEN Hamartoma Tumor Syndrome

Mendelian MONDO:0017623 Pathograph 20 autosomal dominant disease hereditary neoplastic syndrome developmental defect during embryogenesis

PTEN hamartoma tumor syndrome is an autosomal dominant hereditary cancer and overgrowth syndrome caused by heterozygous germline pathogenic variants in PTEN. PTEN loss increases PI3K/AKT/mTOR signaling and cell growth, producing hamartomas, macrocephaly and other neurodevelopmental features, mucocutaneous lesions, gastrointestinal polyposis, vascular malformations, and elevated risks for breast, thyroid, endometrial, renal, colorectal, and other cancers.

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1
Inheritance
4
Pathophys.
15
Phenotypes
20
Pathograph
1
Genes
3
Treatments
5
Subtypes
1
Trials
6
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
PHTS is inherited in an autosomal dominant manner, with each child of an affected individual having a 50% chance of inheriting the familial PTEN pathogenic variant.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:306498 SUPPORT Other
"- Autosomal dominant"
Orphanet lists autosomal dominant inheritance for PHTS.
PMID:20301661 SUPPORT Human Clinical
"GENETIC COUNSELING: PHTS is inherited in an autosomal dominant manner."
GeneReviews directly states autosomal dominant inheritance for PHTS.
◆

Subtypes

5
Cowden syndrome MONDO:0016063
Adult-presenting multiple hamartoma and cancer-predisposition phenotype with mucocutaneous lesions, macrocephaly, benign hamartomas, and elevated breast, thyroid, endometrial, renal, and colorectal cancer risk.
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome."
GeneReviews lists Cowden syndrome as part of PHTS.
Bannayan-Riley-Ruvalcaba syndrome MONDO:0007924
Childhood-onset PHTS presentation characterized by macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis.
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis."
GeneReviews defines BRRS as a congenital PHTS presentation.
Proteus-like syndrome MONDO:0017571
Proteus-like syndrome is an Orphanet-listed PHTS group disorder in the PTEN-related Proteus spectrum.
Show evidence (1 reference)
ORPHA:306498 SUPPORT Other
"Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome."
Orphanet lists Proteus-like syndrome within the PHTS disease group.
Lhermitte-Duclos disease MONDO:0019002
Dysplastic gangliocytoma of the cerebellum can occur as a PHTS/Cowden spectrum manifestation and is included in the Orphanet disease-group definition.
Show evidence (1 reference)
ORPHA:306498 SUPPORT Other
"Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome."
Orphanet lists Lhermitte-Duclos disease within the PHTS disease group.
Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome MONDO:0015293
SOLAMEN syndrome is an Orphanet-listed PHTS group disorder combining segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus manifestations.
Show evidence (1 reference)
ORPHA:306498 SUPPORT Other
"Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome."
Orphanet lists SOLAMEN syndrome within the PHTS disease group.
⚙

Pathophysiology

4
PTEN loss and PI3K AKT mTOR activation
Germline PTEN pathogenic variants reduce tumor-suppressor lipid phosphatase activity, removing negative regulation of the PI3K/AKT/mTOR signaling axis. This increases cell growth, migration, proliferation, and survival.
PTEN link
PI3K/AKT signaling link ↑ INCREASED TOR signaling link ↑ INCREASED cell proliferation link ↑ INCREASED
Downstream
Hamartomatous tissue overgrowth Increased PI3K/AKT/mTOR signaling drives cellular overgrowth and benign hamartomas.
Multiorgan cancer predisposition Increased survival and proliferation create a tumor-predisposition state in susceptible tissues.
Neurodevelopmental overgrowth and dysregulation PTEN signaling dysregulation affects brain growth and neurodevelopment.
Show evidence (1 reference)
PMID:18781191 SUPPORT Human Clinical
"PTEN is located on chromosome 10q22-23 and negatively regulates the prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival."
This review directly links PTEN loss to PI3K/AKT/mTOR activation and increased cellular growth.
Hamartomatous tissue overgrowth
PTEN pathway activation drives benign disorganized growth of tissue-native elements, producing hamartomas in skin, mucosa, gastrointestinal tract, thyroid, adipose tissue, and other organs.
cell proliferation link ↑ INCREASED
Downstream
Hamartoma
Mucocutaneous papillomatous papules
Hamartomatous polyposis
Multiple lipomas
Show evidence (2 references)
PMID:18781191 SUPPORT Human Clinical
"These syndromes are driven by cellular overgrowth, leading to benign hamartomas in virtually any organ."
This directly supports hamartomatous overgrowth as a core PHTS mechanism.
ORPHA:306498 SUPPORT Other
"A group rare skin tumor or hamartoma diseases characterized by a germline PTEN mutation and clinical manifestations of hamartomas, overgrowth, and increased risk of neoplasia"
Orphanet defines PHTS by germline PTEN mutation with hamartomas and overgrowth.
Multiorgan cancer predisposition
PTEN germline variants predispose to malignant transformation in multiple tissues, especially breast, thyroid, endometrium, kidney, colon/rectum, and skin, with age- and sex-specific cancer risks.
cell proliferation link ↑ INCREASED
Downstream
Breast carcinoma
Thyroid carcinoma
Endometrial carcinoma
Renal cancer
Colon cancer
Melanoma
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"Patients with PTEN hamartoma tumor syndrome (PHTS, comprising Cowden, Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes) are at increased risk of developing cancer due to pathogenic PTEN germline variants."
This cancer-risk review directly supports PTEN-germline-driven multiorgan cancer risk.
Neurodevelopmental overgrowth and dysregulation
PHTS includes childhood neurodevelopmental presentations with intellectual disability, macrocephaly, autism, and developmental delay, consistent with PTEN-dependent regulation of growth and signaling in the developing nervous system.
neurogenesis link ⚠ ABNORMAL
Downstream
Macrocephaly
Autism
Global developmental delay
Show evidence (1 reference)
PMID:31609537 SUPPORT Human Clinical
"PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap."
This childhood clinical review supports neurodevelopmental and overgrowth phenotypes in PHTS.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PTEN Hamartoma Tumor Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Breast 1
Breast carcinoma Breast carcinoma (HP:0003002)
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
This review quantifies breast cancer risk in PHTS cohorts.
Digestive 2
Hamartomatous polyposis Hamartomatous polyposis (HP:0004390)
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis."
GeneReviews directly identifies intestinal hamartomatous polyposis in a PHTS subtype.
Colon cancer Colon cancer (HP:0003003)
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
This review quantifies colorectal cancer risk in PHTS cohorts; colon cancer is used as the closest specific HPO term.
Endocrine 1
Thyroid carcinoma Thyroid carcinoma (HP:0002890)
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
This review quantifies thyroid cancer risk in PHTS cohorts.
Genitourinary 2
Endometrial carcinoma Endometrial carcinoma (HP:0012114)
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
This review quantifies endometrial cancer risk in PHTS cohorts.
Renal cancer Renal neoplasm (HP:0009726)
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
This review quantifies renal cancer risk in PHTS cohorts.
Head and Neck 1
Macrocephaly Macrocephaly (HP:0000256)
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s."
GeneReviews lists macrocephaly among usual Cowden/PHTS manifestations.
Musculoskeletal 1
Multiple lipomas Multiple lipomas (HP:0001012)
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis."
GeneReviews lists lipomas among BRRS/PHTS features.
Nervous System 2
Global developmental delay Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:31609537 SUPPORT Human Clinical
"PHTS incorporates a number of historical clinical presentations including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly-autism/developmental delay syndrome."
This review lists developmental delay as part of a recognized PHTS childhood presentation.
Autism Autism (HP:0000717)
Show evidence (1 reference)
PMID:26564076 SUPPORT Human Clinical
"There is also a broad range of neurodevelopmental effects, with some patients having no challenges and others with severe autism spectrum disorder and mental retardation."
This clinical review supports autism as part of PHTS neurodevelopmental involvement.
Neoplasm 1
Hamartoma Hamartoma (HP:0010566)
Show evidence (1 reference)
ORPHA:306498 SUPPORT Other
"A group rare skin tumor or hamartoma diseases characterized by a germline PTEN mutation and clinical manifestations of hamartomas, overgrowth, and increased risk of neoplasia"
Orphanet defines PHTS as a hamartoma disease group.
Other 4
Mucocutaneous papillomatous papules Generalized papillary lesions (HP:0007482)
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s."
GeneReviews lists trichilemmomas and papillomatous papules as usual PHTS/Cowden manifestations.
Hashimoto thyroiditis Hashimoto thyroiditis (HP:0000872)
Show evidence (1 reference)
ORPHA:306498 SUPPORT Other
"Non-malignant manifestations include macrocephaly, benign thyroid pathology (especially Hashimoto thyroiditis), mucocutaneous hamartomas, colonic polyps, and vascular malformations."
Orphanet specifically lists Hashimoto thyroiditis among benign PHTS manifestations.
Vascular malformations Abnormal blood vessel morphology (HP:0033353)
Show evidence (1 reference)
ORPHA:306498 SUPPORT Other
"Non-malignant manifestations include macrocephaly, benign thyroid pathology (especially Hashimoto thyroiditis), mucocutaneous hamartomas, colonic polyps, and vascular malformations."
Orphanet lists vascular malformations among non-malignant PHTS manifestations.
Melanoma Melanoma (HP:0002861)
Show evidence (1 reference)
PMID:33140411 SUPPORT Human Clinical
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
This review quantifies melanoma risk in PHTS cohorts.
🧬

Genetic Associations

1
PTEN (Causative)
Show evidence (3 references)
PMID:20301661 SUPPORT Human Clinical
"DIAGNOSIS/TESTING: The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing."
GeneReviews defines PHTS diagnosis by heterozygous germline PTEN pathogenic variants.
PMID:26564076 SUPPORT Human Clinical
"While most cases are inherited in a family for generations, following an autosomal dominant pattern, at least 10% and perhaps as many as 44% of cases are due to a new (de novo) mutation."
This supports the de novo PTEN variant rate noted for genetic counseling.
CGGV:assertion_2e9e89c0-8d1b-4276-bd6f-90c7b7190ffb-2024-04-05T170000.000Z SUPPORT Other
"PTEN | HGNC:9588 | PTEN hamartoma tumor syndrome | MONDO:0017623 | AD | Definitive"
ClinGen classifies the PTEN-PTEN hamartoma tumor syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Treatments

3
Cancer surveillance
Action: cancer screening MAXO:0000126
Lifelong surveillance aims to detect PHTS-associated cancers early, including thyroid ultrasound, dermatologic evaluation, breast screening, endometrial assessment, colonoscopy, and renal imaging according to age and family history.
Target Phenotypes: Breast carcinoma ↗ Thyroid carcinoma ↗ Endometrial carcinoma ↗ Renal cancer ↗ Colon cancer ↗ Melanoma ↗
Show evidence (2 references)
PMID:20301661 SUPPORT Human Clinical
"Surveillance: To detect tumors at the earliest, most treatable stages: Children (age <18 years). Yearly thyroid ultrasound from the time of diagnosis (earliest reported at age 7 years) and skin check with physical examination. Adults. Yearly thyroid ultrasound and dermatologic evaluation. Women..."
GeneReviews supports age-based thyroid, skin, breast, endometrial, colon, and renal surveillance in PHTS.
PMID:33140411 SUPPORT Human Clinical
"This review supports breast and thyroid cancer surveillance as proposed by current European and American guidelines."
This cancer-risk review supports breast and thyroid surveillance in PHTS.
Genetic counseling
Action: genetic counseling MAXO:0000079
Counseling informs autosomal dominant recurrence risk, testing of at-risk relatives, reproductive options, and syndrome-specific surveillance.
Show evidence (1 reference)
PMID:20301661 SUPPORT Human Clinical
"Evaluation of relatives at risk: When a PTEN pathogenic variant has been identified in a proband, molecular genetic testing of asymptomatic at-risk relatives can identify those who have the family-specific pathogenic variant and warrant ongoing surveillance."
This supports family counseling and cascade testing for PHTS.
Everolimus investigational therapy
Action: Pharmacotherapy NCIT:C15986
Agent: everolimus ↗
Everolimus targets mTOR overactivity in PHTS and has been tested in a randomized phase II trial for neurocognitive symptoms. The trial showed tolerability and target-engagement/secondary-endpoint signals but did not meet the primary efficacy endpoint, so this remains investigational rather than routine PHTS care.
Target Phenotypes: Autism ↗ Global developmental delay ↗
Show evidence (1 reference)
PMID:35594551 PARTIAL Human Clinical
"Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement."
This phase II trial supports safety but not established efficacy for neurocognitive benefit.
🔬

Clinical Trials

1
NCT02991807 PHASE_II COMPLETED
Randomized double-blind placebo-controlled phase II trial of everolimus in individuals with PTEN mutations, testing safety and neurocognitive or behavioral outcomes.
Target Phenotypes: Autism ↗ Global developmental delay ↗
Show evidence (1 reference)
clinicaltrials:NCT02991807 SUPPORT Human Clinical
"Investigators are conducting research to evaluate the potential safety and efficacy of RAD001 (everolimus) in this patient population, and the potential neurocognitive benefits from treatment with RAD001 or placebo for a six month period."
The trial registry identifies the randomized everolimus study in PTEN mutation carriers.
{ }

Source YAML

click to show 
name: PTEN Hamartoma Tumor Syndrome
creation_date: "2026-05-07T19:55:00Z"
updated_date: "2026-05-07T20:54:41Z"
category: Mendelian
description: >-
  PTEN hamartoma tumor syndrome is an autosomal dominant hereditary cancer and
  overgrowth syndrome caused by heterozygous germline pathogenic variants in
  PTEN. PTEN loss increases PI3K/AKT/mTOR signaling and cell growth, producing
  hamartomas, macrocephaly and other neurodevelopmental features, mucocutaneous
  lesions, gastrointestinal polyposis, vascular malformations, and elevated
  risks for breast, thyroid, endometrial, renal, colorectal, and other cancers.
synonyms:
- PHTS
- PTEN-related hamartoma tumor syndrome
- PTEN hamartoma tumour syndrome
disease_term:
  preferred_term: PTEN hamartoma tumor syndrome
  term:
    id: MONDO:0017623
    label: PTEN hamartoma tumor syndrome
parents:
- autosomal dominant disease
- hereditary neoplastic syndrome
- developmental defect during embryogenesis
prevalence:
- population: Worldwide
  percentage: 1-9 / 100,000
  notes: >-
    Orphanet reports PHTS point prevalence in the 1-9 per 100,000 range.
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| 1-9 / 100 000 | Worldwide | Point prevalence | PMID:40231587 |"
    explanation: Orphadata provides the worldwide point-prevalence class for PHTS.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    PHTS is inherited in an autosomal dominant manner, with each child of an
    affected individual having a 50% chance of inheriting the familial PTEN
    pathogenic variant.
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "- Autosomal dominant"
    explanation: Orphanet lists autosomal dominant inheritance for PHTS.
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GENETIC COUNSELING: PHTS is inherited in an autosomal dominant manner.
    explanation: GeneReviews directly states autosomal dominant inheritance for PHTS.
has_subtypes:
- name: Cowden syndrome
  subtype_term:
    preferred_term: Cowden syndrome
    term:
      id: MONDO:0016063
      label: Cowden disease
  description: >-
    Adult-presenting multiple hamartoma and cancer-predisposition phenotype with
    mucocutaneous lesions, macrocephaly, benign hamartomas, and elevated breast,
    thyroid, endometrial, renal, and colorectal cancer risk.
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS),
      Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome
      (PS), and PTEN-related Proteus-like syndrome.
    explanation: GeneReviews lists Cowden syndrome as part of PHTS.
- name: Bannayan-Riley-Ruvalcaba syndrome
  subtype_term:
    preferred_term: Bannayan-Riley-Ruvalcaba syndrome
    term:
      id: MONDO:0007924
      label: Bannayan-Riley-Ruvalcaba syndrome
  description: >-
    Childhood-onset PHTS presentation characterized by macrocephaly,
    hamartomatous intestinal polyposis, lipomas, and pigmented macules of the
    glans penis.
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BRRS is a congenital disorder characterized by macrocephaly, intestinal
      hamartomatous polyposis, lipomas, and pigmented macules of the glans
      penis.
    explanation: GeneReviews defines BRRS as a congenital PHTS presentation.
- name: Proteus-like syndrome
  subtype_term:
    preferred_term: Proteus-like syndrome
    term:
      id: MONDO:0017571
      label: Proteus-like syndrome
  description: >-
    Proteus-like syndrome is an Orphanet-listed PHTS group disorder in the
    PTEN-related Proteus spectrum.
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba
      syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental
      outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome.
    explanation: Orphanet lists Proteus-like syndrome within the PHTS disease group.
- name: Lhermitte-Duclos disease
  subtype_term:
    preferred_term: Lhermitte-Duclos disease
    term:
      id: MONDO:0019002
      label: Lhermitte-Duclos disease
  description: >-
    Dysplastic gangliocytoma of the cerebellum can occur as a PHTS/Cowden
    spectrum manifestation and is included in the Orphanet disease-group
    definition.
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba
      syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental
      outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome.
    explanation: Orphanet lists Lhermitte-Duclos disease within the PHTS disease group.
- name: SOLAMEN syndrome
  display_name: Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
  subtype_term:
    preferred_term: segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
    term:
      id: MONDO:0015293
      label: segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
  description: >-
    SOLAMEN syndrome is an Orphanet-listed PHTS group disorder combining
    segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal
    nevus manifestations.
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba
      syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental
      outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome.
    explanation: Orphanet lists SOLAMEN syndrome within the PHTS disease group.
pathophysiology:
- name: PTEN loss and PI3K AKT mTOR activation
  description: >-
    Germline PTEN pathogenic variants reduce tumor-suppressor lipid phosphatase
    activity, removing negative regulation of the PI3K/AKT/mTOR signaling axis.
    This increases cell growth, migration, proliferation, and survival.
  genes:
  - preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  biological_processes:
  - preferred_term: PI3K/AKT signaling
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  - preferred_term: cell proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  downstream:
  - target: Hamartomatous tissue overgrowth
    causal_link_type: DIRECT
    description: Increased PI3K/AKT/mTOR signaling drives cellular overgrowth and benign hamartomas.
  - target: Multiorgan cancer predisposition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Increased survival and proliferation create a tumor-predisposition state in susceptible tissues.
  - target: Neurodevelopmental overgrowth and dysregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: PTEN signaling dysregulation affects brain growth and neurodevelopment.
  evidence:
  - reference: PMID:18781191
    reference_title: PTEN hamartoma tumor syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTEN is located on chromosome 10q22-23 and negatively regulates the
      prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity.
      Loss of PTEN activates this pathway and leads to increased cellular
      growth, migration, proliferation, and survival.
    explanation: This review directly links PTEN loss to PI3K/AKT/mTOR activation and increased cellular growth.
- name: Hamartomatous tissue overgrowth
  description: >-
    PTEN pathway activation drives benign disorganized growth of tissue-native
    elements, producing hamartomas in skin, mucosa, gastrointestinal tract,
    thyroid, adipose tissue, and other organs.
  biological_processes:
  - preferred_term: cell proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  downstream:
  - target: Hamartoma
    causal_link_type: DIRECT
  - target: Mucocutaneous papillomatous papules
    causal_link_type: DIRECT
  - target: Hamartomatous polyposis
    causal_link_type: DIRECT
  - target: Multiple lipomas
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:18781191
    reference_title: PTEN hamartoma tumor syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These syndromes are driven by cellular overgrowth, leading to benign
      hamartomas in virtually any organ.
    explanation: This directly supports hamartomatous overgrowth as a core PHTS mechanism.
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A group rare skin tumor or hamartoma diseases characterized by a germline
      PTEN mutation and clinical manifestations of hamartomas, overgrowth, and
      increased risk of neoplasia
    explanation: Orphanet defines PHTS by germline PTEN mutation with hamartomas and overgrowth.
- name: Multiorgan cancer predisposition
  description: >-
    PTEN germline variants predispose to malignant transformation in multiple
    tissues, especially breast, thyroid, endometrium, kidney, colon/rectum, and
    skin, with age- and sex-specific cancer risks.
  biological_processes:
  - preferred_term: cell proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  downstream:
  - target: Breast carcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Thyroid carcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Endometrial carcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Renal cancer
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Colon cancer
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Melanoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with PTEN hamartoma tumor syndrome (PHTS, comprising Cowden,
      Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes) are at increased
      risk of developing cancer due to pathogenic PTEN germline variants.
    explanation: This cancer-risk review directly supports PTEN-germline-driven multiorgan cancer risk.
- name: Neurodevelopmental overgrowth and dysregulation
  description: >-
    PHTS includes childhood neurodevelopmental presentations with intellectual
    disability, macrocephaly, autism, and developmental delay, consistent with
    PTEN-dependent regulation of growth and signaling in the developing nervous
    system.
  biological_processes:
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: ABNORMAL
  downstream:
  - target: Macrocephaly
    causal_link_type: DIRECT
  - target: Autism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Global developmental delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31609537
    reference_title: "PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal
      dominant condition associated with intellectual disability, overgrowth,
      and tumor predisposition phenotypes, which often overlap.
    explanation: This childhood clinical review supports neurodevelopmental and overgrowth phenotypes in PHTS.
phenotypes:
- category: Growth
  name: Macrocephaly
  description: >-
    Macrocephaly is a common PHTS feature and is especially prominent in
    Bannayan-Riley-Ruvalcaba and macrocephaly-autism/developmental-delay
    presentations.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals usually have macrocephaly, trichilemmomas, and
      papillomatous papules, and present by the late 20s.
    explanation: GeneReviews lists macrocephaly among usual Cowden/PHTS manifestations.
- category: Neoplastic
  name: Hamartoma
  description: >-
    Benign hamartomas across skin, mucosa, gastrointestinal tract, thyroid, and
    other tissues are central to the syndrome group.
  phenotype_term:
    preferred_term: Hamartoma
    term:
      id: HP:0010566
      label: Hamartoma
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A group rare skin tumor or hamartoma diseases characterized by a germline
      PTEN mutation and clinical manifestations of hamartomas, overgrowth, and
      increased risk of neoplasia
    explanation: Orphanet defines PHTS as a hamartoma disease group.
- category: Dermatologic
  name: Mucocutaneous papillomatous papules
  description: >-
    Trichilemmomas and papillomatous papules are characteristic mucocutaneous
    findings in Cowden-spectrum PHTS.
  phenotype_term:
    preferred_term: mucocutaneous papillomatous papules
    term:
      id: HP:0007482
      label: Generalized papillary lesions
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals usually have macrocephaly, trichilemmomas, and
      papillomatous papules, and present by the late 20s.
    explanation: GeneReviews lists trichilemmomas and papillomatous papules as usual PHTS/Cowden manifestations.
- category: Gastrointestinal
  name: Hamartomatous polyposis
  description: >-
    Gastrointestinal hamartomatous polyposis is prominent in BRRS and occurs
    across the PHTS spectrum.
  phenotype_term:
    preferred_term: Hamartomatous polyposis
    term:
      id: HP:0004390
      label: Hamartomatous polyposis
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BRRS is a congenital disorder characterized by macrocephaly, intestinal
      hamartomatous polyposis, lipomas, and pigmented macules of the glans
      penis.
    explanation: GeneReviews directly identifies intestinal hamartomatous polyposis in a PHTS subtype.
- category: Neoplastic
  name: Multiple lipomas
  description: >-
    Multiple lipomas are a common benign-tumor manifestation of
    Bannayan-Riley-Ruvalcaba spectrum PHTS.
  phenotype_term:
    preferred_term: Multiple lipomas
    term:
      id: HP:0001012
      label: Multiple lipomas
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BRRS is a congenital disorder characterized by macrocephaly, intestinal
      hamartomatous polyposis, lipomas, and pigmented macules of the glans
      penis.
    explanation: GeneReviews lists lipomas among BRRS/PHTS features.
- category: Endocrine
  name: Hashimoto thyroiditis
  description: >-
    Benign thyroid disease, especially Hashimoto thyroiditis, is a
    non-malignant PHTS feature.
  phenotype_term:
    preferred_term: Hashimoto thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto thyroiditis
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Non-malignant manifestations include macrocephaly, benign thyroid
      pathology (especially Hashimoto thyroiditis), mucocutaneous hamartomas,
      colonic polyps, and vascular malformations.
    explanation: Orphanet specifically lists Hashimoto thyroiditis among benign PHTS manifestations.
- category: Cardiovascular
  name: Vascular malformations
  description: >-
    Vascular malformations occur across the PHTS spectrum; a broad HPO vascular
    morphology term is used because the Orphanet statement does not specify a
    single lesion class.
  phenotype_term:
    preferred_term: Vascular malformations
    term:
      id: HP:0033353
      label: Abnormal blood vessel morphology
  evidence:
  - reference: ORPHA:306498
    reference_title: PTEN hamartoma tumor syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Non-malignant manifestations include macrocephaly, benign thyroid
      pathology (especially Hashimoto thyroiditis), mucocutaneous hamartomas,
      colonic polyps, and vascular malformations.
    explanation: Orphanet lists vascular malformations among non-malignant PHTS manifestations.
- category: Neurologic
  name: Global developmental delay
  description: >-
    Developmental delay and intellectual disability are important childhood
    PHTS presentations.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31609537
    reference_title: "PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PHTS incorporates a number of historical clinical presentations including
      Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a
      macrocephaly-autism/developmental delay syndrome.
    explanation: This review lists developmental delay as part of a recognized PHTS childhood presentation.
- category: Neurobehavioral
  name: Autism
  description: >-
    Autism spectrum disorder is part of the broad neurodevelopmental spectrum
    reported in PHTS.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:26564076
    reference_title: PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is also a broad range of neurodevelopmental effects, with some
      patients having no challenges and others with severe autism spectrum
      disorder and mental retardation.
    explanation: This clinical review supports autism as part of PHTS neurodevelopmental involvement.
- category: Neoplastic
  name: Breast carcinoma
  description: >-
    Female breast cancer is one of the highest-penetrance malignancy risks in
    PHTS, with published cumulative lifetime risk estimates as high as 67-85%.
  phenotype_term:
    preferred_term: Breast carcinoma
    term:
      id: HP:0003002
      label: Breast carcinoma
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
    explanation: This review quantifies breast cancer risk in PHTS cohorts.
- category: Neoplastic
  name: Thyroid carcinoma
  description: >-
    Non-medullary thyroid carcinoma, usually follicular or papillary, is a major
    PHTS cancer risk.
  phenotype_term:
    preferred_term: Thyroid carcinoma
    term:
      id: HP:0002890
      label: Thyroid carcinoma
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
    explanation: This review quantifies thyroid cancer risk in PHTS cohorts.
- category: Neoplastic
  name: Endometrial carcinoma
  description: >-
    Endometrial carcinoma risk is substantially elevated in female PHTS
    patients.
  phenotype_term:
    preferred_term: Endometrial carcinoma
    term:
      id: HP:0012114
      label: Endometrial carcinoma
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
    explanation: This review quantifies endometrial cancer risk in PHTS cohorts.
- category: Neoplastic
  name: Renal cancer
  description: >-
    Renal cancer risk is increased in PHTS; HPO currently binds this to the
    broader renal neoplasm term.
  phenotype_term:
    preferred_term: Renal cancer
    term:
      id: HP:0009726
      label: Renal neoplasm
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
    explanation: This review quantifies renal cancer risk in PHTS cohorts.
- category: Neoplastic
  name: Colon cancer
  description: >-
    Colorectal cancer risk is increased in PHTS, supporting colonoscopic
    surveillance.
  phenotype_term:
    preferred_term: Colon cancer
    term:
      id: HP:0003003
      label: Colon cancer
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
    explanation: This review quantifies colorectal cancer risk in PHTS cohorts; colon cancer is used as the closest specific HPO term.
- category: Neoplastic
  name: Melanoma
  description: >-
    Melanoma is part of the PHTS tumor spectrum, with reported cumulative
    lifetime risk estimates up to 6% in reviewed cohorts.
  phenotype_term:
    preferred_term: Melanoma
    term:
      id: HP:0002861
      label: Melanoma
  evidence:
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
    explanation: This review quantifies melanoma risk in PHTS cohorts.
genetic:
- name: PTEN
  association: Causative
  gene_term:
    preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  notes: >-
    Heterozygous germline pathogenic variants in PTEN define the molecular
    diagnosis of PHTS. A substantial minority of cases arise from de novo PTEN
    variants, which is important for recurrence-risk counseling.
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DIAGNOSIS/TESTING: The diagnosis of PHTS is established in a proband by
      identification of a heterozygous germline PTEN pathogenic variant on
      molecular genetic testing.
    explanation: GeneReviews defines PHTS diagnosis by heterozygous germline PTEN pathogenic variants.
  - reference: PMID:26564076
    reference_title: Eng C. PTEN Hamartoma Tumor Syndrome in the Genomic Age.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While most cases are inherited in a family for generations, following an
      autosomal dominant pattern, at least 10% and perhaps as many as 44% of
      cases are due to a new (de novo) mutation.
    explanation: This supports the de novo PTEN variant rate noted for genetic counseling.
  - reference: CGGV:assertion_2e9e89c0-8d1b-4276-bd6f-90c7b7190ffb-2024-04-05T170000.000Z
    reference_title: "PTEN / PTEN hamartoma tumor syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PTEN | HGNC:9588 | PTEN hamartoma tumor syndrome | MONDO:0017623 | AD | Definitive"
    explanation: ClinGen classifies the PTEN-PTEN hamartoma tumor syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
diagnosis:
- name: PTEN molecular genetic testing
  description: >-
    Molecular genetic testing for heterozygous germline PTEN pathogenic variants
    establishes the diagnosis and enables predictive testing for relatives.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Heterozygous germline PTEN pathogenic variant.
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DIAGNOSIS/TESTING: The diagnosis of PHTS is established in a proband by
      identification of a heterozygous germline PTEN pathogenic variant on
      molecular genetic testing.
    explanation: This supports PTEN molecular testing as diagnostic for PHTS.
treatments:
- name: Cancer surveillance
  description: >-
    Lifelong surveillance aims to detect PHTS-associated cancers early, including
    thyroid ultrasound, dermatologic evaluation, breast screening, endometrial
    assessment, colonoscopy, and renal imaging according to age and family
    history.
  treatment_term:
    preferred_term: cancer screening
    term:
      id: MAXO:0000126
      label: cancer screening
  target_phenotypes:
  - preferred_term: Breast carcinoma
    term:
      id: HP:0003002
      label: Breast carcinoma
  - preferred_term: Thyroid carcinoma
    term:
      id: HP:0002890
      label: Thyroid carcinoma
  - preferred_term: Endometrial carcinoma
    term:
      id: HP:0012114
      label: Endometrial carcinoma
  - preferred_term: Renal cancer
    term:
      id: HP:0009726
      label: Renal neoplasm
  - preferred_term: Colon cancer
    term:
      id: HP:0003003
      label: Colon cancer
  - preferred_term: Melanoma
    term:
      id: HP:0002861
      label: Melanoma
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: To detect tumors at the earliest, most treatable stages:
      Children (age <18 years). Yearly thyroid ultrasound from the time of
      diagnosis (earliest reported at age 7 years) and skin check with physical
      examination. Adults. Yearly thyroid ultrasound and dermatologic
      evaluation. Women beginning at age 30 years. Monthly breast
      self-examination; annual breast screening (at minimum mammogram; MRI may
      also be incorporated). Starting by age 35 years, consider transvaginal
      ultrasound or endometrial biopsy. Men and women. Colonoscopy beginning at
      age 35 years with frequency dependent on degree of polyposis identified
      or family history of early-onset colon cancer (before age 40); biennial
      (every 2 years) renal imaging (CT or MRI preferred) beginning at age 40
      years.
    explanation: GeneReviews supports age-based thyroid, skin, breast, endometrial, colon, and renal surveillance in PHTS.
  - reference: PMID:33140411
    reference_title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This review supports breast and thyroid cancer surveillance as proposed by
      current European and American guidelines.
    explanation: This cancer-risk review supports breast and thyroid surveillance in PHTS.
- name: Genetic counseling
  description: >-
    Counseling informs autosomal dominant recurrence risk, testing of at-risk
    relatives, reproductive options, and syndrome-specific surveillance.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301661
    reference_title: PTEN Hamartoma Tumor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evaluation of relatives at risk: When a PTEN pathogenic variant has been
      identified in a proband, molecular genetic testing of asymptomatic at-risk
      relatives can identify those who have the family-specific pathogenic
      variant and warrant ongoing surveillance.
    explanation: This supports family counseling and cascade testing for PHTS.
- name: Everolimus investigational therapy
  description: >-
    Everolimus targets mTOR overactivity in PHTS and has been tested in a
    randomized phase II trial for neurocognitive symptoms. The trial showed
    tolerability and target-engagement/secondary-endpoint signals but did not
    meet the primary efficacy endpoint, so this remains investigational rather
    than routine PHTS care.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: everolimus
      term:
        id: CHEBI:68478
        label: everolimus
  target_phenotypes:
  - preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35594551
    reference_title: A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Everolimus is well tolerated in PHTS; adverse events were similar to
      previous reports. The primary efficacy endpoint did not reveal
      improvement.
    explanation: This phase II trial supports safety but not established efficacy for neurocognitive benefit.
clinical_trials:
- name: NCT02991807
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Randomized double-blind placebo-controlled phase II trial of everolimus in
    individuals with PTEN mutations, testing safety and neurocognitive or
    behavioral outcomes.
  target_phenotypes:
  - preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: clinicaltrials:NCT02991807
    reference_title: A Randomized Double-Blind Controlled Trial of Everolimus in Individuals With PTEN Mutations (RAD001XUS257T)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigators are conducting research to evaluate the potential safety and
      efficacy of RAD001 (everolimus) in this patient population, and the
      potential neurocognitive benefits from treatment with RAD001 or placebo
      for a six month period.
    explanation: The trial registry identifies the randomized everolimus study in PTEN mutation carriers.
datasets: []
references:
- reference: ORPHA:306498
  title: PTEN hamartoma tumor syndrome
  findings:
  - statement: >-
      Orphanet defines PHTS as a germline PTEN hamartoma/overgrowth and
      neoplasia-risk disease group.
    supporting_text: >-
      A group rare skin tumor or hamartoma diseases characterized by a germline
      PTEN mutation and clinical manifestations of hamartomas, overgrowth, and
      increased risk of neoplasia
- reference: PMID:18781191
  title: PTEN hamartoma tumor syndromes.
  findings:
  - statement: >-
      PTEN loss activates PI3K/AKT/mTOR signaling and increases cellular growth,
      migration, proliferation, and survival.
    supporting_text: >-
      Loss of PTEN activates this pathway and leads to increased cellular
      growth, migration, proliferation, and survival.
- reference: PMID:20301661
  title: PTEN Hamartoma Tumor Syndrome.
  findings:
  - statement: >-
      GeneReviews summarizes PHTS clinical features, molecular diagnosis,
      inheritance, management, surveillance, and genetic counseling.
    supporting_text: >-
      The diagnosis of PHTS is established in a proband by identification of a
      heterozygous germline PTEN pathogenic variant on molecular genetic testing.
- reference: PMID:33140411
  title: A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
  findings:
  - statement: >-
      PHTS has increased risks of breast, endometrial, thyroid, renal,
      colorectal, and melanoma cancers.
    supporting_text: >-
      The tumor spectrum included female breast cancer (CLTRs including
      sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19%
      to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal
      cancer (9% to 32%), and melanoma (0% to 6%).
- reference: PMID:31609537
  title: "PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature."
  findings:
  - statement: >-
      Childhood PHTS presentations include intellectual disability, overgrowth,
      tumor predisposition, Cowden syndrome, BRRS, and macrocephaly-autism or
      developmental delay presentations.
    supporting_text: >-
      PHTS incorporates a number of historical clinical presentations including
      Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a
      macrocephaly-autism/developmental delay syndrome.
- reference: PMID:35594551
  title: A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome.
  findings:
  - statement: >-
      Everolimus was tolerated in a phase II PHTS trial but did not meet the
      primary efficacy endpoint.
    supporting_text: >-
      Everolimus is well tolerated in PHTS; adverse events were similar to
      previous reports. The primary efficacy endpoint did not reveal improvement.
📚

References & Deep Research

References

6
ORPHA:306498
PTEN hamartoma tumor syndrome
1 finding
Orphanet defines PHTS as a germline PTEN hamartoma/overgrowth and neoplasia-risk disease group.
"A group rare skin tumor or hamartoma diseases characterized by a germline PTEN mutation and clinical manifestations of hamartomas, overgrowth, and increased risk of neoplasia"
PMID:18781191
PTEN hamartoma tumor syndromes.
1 finding
PTEN loss activates PI3K/AKT/mTOR signaling and increases cellular growth, migration, proliferation, and survival.
"Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival."
PMID:20301661
PTEN Hamartoma Tumor Syndrome.
1 finding
GeneReviews summarizes PHTS clinical features, molecular diagnosis, inheritance, management, surveillance, and genetic counseling.
"The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing."
PMID:33140411
A review on age-related cancer risks in PTEN hamartoma tumor syndrome.
1 finding
PHTS has increased risks of breast, endometrial, thyroid, renal, colorectal, and melanoma cancers.
"The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%)."
PMID:31609537
PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature.
1 finding
Childhood PHTS presentations include intellectual disability, overgrowth, tumor predisposition, Cowden syndrome, BRRS, and macrocephaly-autism or developmental delay presentations.
"PHTS incorporates a number of historical clinical presentations including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly-autism/developmental delay syndrome."
PMID:35594551
A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome.
1 finding
Everolimus was tolerated in a phase II PHTS trial but did not meet the primary efficacy endpoint.
"Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement."

Deep Research

1
PTEN Hamartoma Tumor Syndrome Evidence-Backed Research Fallback ▸

PTEN Hamartoma Tumor Syndrome Evidence-Backed Research Fallback

Provider Attempts

The primary deep-research provider attempts did not return usable research documents within bounded command budgets. The review-requested longer command, timeout 300s just research-disorder openai PTEN_Hamartoma_Tumor_Syndrome, also timed out with exit code 124 after starting research/PTEN_Hamartoma_Tumor_Syndrome-deep-research-openai.md. No partial provider artifact was left on disk. The curation therefore uses a manual evidence-backed synthesis from fetched structured and literature caches.

Evidence Synthesis

ORPHA:306498 defines PTEN hamartoma tumor syndrome as a rare skin tumor/hamartoma disease group characterized by germline PTEN mutation, hamartomas, overgrowth, and increased neoplasia risk. The same Orphanet record supplies the autosomal dominant inheritance, worldwide prevalence band, and the PHTS group scope that includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and SOLAMEN syndrome.

PMID:18781191 anchors the core molecular mechanism: PTEN loss releases negative regulation of PI3K/AKT/mTOR signaling, increasing cellular growth, migration, proliferation, and survival. The YAML models this as PTEN loss and PI3K-AKT-mTOR activation, with downstream hamartomatous tissue overgrowth and multiorgan cancer predisposition. These mechanism nodes are intentionally atomic so the graph separates molecular signaling from tissue-level and clinical consequences.

PMID:20301661 provides the GeneReviews clinical frame for PHTS. It supports the PHTS subtype scope, the typical Cowden presentation with macrocephaly, trichilemmomas, papillomatous papules, and benign/malignant tumors, the BRRS presentation with macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules, molecular diagnosis by heterozygous germline PTEN pathogenic variant testing, autosomal dominant counseling, cascade testing, and surveillance recommendations for thyroid, skin, breast, endometrial, colon, and renal cancer risk.

PMID:33140411 is the main human clinical cancer-risk source. It supports the neoplastic phenotype set for breast carcinoma, endometrial carcinoma, thyroid carcinoma, renal neoplasm, colorectal cancer, and melanoma, with cumulative lifetime risk ranges drawn from cohort studies. The cancer-risk phenotypes and surveillance treatment entry are therefore modeled as human clinical evidence rather than mechanistic inference alone.

PMID:31609537 and PMID:26564076 cover the childhood and genomic-era neurodevelopmental spectrum. They support macrocephaly, developmental delay, autism spectrum manifestations, and broad neurodevelopmental overgrowth in PHTS. PMID:26564076 also supports the genetic-counseling note that at least 10% and perhaps as many as 44% of cases arise from de novo PTEN mutation.

PMID:35594551 and clinicaltrials:NCT02991807 support the investigational everolimus entry. Everolimus targets mTOR overactivity and was studied in a randomized phase II PHTS trial for neurocognitive symptoms, but the cited trial did not meet the primary efficacy endpoint; it is therefore represented as investigational pharmacotherapy rather than standard care.

Scope Confirmation

The YAML intentionally centers on the syndrome-group PHTS entry rather than the already-curated Cowden syndrome file. It includes PTEN as the defining causative gene, Orphanet/GeneReviews subtype coverage, OAK-verified MONDO subtype bindings, representative non-malignant manifestations, major cancer-risk phenotypes, PTEN molecular testing, surveillance, genetic counseling, and the completed everolimus trial. Reviewer-suggested subtype MONDO IDs were checked with OAK and found to resolve to unrelated disorders locally, so the YAML uses the verified local MONDO IDs instead.