Non-nutritional rickets: Approach, precision medicine, and outcomes

Table 3 Rare forms of fibroblast growth factor 23 mediated Hereditary HR[113]

No.	Entity	Gene (chromosome)	Inheritance	Physiological role	Phenotype	Comments
1	Raine syndrome (ARHR3)	FAM20C (7p22.3)	AR	Kinase for FGF-23 and calcium binding phosphoprotein family of proteins (including SIBLING group)[34]	Ocular proptosis, mid-facial hypoplasia, depressed nasal bridge, cerebral calcifications (in parietal and occipital periventricular white matter), micrognathia, cleft palate, choanal atresia, corpus callosum and hypophysis dysgenesis, osteosclerosis and periosteal reaction. In lethal forms, mortality within the 1st month of life. Non-lethal forms have developmental delay, seizures and hypoacusis, amongst others	No genotype-phenotype correlation. Differentials include congenital cytomegalovirus infection, Crouzon syndrome, osteopetrosis dysplasia and desmosterolosis. Cerebral calcifications, osteopetrosis and rickets may also be seen in RTA due to carbonic anhydrase type 2 deficiency, but the calcification is predominantly in basal ganglia and the cortex
2	HR with hyperparathyroidism	Translocation between chromosomes 13 and 9, and the breakpoint on chromosome 13 is located adjacent to the Klotho gene	AD	Implicated in regulation of FGF signaling, aging and calcium homeostasis	Hypercalcemia. Raised PTH (similar to values in CR)	Very rare entity - only 2 reported cases
3	Fibrous dysplasia	GNAS	Post-zygotic mutation, unlikely to be hereditary	Encodes alpha subunit of stimulatory G-protein required for receptor binding of various hormones	Precocious puberty, hyperthyroidism, thyroid nodular disease, café-au-lait macules. Up to half the patients may have hypophosphatemia	Anecdotal evidence exists in favor of use of burosumab. Bisphosphonates and denosumab have been found to reduce the risk of fractures but increased risk of hypophosphatemia
4	Opsismodysplasia	INPPL1 (11q13.4)	AR	Encodes Src homology 2 domain-containing inositol phosphatases. It functions as a 5-phosphatase that modulates intracellular signaling and metabolic pathway	Relative macrocephaly with frontal prominence, midfacial hypoplasia, a low nasal bridge, short nose with anteverted nostrils, and an elongated philtrum; a constricted thoracic cage; small hands and feet; delayed epiphyseal ossification, metaphyseal cupping, and platyspondyly	Raised FGF-23 not seen in all patients
5	Osteoglophonic dysplasia	FGFR1 (heterozygous gain of function mutations)	AD	Tyrosine kinase family of receptors required for modulation of bone development	Tower-shaped skull, craniosynostosis, prominent supraorbital ridge, maxillary hypoplasia, depressed nasal bridge, mandibular prognathism, dental anomalies, vertebral anomalies, rhizomelic short stature, non-ossifying fibromasbone mineralization defects	Comprises of craniosynostosis (classical of FGFR1 AND FGFR2 mutations) and dwarfism (as in FGFR3 mutations) related manifestations
6	Jansen metaphyseal chondrodysplasia	PTHR1	AD (most cases de novo)	G-protein coupled receptor on kidney, bone and chondrocytes for PTH and PTHrP	Shortened limbs starting infancy. Radiographs reveal rachitic changes, bone erosions and cortical thinning. Patients biochemically have increased serum calcium, reduced phosphate levels, and raised alkaline phosphatase-are present, despite normal concentrations of PTH and PTHrP	H223R mutation has more severe hypercalcemia compared to the I458K and T410R mutations
7	Schimmel penning-Feuerstein-Mims syndrome/cutaneous skeletal hypophosphatemia syndrome	Somatic gain-of-function mosaicisms in RAS genes (HRAS, NRAS, and KRAS)		Encodes small GTPase proteins that act as molecular switches regulating fundamental cellular processes, including growth, proliferation, differentiation, survival, and motility		Burosumab was found to be effective in some cases

ARHR3: Autosomal recessive hypophosphatemic ricket 3; HR: Hypophosphatemic rickets; FAM20C: Family with sequence similarity 20-member C; GNAS: Guanine nucleotide-binding protein alpha-stimulating; INPPL1: Inositol polyphosphate phosphatase-like 1; FGFR1: Fibroblast growth factor receptor 1; PTHR1: Parathyroid hormone receptor 1; RAS: Rat sarcoma viral oncogene homolog; HRAS: Harvey rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma rat sarcoma viral oncogene homolog; KRAS: Kirsten rat sarcoma viral oncogene homolog; AR: Autosomal recessive; AD: Autosomal dominant; FGF-23: Fibroblast growth factor 23; SIBLING: Small integrin-binding ligand, N-linked glycoproteins; PTH: Parathyroid hormone; PTHrP: Parathyroid hormone-related protein; CR: Calcipenic rickets; RTA: Renal tubular acidosis; FGFR2: Fibroblast growth factor receptor 2; FGFR3: Fibroblast growth factor receptor 3; H223R: Histidine 223 to arginine; I458K: Isoleucine 458 to lysine; T410R: Threonine 410 to arginine.