Value of rare diseases reference centers: impact on diagnosis and access to specialized care in fibrous dysplasia of bone.

INTRODUCTION: Reference Centers and Rare Disease Health Networks aim to improve the management of patients with rare diseases. The French reference center for Fibrous Dysplasia was certified in 2006. OBJECTIVE: The objective of our study was to assess the effectiveness of our reference center since its constitution. METHODS: In a retrospective cohort study, we compared the activity of our center, including the time elapsed between access to the center and the diagnostic delay of patients with Fibrous Dysplasia between two periods, 1994-2006 (before certification) and 2007-2019 (after certification). Data were extracted from patients' records (Easily®). Wilcoxon and Fisher tests were performed, using R®. RESULTS: Our cohort included 527 patients with Fibrous Dysplasia/Mc Cune Albright syndrome. The activity of the Fibrous Dysplasia center increased from 139 patients in the first period (1994-2006) to an additional 388 patients for the second period (2007-2019). Mean time elapsed to diagnosis of Fibrous Dysplasia was 1.5 years before 2007 and 1.9 years after 2007 (p = 0.12). Diagnosis was made before referral in over 80% of patients. There was a non-significant decrease in the number of patients with delayed diagnosis: 37 patients (44%) in the first period had a diagnostic delay and 94 patients (33%) in the second period (p = 0.07). Patients were referred to our center on average 6.8 years (before 2007) and 7.9 years (after 2007) after their diagnosis (p = 0.77). CONCLUSION: Healthcare organization with reference centers significantly impacted the management of patients with Fibrous Dysplasia/Mc Cune Albright syndrome, with a substantial increase in the activity of our center, that roughly tripled since certification. This healthcare organization was also associated with a trend toward decreasing diagnostic delay. However, diagnostic delay affected more than a third of patients and the time to access to the center remained extended (≈7-8 years after diagnosis). The current challenge lies in informing primary care providers and patients about education to rare diseases and existence of reference centers for earlier and more effective specialized management.

GNAS mutated thyroid carcinoma in a patient with Mc Cune Albright syndrome.

Mc Cune-Albright syndrome (MAS) is a rare disorder defined by the triad of polyostotic fibrous dysplasia, "café au lait" skin hyperpigmentation and hyperfunctioning endocrinopathies, such as precocious puberty. MAS is caused by an activating post zygotic somatic mutation of GNAS gene, coding for the alpha-subunit of the stimulatory G protein (Gsalpha). In endocrine tissues, this mutation results in overproduction of hormones and endocrine cell hyperfunction and proliferation. Whereas the association of hyperthyroidism and thyroid adenomas is well known in MAS, the relation with thyroid carcinoma has rarely been observed. We report the occurrence of a thyroid carcinoma in an 18-years old woman with MAS, revealed by subclinical hyperthyroidism detected during her systematic annual follow-up. Ultrasound and thyroid scintigraphy revealed the presence of a nodule in the right lobe. Pathology on hemithyroidectomy revealed an unexpected thyroid follicular carcinoma. Neoplastic thyroid cells harbored the GNAS R201C activating mutation. This observation suggests that MAS may predispose patients to thyroid carcinomas and supports the importance of thyroid assessment by physical examination, hormonal blood test and ultrasound, in the follow-up of patients with MAS. Because ultrasound diagnostic is challenging in MAS, needle puncture of palpable nodules should be advised.

Are mummy characteristics reliable indicators of diapause and cold tolerance in the parasitoid wasp Aphidius rhopalosiphi (Braconidae, aphidiinae) ?

Many insect species have evolved different overwintering survival strategies such as cold tolerance or diapause. This study investigated the relationship between Aphidius rhopalosiphi mummy colour and cold tolerance and diapause. Mummy colour was insufficient to discriminate diapausing from non-diapausing individuals. This phenotypic character seems to reflect environmental conditions rather than direct developmental time and cocoon thickness (identification criteria of diapause). There is, however, a relationship between cold tolerance and mummy colour. Dark mummies exhibited significantly higher water content, survival at low temperature and lower supercooling point values than pale mummies. Mummy colour in Aphidius rhopalosiphi seems to be a phenotypic indicator of the cold tolerance.