IllnessOsteopetrosis, differential diagnosis

NGS +

Osteopetrosis causes abnormally high bone density, thus increasing also brittleness. Autosomal dominant osteopetrosis is usually the mildest form and sometimes completely asymptomatic, especially in young children. On the other hand, in late childhood or adolescence the main features in affected individuals include multiple fractures, scoliosis or other spinal abnormalities, hip osteoarthritis and osteomyelitis. Autosomal recessively inherited osteopetrosis causes a more severe form already in early childhood. Dense bone tissue constricts cranial nerves with paralysis of facial muscles, loss of vision and hearing, and can also lead to bone marrow suppression with anemia, hemorrhage and recurrent infections, the latter of which can be life-threatening in infancy or early childhood. In addition, slowed growth rates and small stature are observed as well as dental abnormalities and hepatosplenomegaly, sometimes also accompanied by brain malformations, intellectual disability or epilepsy. X-linked osteopetrosis is rare and, in addition to dense bone structure, lymphedema, anhydrotic ectodermal dysplasia and immunodeficiency are observed. Mutations in the CLCN7 gene are responsible for approximately 75% of autosomal dominant osteopetrosis cases, 10-15% of cases are inherited in an autosomal recessive manner. TCIRG1 mutations cause half of autosomal recessive osteopetrosis. The X-linked type is caused by mutations in the IKBKG gene. In less than one-third of all cases, the cause of the disease cannot be elucidated by molecular genetics, even when up to 25 associated genes are studied. The 70% yield rate implies that the clinical diagnosis cannot be refuted by a negative molecular genetic result.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1127/

• Alias: Marble bone disease; Albers-Schonberg disease
• Allelic: Bleeding disorder, platelet-type, 18 (RASGRP2)
• Allelic: Bone mineral density variability 1 (LRP5)
• Allelic: Coronary artery disease, autosomal dominant, 2 (LRP6)
• Allelic: Exudative vitreoretinopathy 4 (LRP5)
• Allelic: Hyperostosis, endosteal (LRP5)
• Allelic: Hypopigmentation, organomegaly, delayed myelination + development (CLCN7)
• Allelic: Leukoencephalopathy, diffuse hereditary, with spheroids 1 (CSF1R)
• Allelic: Osteolysis, familial expansile (TNFRSF11A)
• Allelic: Osteoporosis (LRP5)
• Allelic: Osteoporosis-pseudoglioma syndrome (LRP5)
• Allelic: Osteosclerosis (LRP5)
• Allelic: Paget disease of bone 2, early-onset (TNFRSF11A)
• Allelic: Polycystic liver disease 4 with/-out kidney cysts (LRP5)
• Allelic: Tooth agenesis, selective, 7 (LRP6)
• Allelic: van Buchem disease, type 2 (LRP5)
• Brain abnormalities, neurodegeneration + dysosteosclerosis (CSF1R)
• Chondrocalcinosis (ANKH)
• Craniodiaphyseal dysplasia, AD (SOST)
• Craniometaphyseal dysplasia (ANKH)
• Craniometaphyseal dysplasia, AR (GJA1)
• Endosteal hyperostosis [GeneReviews] (LRP6)
• Histiocytosis-lymphadenopathy plus syndrome [dysosteosclerosis] (SLC29A3)
• Leukocyte adhesion deficiency, type III (FERMT3)
• Osteoclast-poor AR osteopetrosis
• Osteopetrosis, AD 1 (LRP5)
• Osteopetrosis, AD 2 (CLCN7)
• Osteopetrosis, AD 3 (PLEKHM1)
• Osteopetrosis, AR 1 (TCIRG1)
• Osteopetrosis, AR 2 (TNFSF11)
• Osteopetrosis, AR 3, with renal tubular acidosis (CA2)
• Osteopetrosis, AR 4 (CLCN7)
• Osteopetrosis, AR 5 (OSTM1)
• Osteopetrosis, AR 6 (PLEKHM1)
• Osteopetrosis, AR 7 (TNFRSF11A)
• Osteopetrosis, AR 8 (SNX10)
• Osteosclerotic metaphyseal dysplasia (LRRK1)
• Pycnodysostosis (CTSK)
• Sclerosteosis 1 (SOST)
• Van Buchem disease [Hyperostosis corticalis generalisata] (SOST)