Genetics

Germline loss-of-function mutations of STK11 (LKB1) on chromosome 19p13.3 — encodes a serine/threonine kinase that activates AMPK and negatively regulates the mTOR pathway.
Autosomal dominant; high (~95%) penetrance.
~50% sporadic / de novo, ~50% inherited.
Confirm by clinical Beggs criteria (next section) or germline STK11 testing.

Clinical diagnostic criteria (Beggs et al., 2010)

Definite PJS — any one of:

≥2 histologically confirmed Peutz-Jeghers polyps.
Any number of PJS polyps in an individual with a family history of PJS in a first-degree relative.
Characteristic mucocutaneous pigmentation in an individual with a family history of PJS.
Any number of PJS polyps in an individual with characteristic mucocutaneous pigmentation.

Multiple small (1–5 mm), brown to blue-black, macular lentigines.
Distribution — lip vermilion (especially the lower lip), perioral skin, buccal mucosa, gingiva, hard palate, periorbital skin, dorsa of fingers, palmar creases, plantar surfaces, perianal skin.
Onset typically in infancy / early childhood.
Lentigines on the lips and around the mouth often fade in adulthood, but oral mucosal lentigines persist throughout life — examine the oral cavity in any adult with possible PJS.
Differential — Carney complex (similar lip / oral lentigines + cardiac myxomas + endocrine tumours; PRKAR1A — see monograph); Laugier-Hunziker syndrome (similar lentigines without other features; benign); LEOPARD/Noonan syndromes; familial benign labial pigmentation; physiological racial labial pigmentation.

Onset typically in childhood / early adolescence.
Distribution — small bowel (jejunum > ileum > duodenum) most common; also stomach, colon, rectum.
Histology — characteristic Peutz-Jeghers polyp with arborising smooth-muscle stalk supporting hyperplastic glandular epithelium.
Complications — recurrent intussusception (the leading cause of childhood / young adult presentation), GI bleeding, iron-deficiency anaemia, obstruction.
Many patients have multiple bowel resections by adulthood — risk of short bowel syndrome with aggressive surgical management.

Any cancer ~80%.
Colorectal cancer ~40%.
Gastric cancer ~30%.
Small-bowel cancer ~13%.
Breast cancer ~50% (women) — comparable to BRCA risk.
Pancreatic cancer ~10%.
Lung cancer ~7–17% (cohort-dependent; Hearle 2006 and van Lier 2010 estimates).
Gynaecological — ovarian sex cord tumour with annular tubules (SCTAT) ~20%; "adenoma malignum" of the cervix (rare but characteristic); endometrial.
Testicular Sertoli cell tumour (boys) — produces precocious puberty / gynaecomastia.

Multidisciplinary care — gastroenterology, oncology, breast / gynaecology, dermatology, clinical genetics; lifelong.
UK BSG / European consensus surveillance schedule (broad strokes):
- Upper GI endoscopy and colonoscopy from age 8 (then every 1–3 years based on findings).
- Video capsule endoscopy of small bowel from age 8.
- MRI breast from age 25; mammography from age 30; risk-reducing mastectomy considered.
- Annual gynaecological examination + transvaginal ultrasound from age 18; cervical cytology.
- MRI / endoscopic ultrasound pancreas annually from age 30.
- Annual testicular examination ± USS from infancy (Sertoli tumours produce precocious puberty).
- Annual physical examination and surveillance for symptoms.
Polypectomy of significant polyps at endoscopy.
Genetic counselling and cascade testing.

Reassurance — the lentigines are benign and frequently fade in adulthood.
Cosmetic camouflage.
Q-switched laser (Nd:YAG, ruby, alexandrite) for prominent lesions.
Topical depigmenting agents (limited efficacy).
The dermatological priority is recognition and referral, not treatment of the lentigines.