Loss of Functional Osteoprotegerin: More Than a Skeletal Problem.
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.



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.



We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous).



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.



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.
Pediatric Endocrinology and Diabetology, Klinik für Kinderheilkunde II and.|Center for Rare Bone Diseases, EZSE and Departments of.
Corinna
C
Grasemann
Center for Rare Bone Diseases, EZSE and Departments of.|Endocrinology, Diabetology, and Metabolism.
Nicole
N
Unger
Center for Rare Bone Diseases, EZSE and Departments of.|Orthopedics and Trauma Surgery.
Matthias
M
Hövel
Center for Rare Bone Diseases, EZSE and Departments of.|ENT, and.
Diana
D
Arweiler-Harbeck
Pediatric Neonatology, Klinik für Kinderheilkunde I and.
Ralf
R
Herrmann
Pediatric Hematology and Oncology, Klinik für Kinderheilkunde III and Departments of.
Michael M
MM
Schündeln
Neurosurgery.
Oliver
O
Müller
Radiology and Neuroradiology, University Hospital Essen and The University of Duisburg-Essen, 45122 Essen, Germany.
Bernd
B
Schweiger
Pediatric Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany.
Ekkehart
E
Lausch
Department of General Paediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, 40225 Düsseldorf, Germany.
Thomas
T
Meissner
Pediatric Endocrinology and Diabetology, Klinik für Kinderheilkunde II and.
Cordula
C
Kiewert
Pediatric Endocrinology and Diabetology, Klinik für Kinderheilkunde II and.
Berthold P
BP
Hauffa
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6 NH, United Kingdom; and.|Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B4 6 NH, United Kingdom.
Nick J
NJ
Shaw
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010001:Osteitis Deformans / Q000235:genetics* / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis
D015415:Biomarkers; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human