Three new mutations in the PHEX gene — which provides instructions for making an enzyme primarily active in the bones and teeth — were found in a study of Polish children with X-linked hypophosphatemia (XLH). The study also highlighted the importance of early treatment for stunted growth, common in XLH. Titled “X-linked hypophosphatemic rickets in children: clinical phenotype, therapeutic strategies and molecular background,” the study was published in the journal Endokrynologia Polska. XLH is the most common form of hypophosphatemic rickets, or HR, and is characterized by weakness in the bones and problems in teeth, among other symptoms. The disorder is caused by mutations in the PHEX gene, which lead to greater production of fibroblast growth factor 23 (FGF23). As such, reabsorption of phosphate in the kidneys is reduced, as is the production of vitamin D, both crucial for bone growth and remodeling. Now, researchers at Poznan University of Medical Sciences, in Poland, investigated the clinical features, therapeutic strategies, and genetic background of HR in hospitalized children. A total of 11 HR patients — six girls and five boys, with a mean age of 11.6 years — were involved in the study and followed for 4.5 years on average. Their age at diagnosis varied from 1 to 9 years. All patients were treated with alfacalcidol (a vitamin D analog) and phosphorus, the mineral found in phosphate compounds; three were given an engineered form of growth hormone (rhGH). Clinical measures such as height standard deviation, predicted adult height, and bone age were estimated using standard methods. A genetic analysis of the PHEX gene was conducted for all participants, while the FGF23 gene, which codes for the protein of the same name, was analyzed in five patients. All but one patient showed bowing of the legs, or genu varum. Orthopedic surgeries were performed in six children, three as a result of late diagnosis. Dental or gum problems (36%) and short stature (81.8%) also were observed. The mean height standard deviation score was 2.99. The most common biochemical abnormalities at the time of diagnosis or during the first hospital stay were hypophosphatemia, or low phosphate levels, found in all participants, and high levels of the liver damage marker alkaline phosphatase, observed in 10 children. Six of the children had decreased excretion of phosphorus in the urine. In all patients, kidney reabsorption of phosphate was normal but dropped during follow-up. Normalization of alkaline phosphatase was observed during treatment in six children. Unlike the increases seen in two patients with early diagnosis, one girl with a late diagnosis who started rhGH therapy after puberty did not improve her height. “It seems that the time of therapy introduction is the key point,” the researchers wrote. Still, the team added that since the “group is heterogeneous, and because of the different types of therapy and sometimes a short observation period, it is hard to clearly specify the conclusions regarding growth, time of diagnosis and laboratory findings.” Regarding genetic analysis, PHEX gene mutations were found in 10 patients. Two previously unknown PHEX mutations were identified in two children, one of which was found in a patient who also had a known gene variant (polymorphism) known as rs3752433. In one participant, the team found a new deletion of a part of the gene and two polymorphisms, both of which may lead to abnormal function of the PHEX protein. Other known mutations were observed in the remaining patients. The genetic analysis of FGF23 did not identify any disease-causing variants. Among the study's limitations were the small number of participants and the short observation period. In addition, the scientists said that periodic non-compliance of treatment in some patients may have affected the results. Nonetheless, the investigators said the findings highlight the need for identifying the disease and its symptoms as early as possible. "Early diagnosis and implementation of conventional treatment and rhGH can improve patient height and minimise bone deformities,” the researchers wrote. "Molecular analysis is necessary to confirm the clinical diagnosis of HR and conduct appropriate genetic counselling in families with HR patients," they concluded.