Research Article: Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3

Date Published: March 5, 2018

Publisher: Public Library of Science

Author(s): Sezer Acar, Huda A. BinEssa, Korcan Demir, Roua A. Al-Rijjal, Minjing Zou, Gönül Çatli, Ahmet Anık, Anwar F. Al-Enezi, Seçil Özışık, Manar S. A. Al-Faham, Ayhan Abacı, Bumin Dündar, Walaa E. Kattan, Maysoon Alsagob, Salih Kavukçu, Hamdi E. Tamimi, Brian F. Meyer, Ece Böber, Yufei Shi, Francesc Palau.


Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.

Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.

Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887–22,395,767del (179880 bp deletion including exon 16–22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.

This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.

Partial Text

Hereditary hypophosphatemia or hypophosphatemic rickets (HR) when it occurs in children is a group of rare renal phosphate-wasting disorders with a prevalence of 3.9 per 100,000 live births [1]. It is characterized by hypophosphatemia and bone mineralization defects such as rickets and osteomalacia [2–4]. The patients usually present with a spectrum of clinical features such as growth retardation with disproportioned short stature, enlargement of growth plates of rapidly growing bones, lower limb deformities, bone pain, loss of teeth, and dental abscess.

Hereditary hypophosphatemia were diagnosed in 23 patients from 15 families: 17 children (mean age at diagnosis 4.9±1.9 years, age range 1.3–8.9 years), and 6 adults (mean age at diagnosis 34.2±4.5 years, age range 28–40 years). All the children had clinical and laboratory features of rickets such as genu varum deformity, metaphyseal X-ray findings, and/or fractures. The X-ray images of metaphyseal widening and irregularity, cupping and fraying of the metaphyseal region, haziness of cortical margins and epiphysis, and enlargement of the space between the epiphysis and metaphysis were present in all HR children except for X-3 and X-4. Loss of teeth and gum abscess were observed in case IX-3. Cases III-3, VI-4, and VII-3 had undergone a surgical operation for correction of severe lower limb deformities. Bone pain was not recorded in any of the cases.

In the present study, we investigated 23 patients from 15 unrelated families with hereditary hypophosphatemia. Disease-causing mutations were found in 21 patients and one asymptomatic sibling (carrying compound heterozygous SLC34A3 mutations) including 8 novel mutations: 6 in PHEX, and 2 in SLC34A3. De novo PHEX mutations were found in 6 out of 12 families. Together with our previous studies [30–32], we have investigated 50 patients from 31 unrelated families with hereditary hypophosphatemia, representing the largest series of patients from Turkish population. Among the 31 families, PHEX, FGF23, CLCN5, and SLC34A3 mutations was found in 26 (83.9%), 1 (3.2%), 1 (3.2%), and 1 (3.2%) families, respectively. The overall mutation detection rate is about 94% (29/31) and PHEX mutation is the most common genetic defect in the Turkish patients. Other mutations are rare such as FGF23, DMP1, ENPP1, SLC34A1, SLC34A3, and CLCN5. In fact, we have not detected DMP1, ENPP1, or SLC34A1 mutation in our patients. Our data are similar to those from other parts of the would such as Italy [2], Denmark [5] and US [6].




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