Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia

Abstract

Skeletal dysplasias are a complex group of more than 350 disorders with phenotypic and genotypic heterogeneity affecting bone and cartilage growth. We studied a 2-year-old girl and her 21-year-old mother with disproportionate short stature. In addition to typical features of hypochondroplasia found in both patients, the child had deformities of the extremity bones, metaphyseal flares, and bilateral transverse (Bowdler) fibular spurs with overlying skin dimples detected at birth. Intravenous pamidronate was started in the child since the age of 17 days, and then every two months. Exome sequencing revealed that the girl was heterozygous for a missense mutation (c.1651A>G, p.Ile538Val) in exon 13 of FGFR3, a known mutation for hypochondroplasia, inherited from her mother. Interestingly, the child also harbored compound heterozygous missense mutations in exon 12 of ALPL, c.1460C>T (p.Ala487Val) inherited from her mother and c.1479C>A (p.Asn493Lys) inherited from her healthy father. The former mutation was previously reported in perinatal hypophosphatasia while the latter was novel. Constantly reduced serum alkaline phosphatase levels including the one before the pamidronate administration and a substantially elevated level of plasma pyridoxal 5'-phosphate detected at age 28 months supported the diagnosis of hypophosphatasia. After a definite diagnosis was achieved, pamidronate was withdrawn at the age of 28 months. No adverse events were observed during pamidronate therapy. In conclusion, we describe a unique case with monoallelic FGFR3 and biallelic ALPL mutations leading to features of both hypochondroplasia and hypophosphatasia.

Whole Exome Sequencing Aids the Diagnosis of Fetal Skeletal Dysplasia

“…Thus, c.984_986del may reduce the enzymatic activity too. c.1460C>T (p.A487V) and c.1466G>C (p.C489S) were reported early, of which the latter one exhibited a diminished ALP activity, less located on the cell surface and failed to become the mature form (Satou et al, 2012;Porntaveetus et al, 2017). This suggested that p.487-489 of ALPL protein may play an important role in enzymatic activity.…”

Whole Exome Sequencing Aids The Diagnosis of Fetal Skeletal Dysplasia

“…Thus, c.984_986del may reduce the enzymatic activity, too. c.1460C > T (p.A487V) and c.1466G > C (p.C489S) were reported early, of which the latter one exhibited a diminished ALP activity, less located on the cell surface and failed to become the mature form [21,22]. This suggested that p. 487-489 may play an important role in enzymatic activity.…”

Amelogenesis imperfecta: A novel FAM83H mutation and characteristics of periodontal ligament cells

“…The peripheral blood leucocytes were subjected to extraction of genomic DNA. The DNA sample was prepared according to previous publications (Porntaveetus, Srichomthong, Suphapeetiporn, & Shotelersuk, ). Sequencing was performed at Macrogen, Inc. (Seoul, Korea).…”