Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology

Abstract

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Keywords: hereditary rickets; management; non-hereditary rickets; nutritional rickets; treatment.

Figure 1

Classification of the main forms of rickets based on the pathogenesis. XLH, X-linked hypophosphatemic rickets; ADHR, autosomal dominant hypophosphatemic rickets; ARHR1, autosomal recessive hypophosphatemic rickets type 1; ARHR2, autosomal recessive hypophosphatemic rickets type 2; PFD, polyostotic fibrous dysplasia; HHRH, hypophosphatemic rickets with hypercalciuria; NPHLPO1, nephrolithiasis/osteoporosis, hypophosphatemic, 1. NHERF1, nephrolithiasis/osteoporosis, hypophosphatemic, 2; VDDR1A, vitamin D-dependent rickets type 1A; VDDR1B, vitamin D-dependent rickets type 1B; VDDR2A, vitamin D-dependent rickets type 2A; VDDR2B, vitamin D-dependent rickets type 2B; VDDR3, vitamin D-dependent rickets type 3; TIO, Tumor-induced osteomalacia; HPP, hypophosphatasia.

Figure 2

Radiographic features at the wrist and at the hand in patients with nutritional vitamin D deficiency rickets and some forms of hereditary rickets. In patients with hereditary rickets, the diagnosis was confirmed by genetic analyses. All patients showed widening and fraying of the epiphyseal plate and metaphyseal concavity of the ulna. The white and black arrows showed fractures.

Figure 3

Algorithm for the evaluation of a patient with confirmed rickets by clinical signs, increased alkaline phosphatase activity, and radiographic lesions of rickets. The primary differential diagnosis is based on the presence of hypocalcemia (hypocalcemic rickets) or hypophosphatemia (hypophosphatemic rickets). Measurement of serum concentrations of 25(OH)D and 1,25(OH)₂D may indicate the biochemical diagnosis of the various forms of hypocalcemic rickets. Measurement of TmP/GFR values represents the first step for the selection of the patients with hypophosphatemic rickets. Thereafter, measurement of FGF23 concentration may suggest the biochemical diagnosis of the various forms of hypophosphatemic rickets. For additional detais see text. XLH, X-linked hypophosphatemic rickets; ADHR, autosomal dominant hypophosphatemic rickets; ARHR1, autosomal recessive hypophosphatemic rickets type 1; ARHR2, autosomal recessive hypophosphatemic rickets type 2; HHRH, hypophosphatemic rickets with hypercalciuria; VDDR1A, vitamin D-dependent rickets type 1A; VDDR1B, vitamin D-dependent rickets type 1B; VDDR2A, vitamin D-dependent rickets type 2A; VDDR2B, vitamin D-dependent rickets type 2B; VDDR3, vitamin D-dependent rickets type 3; TIO, Tumor-induced osteomalacia. *Genetic testing is important to confirm the suspected diagnosis. L, low values; N, normal values; H, high values.