ESPE Abstracts

In 2004, in France a national plan for rare diseases was structured. The improvement in healthcare provision for rare diseases constitutes a major challenge for public health owing to the epidemiological data, the consequences of these pathologies for the quality of life of the patients and their families and the challenges for research in the domains of diagnosis and treatment. In 2007, with a significant experience about gynaecological care of children and adolescents with rare diseases, a National Center of Gynaecologic Rare Diseases has been created.

Pathologies of center are: rare benign breast disease, gynaecological consequences of inherited bleeding disorders, Mullerian malformations and gynaecological consequences of rare chronic disease.

Rare chronic disease can disrupt ovarian function or gonadotropic axis due to the disease itself or because of their consequences. For example, premature ovarian failure (POF) has been described in rare hereditary metabolic disorders like in patients with galactosemia or congenital disorders of glycosylation (CDG) syndrome. Classic galactosemia and CDG syndrome are rare hereditary disorder of galactose metabolism and glycoprotein synthesis respectively. Long-term diet-independent complications of galactosemia consist of premature ovarian failure and cognition sequalae. CDG I type is the most frequent form of CDG is characterised by multisystem manifestations, in particular the nervous system.

We report clinical criteria, biological and sonographic characteristics to evaluate the gonadal function in these women, establish recommendations on the management of their puberty and fertility and assess the indications of ovarian preservation for women with galactosemia.

We report 101 filled questionnaires, from 45 males and 56 females with galactosemia. Sixty-nine percent of women had a spontaneous puberty with a first stage of breast development appearing at 12 years (n=31) and 25/31 women had spontaneous menarche at 14.6 years (14 women had induced menarche at 17 years old). This is significantly later than in 251 girls from a French cohort who had menses at 12.6 years (P<0.01). Fifty percent of women had secondary amenorrhea. Eleven girls under 16 had an FSH dosage, with an average of 8.1 IU/l for girls with spontaneous puberty and 103 IU/l, for girls without. Women over 16 years old had an average FSH level of 73 IU/l. All the pelvic ultrasounds (n=15) showed small ovaries <0.3 cm³ without visible follicles. Four women out of five desiring a pregnancy succeeded, 3/4 with spontaneous puberty, 2/4 with regular menstrual cycles.

Premature ovarian failure (POF) has been usually described in CDG women. We report ovarian function in 17 patients CDG Ia (15.7 years (1.9–35.9) and two patients with CDG1b. In the ten patients with CDG1a aged of more 13 years old, none had spontaneous puberty. FSH level (n=17) was high, except in two patients aged 8.8 and 9.3 years old and AMH (n=13) was undetectable or below the normal range. In pelvic ultrasound (n=15), normal ovary area was described in only one patient. In contrast, in two patients with CDG 1b, one had spontaneous puberty and FSH and AMH levels were normal. Finally, 64% (9/14) had a risk of thrombosis (antithombine III, and/or protein S and/or protein C defect) and 7/14 had bleeding disorders.

In conclusion, in galactosemia and CDG syndrome patients, POF consist a long-term complication. POF seems fluctuating in galactosemia and more severe and precocious in CDG I syndrome. In these two pathologies, mechanisms of ovarian injury remained to be fully elucidated and which help us to understand pathways in ovary or gonadotropic axis. POF is often overlooked in adolescents with chronic rare disease. With other rare disease centers (for example centers for metabolic disorders), a systematic follow up of the puberty for these patients can be organized. Moreover, the center is multidisciplinary. So, with adult colleagues and surgeon colleagues we can organize transition and preservation of fertility. We believe that such a center for rare gynaecological disorders is fully relevant to improve quality of care.