As the coordinator of collaborations with European and international networks of expertise for the update of the Orphanet nomenclature and classification of rare diseases, I would like to offer some comments on the issue discussed in this exchange.

The Orphanet nomenclature has been established to not only provide comprehensive, expert-validated, and structured information to health professionals involved in the pathway of rare diseases patients, but also as an answer to the previous lack of a specific and exhaustive terminology when it came to diseases defined as rare according the European definition (1999). By providing clinical terms that precisely match each rare disorder known to the biomedical literature, the ORPHA coding system enables the identification of the diagnosis officially recognised for each affected patient, as well as their tracking across healthcare and research information systems and records.

A rare disorder may be unisystemic, or may be a syndrome associating several clinical manifestations and/or malformations affecting different biological systems. Of the 6,000 rare disorders registered by Orphanet, 70% are multisystemic, and this clearly illustrates the multidimensionality of rare diseases: the pathway of one given patient across healthcare structures will necessarily involve specialised consults and management from different fields of expertise, and challenges specific to each medical specialty will arise.

For example, in a patient with a congenital syndrome associating cardiac defects, ocular anomalies, renal malformations, and respiratory anomalies, it will be important for each specialist to have a precise clinical description, especially when surgical intervention is involved - renal surgeons will want to identify the kind of renal malformation, and the same goes for the cardiac pediatric surgeon.

On the other hand, from a technical point of view, consistent data sharing and statistical reporting is not possible if the patient's "main diagnosis" is registered using a variable constellation of clinical terms, with these terms varying from one registry to another depending on the medical specialty of interest, and actually reflecting a detailed clinical description of the patient rather than the main diagnosis. It is possible however to enrich the main diagnosis, represented by the ORPHAcode, with additional information as needed by the medical specialties. But this calls for the design of information systems that cater and are adapted to these needs, and also and very importantly, for carefully crafted consensus recommendations to ensure that patient data are registered in a consistent fashion between different information systems and areas of expertise both at national and European levels.

This emphasizes that the issue at hand relates to the inherent complexity of rare diseases and the considerably broader problem of how to effectively share patient data while ensuring interoperability between different systems and registries. It cannot be reduced to a matter of arbitrary rigidity on Orphanet's part: Orphanet is as a rare disease knowledge base, that offers a standardised medical terminology for the identification of rare diagnoses, and cannot as such be expected to solve all these broader issues that extend far beyond its scope of action (although we do participate in numerous related