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Loss of Functional Osteoprotegerin: More Than a Skeletal Problem
- Source :
- The Journal of Clinical Endocrinology & Metabolism. 102:210-219
- Publication Year :
- 2016
- Publisher :
- The Endocrine Society, 2016.
-
Abstract
- 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.
- Subjects :
- Adult
Male
0301 basic medicine
Heterozygote
medicine.medical_specialty
Adolescent
Bone disease
Hearing loss
Endocrinology, Diabetes and Metabolism
Clinical Biochemistry
Medizin
030209 endocrinology & metabolism
Disease
Biochemistry
Short stature
03 medical and health sciences
0302 clinical medicine
Endocrinology
Osteoprotegerin
Internal medicine
medicine
Humans
Child
Genetic Association Studies
Aged
Muscle contracture
business.industry
Biochemistry (medical)
Infant
Heterozygote advantage
Exons
Middle Aged
Osteitis Deformans
Prognosis
medicine.disease
Pedigree
Osteopenia
Phenotype
030104 developmental biology
Child, Preschool
Mutation
Female
medicine.symptom
business
Biomarkers
Subjects
Details
- ISSN :
- 19457197 and 0021972X
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Accession number :
- edsair.doi.dedup.....9548e5a54bd306bc3e54ee4f5a3f7130