In uncommon diseases, or in orphan diseases, musculoskeletal disorders can be the hallmark of the diseases. This can be a difficult diagnostic issue. Clinicians are aware of characteristic clinical phenotypes such as clubbing or Jaccoud’s arthropathy, or common bone or joint disorders such as avascular ostenonecrosis (AVN) or chronic arthropathies of the small joints of hands. These symptoms or syndromes will lead physicians to review a (long) list of diseases, with frequent diagnosis such as steroid-induced AVN, alcohol-induced AVN. The key point will be not to miss a rare condition, namely Gaucher’s disease when facing AVN, as an example. In this issue, we have tried to bring to memory of clinicians a survey of rare or less rare metabolic conditions first, and of uncommon but memorable clinical features.

Chondrocalcinosis (CC) or calcium pyrophosphate (CPP) crystal-induced arthropathies have recently been reviewed by the EULAR; recommendation #9 for diagnostic and another recommendation #8 for management enforce the needs to assess predisposing metabolic disease including hemochromatosis and hypomagnesaemia. These assessment should be considered especially when CC or CPPD deposition disease are diagnosed in younger patients (below 55).

Hemochromatosis in not so uncommon but rheumatic manifestations should be kept in mind; Pascal Gugenhbul and coll, from Brittany, a place with a high prevalence of genetic hemochromatosis, will review bone and joint involvement. Similarly Leonardo Punzi et al used to manage rare renal dysfunction leading to magnesium leak, namely Bartter’s and Gitelman’s diseases.

Beside iron overload of genetic origin, there are also rare metabolic disease, often considered as orphan diseases, which are presenting as rheumatic or bone disorders. As such Wilson’s disease, defined as an autosomal recessive disorder characterized by release of free copper and dramatic accumulation on intracellular copper in the liver, will subsequently trigger hepatic and central nervous system disorders. As a consequence, bone or even joints might also been involved, and Quemeneur et al provided a thorough review. Gaucher’s disease can present with many puzzling bone and joint lesions, reviewed by Mistry et al. Rare thesaurismosis and xanthomatosis can also be encountered by paediatricians, internists, and rheumatologists. Lysosomial enzyme deficiency can provide a large spectrum of musculoskeletal conditions including osteoporosis, joint contractures, radiographic bone abnormalities, growth retardation; similarly glycogen storage diseases can trigger muscle symptoms, osteoporosis, and even hyperuricemia and gout. This chapter will be covered by Chalès et al, whom expertise will bring clinical insigths.

In all these orphan conditions, when considering the number of patients involved, a bunch of knowledge have been achieved over the last decade, including genetics, pathophysiological studies, leading to diagnostic tests and targeted therapy. There is a new day life for these patients with Gaucher’s disease, certain muccopolysaccharidosis and glycogen storage diseases. Other conditions have not been reviewed due to the limitation of space, such as Fabry’s disease , hypophosphatasia , alcaptonuria and ochronosis , but in all these conditions similar progresses have been achieved and management improved.

Clinical rheumatologists should also been aware of particular phenotypes such as Jaccoud’s arthropathy and pachydermoperiostosis. These conditions and related-diagnosis have been reviewed by Santiago and Martin-Lavin et al, respectively, bringing an update. Two other rare conditions should be known from rheumatologists since they are at the frontier between several subspecialties, dermatology and ophtalomology for Blau’s syndrome reviewed by Punzi et al, and pediatrics, dermatology, and internal medicine for tumoral calcinosis, thanks to the expertise of White. In all these ’ diseases or syndromes, a critical issue is the basic knowledge by physicians of these conditions to avoid delay in diagnosis. Indeed sarcoidosis-like condition in children or teens, with positive “family history of sarcoidosis”, strongly suggests Blau’s syndrome.

Whatever these conditions, we should add that expertise is a key point when considering diagnosis and management of these rare (or less rare) conditions. Some treatments have high costs, and limitation to their access to local regulations. An important path has been made in several countries by the constitution of patient associations, on one hand, and by the implementation of Reference centres for these diseases, on the other hand. In Europe, from 1999, European regulations for the development of orphan drug have triggered such programs. In France, for example, National Reference centres have been formed following the Plans National Maladies Rares (’rare diseases national program’) PNMR 1 2005–2008 and the current PNMR 2 2011–2014 . Following the first program, 131 National Reference centres for orphan diseases have been certified, with specific funding, and 501 National Competence centres spread in the country have been affiliated to the National Reference centres. They are dedicated to care, from childhood to adulthood, to specific management and treatment, to research programs, and to patient education and information. Data bases and registries, at the European level, for instance in Wilson’s disease (“EuroWilson”) have fostered important results and patient care update.

Rarity of experts and of patients need to achieve such collaborations in order to establish relationships between genotypes and phenotypes. Natural history of rare or even very rare diseases will benefit from such strategy and international interaction. It should be mentioned that the European parliament is supporting this effort in Europe. Patient’s associations should also be acknowledged in collaborating to these programs.

We do thank the contributors of this dedicated Issue and, finally, point out also that many links to the internet have been provided in chapters allowing readers to obtain practical information in their countries.