Hypophosphatemic Rickets

X-linked hypophosphatemia is the most common cause of inherited rickets, due to inactivating variants of PHEX. More than 800 variants have been described to date and one which consists of a single base change in the 3′ untranslated region (UTR) (c.*231A>G) is reported as prevalent in North America. Recently an exon 13–15 duplication has been found to occur in concert with the c.*231A>G variant, and thus it is unclear whether the pathogenicity is solely a function of the UTR variant. We present a family with XLH who harbors the exon 13–15 duplication but does not carry the 3′UTR variant, providing evidence that the duplication itself is the pathogenic variant when these two variants are found in cis.

Las tubulopatías son un grupo heterogéneo de patologías que pueden afectar a distintos segmentos del túbulo renal. Estas tubulopatías pueden ser simples, cuando afectan a un único transportador, o complejas, cuando son varios los transportadores afectados. Estas tubulopatías también podrán ser hereditarias o adquiridas. Dependiendo de la función tubular que se encuentre afectada, cada entidad tiene una edad de aparición, manifestaciones clínicas y analíticas, gravedad y pronóstico propios. El diagnóstico se basará en una adecuada historia clínica que incluya antecedentes familiares (consanguinidad), exploración física que recoja datos de presión arterial, talla, peso, así como alteraciones de los sentidos. Será fundamental la realización de adecuados análisis de función renal y tubular, pruebas de estimulación y de imagen.

The tubulopathies are a heterogeneous group of pathologies that can affect different segments of the renal tubules. They may be simple, when they affect a single transporter, or complex, when several transporters are involved. They may also be hereditary or acquired. Depending on the tubular function that is involved, each entity corresponds to an age when it appears as well as clinical and analytical manifestations, degree of severity and prognosis. Diagnosis is based on an appropriate clinical history that includes family history (consanguinity), a physical examination that includes data on blood pressure, height and weight, together with any sensory disorders. Appropriate analysis of kidney and tubular functioning will be fundamental, together with stimulation and imaging tests.

Calcium and phosphorus metabolism is due to a complicated interplay of calcium, phosphorus, magnesium, vitamin D, and the parathyroid hormone (PTH)-renal axis. Abnormalities in any of these may lead to disorders of calcium and phosphorus in the neonate. In this chapter, we will review the physiology of calcium and phosphorus metabolism, disorders related to hypocalcemia and hypercalcemia, as well as metabolic bone disease in newborns and infants.

This article explores the theory and utility of a syndemic approach for the study of disease in the past. Syndemic principles are examined alongside other theoretical developments within bioarchaeology. Two case studies are provided to illustrate the efficacy of this approach: Tuberculosis and vitamin D deficiency in 18th and 19th century England, and malaria and helminth infections in Early Medieval England.

Public health studies of present syndemics, in addition to published bioarchaeological, clinical and social information relating to the chosen case studies.

The data from these two historical examples are revisited within a syndemic framework to draw deeper conclusions about disease clustering and heterogeneity in the past.

A syndemic framework can be applied to past contexts using clinical studies of diseases in a modern context and relevant paleopathological, archaeological, and historical data.

This approach provides a means for providing a deeper, contextualised understanding ancient diseases, and integrates well with extant theoretical tools in bioarchaeology

Syndemics provides scholars a deep-time perspective on diseases that still impact modern populations.

Many of the variables essential for a truly syndemic approach cannot be obtained from current archaeological, bioarchaeological, or historical methods.

More detailed and in-depth analysis of specific disease clusters within the past and the present, which draws on a comprehensive analysis of the social determinants of health.

Nutritional vitamin D deficiency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23 related), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D dependent rickets. Hypophosphatemia is a feature in all these forms. The diagnosis relies on a combination of clinical, biochemical and radiological features, but genetic testing is required to confirm the diagnosis. We screened 66 patients with hypophosphatemic rickets referred to this center between May 2015 and July 2019 using whole exome sequencing (WES) in addition to the measurement of their intact serum fibroblast growth factor 23 (FGF23) levels. WES revealed 36 pathogenic and 28 likely pathogenic variants in 16 different genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) in 63 patients which helped differentiate between the various forms of hypophosphatemic rickets. Intact serum FGF23 levels were significantly higher in patients with variations in PHEX, FGF23, DMP1 or ENPP1 genes. The major genetic causes of rickets were classic hypophosphatemic rickets with elevated FGF23 levels, distal renal tubular acidosis, and vitamin D dependent rickets. Based on the present results, we propose a customized gene panel for targeted exome sequencing, which will be useful for confirming the diagnosis in most patients with hypophosphatemic rickets.