title: Skeletal implications and management of cystinosis: three case reports and literature review.
abstract: Hypophosphatemic rickets and short stature are observed in nephropathic cystinosis, an orphan autosomal recessive lysosomal storage disease due to a deficiency of cystinosin (CTNS gene). Although bone impairment is not common, it nevertheless appears to be more and more discussed by experts, even though the exact underlying pathophysiology is unclear. Four hypotheses are currently discussed to explain such impairment: copper deficiency, bone consequences of severe hypophosphatemic rickets during infancy, cysteamine toxicity and abnormal thyroid metabolism. In murine models, the invalidation of the CTNS gene is associated neither with renal phosphate wasting nor with renal failure, but causes severe osteopenia and growth retardation, thus raising the hypothesis of a specific underlying bone defect in cystinosis. Moreover, the in vitro ability of mesenchymal stromal cells isolated from bone marrow to differentiate along the osteoblastic lineage is reduced in patients with cystinosis as compared with cells obtained from healthy controls, this cellular abnormality being reverted after cysteamine treatment. From our experience of three pediatric patients with cystinosis and severe bone deformations having undergone a thorough biochemical evaluation, as well as a bone biopsy, we conclude that even though copper deficiency, high-doses cysteamine regimens and abnormal thyroid metabolism may worsen the bone picture in cystinosis patients, the exact pathophysiology of such impairment remains to be defined. The role of chronic hypoparathyroidism due to chronic phosphate wasting could also be discussed. In the future, larger and prospective studies should focus on this topic because of the potential major impact on patients' quality of life.
authors: Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; INSERM, Faculté de Médecine Lyon Est, site Laennec, Lyon, France; Université de Lyon, Lyon, France.
authors: Justine
authors: J
authors: Bacchetta
authors: Divisione di Nefrologia e Dialisi, Ospedale Pediatrico Bambino Gesù , Roma, Italy.
authors: Marcella
authors: M
authors: Greco
authors: Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon , Bron, France.
authors: Aurélia
authors: A
authors: Bertholet-Thomas
authors: Département de Pédiatrie, CHU de Besançon , Besançon, France.
authors: François
authors: F
authors: Nobili
authors: Bone Pathology Unit, Institute of Pathology, University Medical Center Hamburg-Eppendorf , Hamburg, Germany.
authors: Jozef
authors: J
authors: Zustin
authors: Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Université de Lyon, Lyon, France.
authors: Pierre
authors: P
authors: Cochat
authors: Divisione di Nefrologia e Dialisi, Ospedale Pediatrico Bambino Gesù , Roma, Italy.
authors: Francesco
authors: F
authors: Emma
authors: INSERM, Faculté de Médecine Lyon Est, site Laennec, Lyon, France; Université de Lyon, Lyon, France.
authors: Georges
authors: G
authors: Boivin