PTEN Hamartoma Tumour Syndrome

PTEN hamartoma tumour syndrome is an autosomal dominant disorder caused by germline PTEN variants, with macrocephaly, hamartomas and high risks of breast, thyroid, endometrial, kidney and colorectal cancer. It includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and a childhood form with autism and developmental delay.

Pathophysiology. PTEN is a lipid phosphatase that restrains PI3K and AKT signalling. Loss of one allele, followed by loss of the second in tissue, causes unchecked mTOR signalling, overgrowth and tumour formation.

Many cases are de novo. Penetrance rises with age, and the lifetime risk of breast cancer in women is high, with thyroid cancer starting in childhood.

Surveillance starts early and differs between children and adults.

• Macrocephaly (head circumference over the 97th centile) in most
• Mucocutaneous lesions: trichilemmomas, papillomatous papules, acral keratoses
• Penile freckling in boys (Bannayan-Riley-Ruvalcaba syndrome)
• Breast: fibrocystic disease and breast cancer
• Thyroid: goitre, adenomas, follicular and papillary cancer
• Endometrial cancer and uterine fibroids
• Gastrointestinal hamartomatous and other polyps, and colorectal cancer
• Renal cell carcinoma, and melanoma
• Autism spectrum disorder, developmental delay, vascular anomalies, lipomas
• Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma)

• Genetic testing of PTEN by sequencing and deletion and duplication analysis, in anyone meeting clinical features: macrocephaly with autism or developmental delay, trichilemmomas, adult Lhermitte-Duclos disease, or a cluster of typical cancers.
• Clinical assessment: head circumference, skin and mucosal examination, thyroid palpation, and family history.
• Baseline thyroid ultrasound, including in children.
• Cascade testing of relatives, with predictive testing of children when surveillance would change.
• Brain MRI when neurological symptoms or ataxia are present.

Differential diagnosis.

• Peutz-Jeghers syndrome and juvenile polyposis syndrome
• Familial adenomatous polyposis
• Proteus syndrome and PIK3CA-related overgrowth
• Neurofibromatosis type 1
• Tuberous sclerosis complex
• Other causes of macrocephaly with autism

• Breast surveillance in women: clinical breast examination from 25 years, then yearly breast MRI from 30 to 35 years with mammography, and discussion of risk reducing mastectomy.
• Thyroid: yearly ultrasound from diagnosis, including in childhood, with fine needle aspiration of suspicious nodules and surgery (thyroidectomy) for cancer.
• Colon: colonoscopy from about 35 years, repeated every 5 years or more often if polyps are found. Start earlier if symptoms or family history.
• Kidney: renal ultrasound or MRI every 1 to 2 years from about 40 years.
• Uterus: counsel about abnormal bleeding and offer endometrial sampling or ultrasound from about 35 years. Consider hysterectomy when childbearing is complete.
• Skin: yearly skin examination from diagnosis, with excision of suspicious lesions.
• Children: yearly thyroid ultrasound, skin examination, neurodevelopmental assessment, and therapy for autism and developmental delay.
• Treatment of cancers follows the cancer type. Avoid unnecessary radiation exposure when imaging, as far as practicable.
• Targeted drugs: mTOR inhibitors (sirolimus, everolimus) are used in specialist care for some vascular or overgrowth features. Dosing is individual.
• Genetic counselling: 50% chance of inheriting the variant for each child.

Special groups.

• Pregnancy: thyroid, breast and surveillance schedules continue, with specialist input.

Monitoring. Clinical review yearly, with breast, thyroid, colon, kidney, uterine and skin surveillance adjusted for age. Re-evaluate surveillance start ages at each visit.

Referral and escalation. Refer to clinical genetics and the relevant cancer team. Urgent for a breast or thyroid lump, rectal bleeding, postmenopausal bleeding or haematuria.