X-linked dominant hypophosphatemic rickets

X-linked dominant hypophosphatemic rickets is a hereditary renal phosphate-wasting disorder that chiefly affects bone mineralization, leading to rickets, osteomalacia, and impaired growth. The condition is caused by pathogenic variants in the PHEX gene. It typically presents in childhood with signs such as bone deformities and delayed motor milestones. Although it is inherited in an X‐linked dominant pattern, many cases arise from new genetic changes, and the disorder is considered uncommon, affecting approximately 1 to 9 per 100,000 people.

The clinical presentation is marked by consistent skeletal abnormalities. Characteristic features include frontal bossing, tibial and femoral bowing, genu valgum, and a rachitic rosary, all of which are nearly always present. Other common findings are elevated circulating alkaline phosphatase levels, hypophosphatemia, bowed legs, cupped metaphyses of the hand bones, and delayed gross motor development leading to a waddling gait and delayed walking. Abnormal circulating calcium concentrations may also be observed in a subset of individuals. Not all individuals experience every feature, and severity varies considerably.

The disorder results from pathogenic variants in the PHEX gene. Most cases arise from de novo pathogenic variants, meaning there is usually no prior family history. This condition is inherited in an X‐linked dominant manner, where affected females may have less severe symptoms due to variable X-inactivation, while affected males often show more pronounced skeletal abnormalities. Genetic counseling is recommended to discuss recurrence risks and implications for family planning.

Currently, management focuses on supportive care and symptom management since there are no treatments specifically approved for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team to address the skeletal deformities and promote optimal growth. Regular surveillance is an essential part of long-term care, helping to identify complications early and guide therapeutic decisions. Patients should discuss treatment options with their healthcare team, and genetic counseling is recommended for families seeking guidance on inheritance and family planning.

With current standards of care, many individuals with X-linked dominant hypophosphatemic rickets manage their symptoms well into adulthood. The condition exhibits a variable course, with some individuals maintaining relative stability in their skeletal issues while others experience ongoing challenges related to growth and bone health. Outcomes vary depending on symptom severity, age at diagnosis, and access to specialized care. Outcomes described in medical literature continue to evolve as standards of care improve, and families are encouraged to connect with specialists and genetic counselors for further guidance.

There are several clinical trials currently investigating new treatment approaches for X-linked dominant hypophosphatemic rickets. Active research is exploring potential therapies to improve phosphate metabolism and overall bone health. Individuals interested in clinical trials can search ClinicalTrials.gov or discuss trial options with their care team.