SNP Shot: Genomic Insights

Hereditary hypophosphatemic rickets (HHR) is a condition characterized by abnormally low phosphate levels in the blood (hypophosphatemia). Phosphate is crucial for building strong bones and teeth.

Symptoms of HHR usually appear in early childhood and can vary considerably, even within the same family. Some individuals may only have hypophosphatemia, while others experience more severe symptoms like slowed growth and shorter stature compared to their peers. Bone deformities, such as bowed legs or knock knees, can develop, causing pain and mobility issues. These bone problems often become noticeable with weight-bearing activities and can worsen if left untreated.

Additional signs and symptoms of HHR may include premature closure of skull bones (craniosynostosis) and dental problems. Abnormal bone growth at tendon and ligament attachment points (enthesopathy) can also occur. In adults, hypophosphatemia can lead to osteomalacia, a softening of the bones.

Several types of HHR have been identified, each distinguished by its inheritance pattern and underlying genetic cause. The most prevalent form is X-linked hypophosphatemic rickets (XLH), which follows an X-linked dominant inheritance pattern. Rarer forms include X-linked recessive, autosomal dominant, and autosomal recessive types.

A less common form of HHR is hereditary hypophosphatemic rickets with hypercalciuria (HHRH), characterized by both hypophosphatemia and high levels of calcium in the urine (hypercalciuria).

Inheritance:

HHR can be inherited in several ways. XLH, caused by mutations in the PHEX gene on the X chromosome, follows an X-linked dominant inheritance pattern. Females, with two X chromosomes, develop the condition if one copy of the PHEX gene is mutated. Males, with only one X chromosome, develop the condition if their single PHEX gene is mutated. A key characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Less commonly, HHR can be X-linked recessive, often referred to as Dent disease. The gene associated with Dent disease, like PHEX, is also located on the X chromosome. Males develop the condition with one mutated copy of the gene, while females need mutations in both copies, making it much rarer in females.

In rare families, HHR exhibits autosomal dominant inheritance, requiring only one mutated copy of a gene to cause the condition. HHRH follows an autosomal recessive pattern, requiring mutations in both copies of a gene. Parents of individuals with an autosomal recessive condition typically carry one copy of the mutated gene without showing symptoms. However, some parents of children with HHRH may experience hypercalciuria and kidney stones.