A trivial sign to rare genetic disorder

To the Editor

we present a case of clinical ingenuity and importance of multidisciplinary approach to diagnose a rare disorder. A young female in her twenties presented to dermatologist for relatively insignificant facial papular lesion (Figures 1 and 2), which was removed on more than five occasions. Histology of the lesion had appearance of tricholemommas, creating suspicion in the probing dermatologist's mind of Cowden Syndrome (CS), a rare inherited cancer predisposing disease of estimated incidence of one in 200 000. She was referred to a clinical genetician, who also noted acral keratosis affecting feet and macrocephaly, two more diagnostic signs of CS. She was further investigated for carcinoma of breast, thyroid and endometrium. She was found to have thyroid nodule awaiting needle biopsy and uterine fibroid. Triple assessment of breast has excluded breast cancer at present, but she is on annual surveillance. She now has almost certain diagnosis of CS based on Diagnostic criteria for Cowden syndrome (International Cowden consortium 2000) (Table I). Her preliminary results of testing for the PTEN (phosphtase and tensin homolog) gene showed no mutation in coding exons. The promoter region is being looked at, which represent 10% of mutations

Figure 1.

Figure 2.

Table I.  Diagnostic criteria for Cowden syndrome (international Cowden consortium 2000) [1]¹.

Pathognomonic criteria	Major Criteria	Minor Criteria
Mucocutaneous lesion- facial trichilemommas, acral keratosis, papillomatous papule, mucosal lesion	Breast cancer	Other thyroid lesion (eg. Adenoma, multinodular goitre)
	Thyroid cancer (non medullary),	Mental retardation (IQ < 75)
	Macrocephaly (>95^th centile)	GI hamartomas
	Endometrial cancer	Fibrocystic disease of breast
	Lhermitte-Duclos disease (LDD)	Lipoma
		Fibroma
		Genito-Urinary tumour (Renal carcinoma, uterine fibroid)

Making the diagnosis

?Mucocutaneous lesion alone if there are: (a) 6 or more facial papule, of which 3 must be trichilemmomas, or (b) cutanous facial papule and oral mucosal papillomatosis, or (c) oral mucosal papillomaotous and acral keratosis or (d) 6 or more palmoplanter keratosis OR

2 major criteria but one must include macrocephaly or LDD OR

1 major and 3 minor criteria OR

4 minor criteria

family member meeting CS criteria above + the pathognomonic criteria

family member meeting CS criteria above + any one major criterion

family member meeting CS criteria above + two minor criteria.

Cowden's syndrome is an autosomal dominant disorder involving PTEN, a tumour suppressor gene on 10q23.3 that regulates cell cycle arrest and/or apoptosis. Mutation in the PTEN suppressor gene is seen in 80% of CS and in the remaining 20% cases the genetic causes remain undetermined [3]. It is characterized by multiple hamartomatous lesions of the skin, mucous membranes, breast and thyroid. Multiple trichilemommas are pathognomonic. It most commonly includes fibrocystic disease of the breast, fibroadenoma, nipple discharge, virginal hypertrophy of the breast, thyroid adenomas, polyps of the gastrointestinal tract, ovarian cysts and uterine fibroids.

There is an increased risk of developing cancer in patients with CS especially involving breast, thyroid and gastrointestinal tract. The lifetime risk of women developing breast cancer with CS is as high as 50%, affecting young women (average age 38 years) with a third of them involving both breasts [4]. There is evidence that bilateral prophylactic mastectomy reduces the risk of a women developing breast cancer by approximately 90% [2], [5]. Other cancer predisposition includes thyroid cancers and less commonly gastrointestinal and renal cell carcinomas.

Patients with CS are advised regular annual follow-up for a clinical examination and a mammogram, ultrasound scan of thyroid and pelvis, urinary cytology and gastrointestinal endoscopies to detect cancer.

She is the first reported case on CS in Wales. This case report re-emphasizes the importance of a multidisciplinary approach and high degree of clinical suspicion at level of individual clinician in diagnosing the rare potentially life threatening condition.