Vitamin D-dependent rickets type II (VDDR2) is a rare inherited autosomal recessive disorder wherein the genetic mutation results in a defect in the vitamin D receptor (VDR), thus leading to target resistance to 1.25-dihydroxy vitamin D. This results in hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets. We report a case of a four-year-old female child with diffuse alopecia starting 2 weeks after birth, along with frontal bossing, hypoplastic teeth, and an unusual presentation of multiple skin-colored papules over the back. Genetic testing confirmed vitamin D-dependent rickets type 2A.

Vitamin D dependent rickets type 1 (VDDR1) is a rare disease due to pathogenic variants in 1-α hydroxylase gene. We describe our experience with systematic review of world literature to describe phenotype and genotype. Seven patients from six unrelated families with genetically proven VDDR1 from our cohort and 165 probands from systematic review were analyzed retrospectively. The clinical features, biochemistry, genetics, management, and long-term outcome were retrieved. In our cohort, the median age at presentation and diagnosis was 11(4-18) and 40(30-240) months. The delayed diagnoses were due to misdiagnoses as renal tubular acidosis and hypophosphatemic rickets. Four had hypocalcemic seizures in infancy whereas all had rickets by 2 years. All patients had biochemical response to calcitriol, however two patients diagnosed post-puberty had persistent deformity. Genetic analysis revealed two novel (p.Met260Arg, p.Arg453Leu) and a recurring variant (p.Phe443Profs*24). Systematic review showed that seizures as most common presentation in infancy, whereas delayed motor milestones and deformities after infancy. Diagnosis was delayed in 27 patients. Patients with unsatisfactory response despite compliance were >12 years at treatment initiation. Inappropriately normal 1,25(OH)2D may be present, however suppressed ratio of 1,25(OH)2 D/25(OH)D may provide a clue to diagnosis. Various region specific and hot-spot recurrent variants are described. Patients with truncating variants had higher daily calcitriol requirement and greatly suppressed ratio of 1,25(OH)2D/25(OH)D. Delayed diagnosis may lead to permanent short stature and deformities. Truncating variants tend to have severe disease as compared to non-truncating variants. Diagnostic accuracy of 1,25(OH)2 D/25(OH)D ratio needs further validation.

Rickets is a common disease worldwide. In the developed world, its prevalence dramatically decreased but still diagnosed in at-risk populations. The skin plays a critical role in vitamin D synthesis. Therefore, several skin diseases, especially keratinization disorders, could lead to impaired vitamin D metabolism and vitamin D deficient rickets. The article aimed to summarize the current knowledge of skin diseases and conditions associated with rickets. To examine the association between rickets and skin diseases, we performed a systematic review of the literature using PubMed database. The search included studies published from the database inception to August 2019. A total number of 75 articles were included. Identified conditions associated with rickets were ichthyosis being a more common skin diseases, alopecia, epidermal and melanocytic nevi, xeroderma pigmentosum, mastocytosis, psoriasis, and atopic dermatitis. Three types of rickets were identified: vitamin D-dependent rickets, hypocalcemic vitamin D-dependent rickets type 2, and hypophosphatemic rickets. Cutaneous skeletal hypophosphatemia syndrome is a newly described and under-recognized condition. It is defined by the association of epidermal or melanocytic nevi, hypophosphatemic rickets, and elevated levels of fibroblast growth factor 23. Rickets in patients with ichthyosis was mainly due to impaired ability of ichthyotic skin to synthesize vitamin D, poor UV penetration of the skin caused by keratinocyte proliferation, and dark phototype. The latter may be considered a risk factor for rickets in patients with ichthyosis. Despite its rarity, these associations should be properly recognized by dermatologists. Early diagnosis of rickets is important to prevent growth retardation and skeletal deformities.

Rickets refers to deficient mineralization at the growth plate and is usually associated with abnormal serum calcium and/or phosphate. There are several subtypes of rickets, including hypophosphatemic rickets (vitamin-D-resistant rickets secondary to renal phosphate wasting), vitamin D-dependent rickets (defects of vitamin D metabolism) and nutritional rickets (caused by dietary deficiency of vitamin D, and/or calcium, and/or phosphate). Most rickets manifest as bone deformities, bone pain, and impaired growth velocity. Diagnosis of rickets is established through the medical history, physical examination, biochemical tests and radiographs. It is of crucial importance to determine the cause of rickets, including the molecular characterization in case of vitamin D resistant rickets, and initiate rapidly the appropriate therapy. In this review, we describe the different causes and therapies of genetic and nutritional rickets, supported by the recent progress in genetics and development of novel molecules such as anti-FGF23 antibody.