Juvenile Paget’s disease: Report of a family with a novel missense mutation and unique radiological manifestations in a heterozygote

Juvenile Paget’s disease (JPD) is a rare, generalized skeletal disorder characterized by markedly increased bone turnover secondary to enhanced osteoclastic activity. The patients with JPD develop progressive, widespread skeletal involvement and non-skeletal manifestations. Objectives To identify the characteristic molecular, biochemical, radiological, and audiological findings in three siblings with JPD associated with intrafamilial phenotypic variability. Patients and Methods A Saudi family with 3 affected siblings was recruited. Biochemical measurement of serum alkaline phosphatase and markers of bone turnover were performed. Genetic testing and sequencing of a panel of 22 known genes for skeletal dysplasia with increase bone density were performed by next generation sequencing (NGS). Radiological and audiological assessment were also performed. Results Patients showed marked elevation of serum alkaline phosphatase and markers of bone turnover. A novel homozygous mutation c.433T>G (p.Cys145Gly) in exon 3 of TNFRSF11B gene was identified in the 3 affected siblings. Both parents were heterozygous for the mutation. The heterozygote father had thickening of calvarium, a radiological manifestation of JPD. The eldest child (index case) had a unique striking distortion of the skull bones as evidenced by 3-D computed tomography of skull. He had also bilateral inner ear structural deformity and severe sensorineural hearing loss. Conclusions: JPD is a rare disorder that can be highly overlooked due to phenotypic overlap with other disorders of skeletal dysplasia. Mutations affecting cysteine residues result in the most severe JPD phenotypes. NGS is useful for early diagnosis of JPD, a prerequisite for successful treatment strategy.

Loss of Functional Osteoprotegerin: More Than a Skeletal Problem

Introduction: Juvenile Paget’s disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype–phenotype correlation spanning from mild to very severe forms is described. Aim: This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients: We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results: A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion: Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.