Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R

Abstract

Wave-shaped ribs were detected at prenatal ultrasound in a 20(+1) week female fetus. At birth, skeletal radiographs showed marked hypomineralization and suggested hypophosphatasia. However, elevated blood calcium and alkaline phosphatase excluded hypophosphatasia and raised the possibility of Jansen metaphyseal dysplasia. Molecular analysis of the PTH/PTHrP receptor gene (PTH1R) showed heterozygosity for a previously undescribed transversion variant (c.1373T>A), which predicts p.Ile458Lys. In vitro evaluation of wild type and mutant PTH/PTHrP receptors supported the pathogenic role of the p.Ile458Lys substitution, and confirmed the diagnosis of Jansen metaphyseal dysplasia. This disorder may present prenatally with wavy ribs and in the newborn with hypomineralization, and may therefore be confused with hypophosphatasia. The mottled metaphyseal lesions typically associated with this disease appear only in childhood.

Skull Base and Cervical Spine Involvement in Jansen Syndrome: Case Report

“…The epiphyses are large and bulbous with wide expanded diaphyses [1,14,15] . Wavy ribs in prenatal ultrasound have also been identified which can be an important sign for early diagnosis in conjunction with serial radiological and laboratory findings to rule out other diseases that mimic JMD [16] .…”

“…The associated diagnostic laboratory findings to exclude these disorders are asymptomatic hypercalcemia, hypercalciuria, and mild hypophosphatemia, with normal or low levels of parathyroid hormone or parathyroid hormone-related peptide in the plasma [13,16] . The JMD gene has been localized to the 3p22-p21.1 chromosome, which is the parathyroid hormone-related peptide receptor ( PTHR1 ).…”

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

“…In humans, mutations in PTHLH are associated with brachydactyly type E2 (BDE2) [28, 29], and inactivating mutations in its receptor ( PTH1R ) result in Blomstrand dysplasia , a recessive lethal chondrodysplasia characterized by very short limbs and dwarfism due to advanced skeletal maturation [30]. Interestingly, activating mutations in the same receptor cause short-limbed dwarfism, Jansen metaphyseal dysplasia , an autosomal dominant disorder accompanied by hypercalcemia and normal or low serum concentrations of PTH and PTHrP [31, 32]. Mutations in IHH, a signaling molecule, leads to brachydactyly type A1 (BDA1) [33].…”

Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor and Downstream Effector Molecules

“…Marked hypomineralization may also be observed suggesting hypophosphatasia. 92 Although body length is within normal limits at birth, growth becomes increasingly abnormal, eventually leading to the development of short stature. Additional signs may include kyphoscoliosis with a bell-shaped thorax and widened costochondral junctions, metaphyseal enlargement of the joints, waddling gait, prominent supraorbital ridges, and frontonasal hyperplasia.…”

“…Indeed, in several unrelated patients with this disorder, a heterozygous nucleotide exchange, which changes a histidine at position 223 to arginine, was identified at the border between the first intracellular loop and the second membrane-spanning domain of the PTH/PTHrP receptor. 98 In other patients, five additional heterozygous nucleotide exchanges were identified, which change either a threonine at position 410 to proline or arginine (sixth membrane-spanning domain), or isoleucine at position 458 (seventh membrane-spanning domain) to arginine 98 or to lysine 92 (Figure 40.3 and Table 40.1). The mutated residues are predicted to be located at or close to the intracellular surface of the cell membrane and are strictly conserved in all mammalian members of this receptor family, 1 suggesting an important functional role for these three residues.…”