Table 3.

Other Types of Autosomal Recessive Osteopetrosis

GeneDisorderClinical CharacteristicsFeatures Distinguishing this Disorder from CLCN7-Related ARO
CA2 ARO w/renal tubular acidosis (RTA) (OMIM 259730)Generalized osteosclerosis. Cerebral calcifications are typical & may be assoc w/ID. 1Onset of ARO w/RTA is usually later than in infantile malignant form of ARO & disease course is milder.
OSTM1 OSTM1-related ARO (OMIM 259720)~4% of ARO is caused by pathogenic variants in OSTM1. Extremely severe form of ARO w/CNS involvement 2 that is indistinguishable from most severe forms of CLCN7-related ARO.OSTM1-related ARO is frequently assoc w/structural brain anomalies.
PLEKHM1 PLEKHM1-related ARO (OMIM 611497)Very rare, can look like ADOIIPLEKHM1-related ARO appears to be very mild & can regress w/↑ age. 3 One person w/PLEKHM1-related ARO caused by a heterozygous pathogenic variant has been described. 4
SNX10 SNX10-related ARO (OMIM 615085)~4% of ARO is caused by pathogenic variants in SNX10; in particular, "Västerbottenian osteopetrosis" is caused by SNX10 pathogenic variants. Loss of vision, anemia, & bone fragility are frequently observed, warranting use of HSCT. 5SNX10-related ARO appears to be slightly less severe than CLCN7-related ARO.
TCIRG1 TCIRG1-related ARO (OMIM 259700)>50% of ARO is caused by pathogenic variants in TCIRG1.Higher frequency of neurodevelopmental delay & seizures in CLCN7-related ARO than in TCIRG1-related ARO. 6 Noncoding TCIRG1 variants can cause milder phenotype that resembles ADOII.
TNFRSF11A Osteoclast-poor ARO (OMIM 612301)Characterized by onset w/in 1st yr of life & typical ARO manifestations. Investigation of bone biopsy is prerequisite for reliable diagnosis.TNFSF11 pathogenic variants cause a slight T-cell defect & TNFRSF11A pathogenic variants can lead to hypogammaglobulinemia similar to a common variable immune deficiency. 7 It is crucial to rule out TNFSF11- & TNFRSF11A-related ARO, as HSCT is not successful in these persons.
TNFSF11 Osteoclast-poor ARO (OMIM 259710)

ADOII = autosomal dominant osteopetrosis type II; ARO = autosomal recessive osteopetrosis; CNS = central nervous system; ID = intellectual disability; HSCT = hematopoietic stem cell transplantation

1.
2.
3.
4.
5.
6.
7.

From: CLCN7-Related Osteopetrosis

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.