Is endometroid cancer of the ovaries a late manifestation of Alström syndrome?

Authors


Erik Moberg, Department of Endocrinology, Metabolism & Diabetes, M63, Karolinska University Hospital, Stockholm S-141 86, Sweden.
(fax: +46 8 585 824 07; e-mail: erik.moberg@ki.se).

Dear Sir, Alström syndrome is an autosomal recessive disease characterized by congenital retinal dystrophy leading to blindness, neurosensory hearing loss, cardiomyopathy, childhood onset obesity, insulin resistance and type 2 diabetes [1]. A widespread spectrum of phenotypes with a number of organ manifestations was recently reported in a study comprising 182 of the approximately 300 cases known [2]. The mutations in patients with Alström syndrome occur in a newly discovered gene (ALMS 1) of chromosome 2p13 [3] which encode a protein of 4169 amino acids [3, 4]. Today (2007) a total of 81 disease-causing ALMS 1 mutations have been reported [5]. Although the function of this gene is still unknown, deletion studies in mice have demonstrated multiple organ dysfunctions, indicating a role in intracellular trafficking [6]. There is as yet no indication of premature development of malignancy in such models. We here report a case of early bilateral cancer of the ovaries which we propose may be related to Alström syndrome.

The patient was referred to our department in 1999 because of dyslipidemia and diabetes. Alström syndrome had previously been confirmed genetically (mutation identified 10483C>T Ter) [2]. In early childhood, impaired vision was diagnosed and a few years later, a hearing loss was apparent. She was blind from the age of 15 and deaf at the age of 20. At the time of referral, she also had hypertension and a renal impairment but no signs of cardiac failure.

The patient had menarche at the age of 12 and mostly regular menstruations thereafter. In April 2005, at the age of 39, she had metrorrhagia and a pelvic tumour was diagnosed by a gynaecologist. Preoperative cancer-associated antigen, CA125, level was 304 kU L−1 (normal <35). She was operated with hysterectomy, bilateral salpingo oophorectomy and resection of the omentum. The pathological examination showed bilateral endometroid grade 1 tumours of the ovaries and a less well-differentiated tumour of the uterus. Accordingly, the malignancy was classified as endometroid ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) staging classification IIB, which spread to the uterus or alternatively, synchronous tumours of the ovaries and uterus. The patient received adjuvant external radiotherapy 45 Gy and brachy high dose rate (HDR) 5 Gy × 2. This unconventional treatment modality was chosen primarily because of her low renal function, as standard platinum-based chemotherapy carries considerable risk of nephrotoxicity. Treatment was reasonably well tolerated (no grade 3/4 toxicities) and for approximately 2 years there was no sign of recurrence. During autumn 2007, the patient rapidly deteriorated and a computerized tomography scan revealed liver metastases, thereafter the patient died. Unfortunately, an autopsy was not performed.

Comment

Our patient had several characteristics of Alström syndrome in that she was blind from retinal dystrophy, had a progressive sensorineural hearing loss, short stature, overweight, insulin resistance, type 2 diabetes, hypertriglyceridaemia, hypertension and renal failure.

As to gonadal disturbances in female Alström syndrome, there has been reported hirsutism, abnormal breast development, cystic ovaries, precocious puberty, endometriosis, irregular menses or amenorrhea in 42 of 78 patients [2]. Furthermore, childbirth has never been reported in women with Alström syndrome. Our patient had mostly regular menses and there was no history of dysmenorrhea suggesting endometriosis. She had never used contraceptives.

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[  A patient with Alström syndrome and a pelvic tumour where the pathological examination showed a well differentiated endometroid adenocarcinoma of the ovary with confluent growth of the glands with replacement of stroma. ]

Nulliparity is positively associated to ovarian cancer risk whereas oral contraceptive use, pregnancy and lactation are associated with a reduced risk [7, 8]. Also obesity has been associated with ovarian cancer [9]. Interestingly, a recent study showed that the association between body mass index and risk of ovarian cancer was most apparent in nulliparous women [10]. Another study reported that overweight was only a risk factor for ovarian cancer in premenopausal women [11]. Thus, the combination of nulliparity and obesity could, perhaps imply an increased risk for ovarian cancer in female patients with Alström syndrome. Also hormonal alterations such as hyperinsulinaemia, androgen access and high levels of insulin-like growth factor I, which are often seen in patients with Alström syndrome, have been claimed as possible risk factors for ovarian cancer. There is also the possibility that the defect in ALMS 1 gene product may have a malignancy-promoting effect.

Our patient was one of the oldest patients with Alström syndrome reported by Marshall and Minton [2, 6]. Patients frequently not only die prematurely by cardiac or renal failure but also pulmonary disease and liver disease. To our knowledge, endometroid cancer of the ovaries and uterus is not previously reported in association with Alström syndrome. Accordingly, it is possible that this is a manifestation of Alström disease only seen in patients reaching at least the middle ages. Accumulation of further clinical experience of this patient population should be of interest.

Conflict of interest statement

No conflict of interest.

Acknowledgement

Supported by the Swedish Research Council and Heart-Lung Foundation.

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