Genomic coordinate (human 12:4,368,227 FGF23) & (human 12:47,841,537 VDR) & (human 12:57,762,334 CYP27B1).
Cytoband (human 12p13.32 FGF23) & (human 12q13.11 VDR) & (human 12q14.1 CYP27B1).
OMIM’ genes: 12 @ 12p13.32, 12 @ 12q13.11, 28 @ 12q14.1.
Polymorphs: 256 FGF23 & 508 VDR & 498 CYP27B1.
Hyperbolic Umbilic Chromosome = 1,200 genes.
Here I present: “Chromosome-12 loci of RICKETS (osteomalacia)”, Victor McKusick, Mendelian Inheritance in Man’, 1966.
INTRODUCTION.
Three (3) distinct genetic forms of rickets, detailing their unique chromosomal-12 loci and affected genes are discussed below.
Conditions Listed in the Table.
Vitamin D-Dependent Rickets, Type 1A (VDDR1A): Mapped to the long arm (q) of chromosome 12, arising from pathogenic variations in the CYP27B1 gene. This gene encodes the 1α-hydroxylase enzyme, which is critical for converting vitamin D into its active form.
Vitamin D-Dependent Rickets, Type 2A (VDDR2A): Located at 12q13.11 and caused by mutations in the VDR gene. This alters the vitamin D receptor, making body tissues resistant to the active hormone.
Autosomal Dominant Hypophosphatemic Rickets (ADHR): Positioned at 12p13.32 and linked to the FGF23 gene. This mutation leads to an excess of fibroblast growth factor 23, resulting in renal phosphate wasting.
General Clinical Overview
Genetic variants in these pathways lead to severe systemic disruption of mineral homeostasis. Because these are distinct hereditary conditions rather than basic nutritional deficiencies, standard over-the-counter vitamin D3 supplements are typically ineffective on their own. Common presentation features across these conditions include:
Skeletal Changes: Soft or weak bones, skeletal deformities (such as bowed legs), joint widening, and an increased risk of bone fractures.
Growth and Muscle Impairment: Delayed bone development, shorter stature, severe muscle weakness, and poor muscle tone (hypotonia).
Biochemical Abnormalities: Disruptions in calcium and phosphate absorption, often leading to secondary hyperparathyroidism or hypocalcemic seizures in early life.
