Ocular Symptoms of Osteopetrosis

Key Points at a Glance

Osteopetrosis is a group of genetic disorders characterized by diffuse bone sclerosis due to osteoclast dysfunction.
Excessive bone growth of the optic canal causes compressive optic neuropathy, leading to progressive vision loss and blindness.
Various ocular symptoms such as proptosis, nystagmus, strabismus, and cranial nerve palsy are present.
The infantile malignant form (ARO) is severe and, if left untreated, is usually fatal within 10 years.
Treatment indications vary by genotype, and identification of the causative gene is essential for determining treatment strategy.
Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for the infantile malignant form, but it is ineffective in cases with RANKL mutations.
Early diagnosis and early treatment intervention increase the possibility of preserving vision.

1. Ocular Symptoms of Osteopetrosis

Osteopetrosis is a group of inherited metabolic bone diseases characterized by diffuse bone sclerosis due to impaired osteoclast formation and function. It was first reported in 1904 by the German radiologist Albers-Schönberg and was initially called “marble bone disease.” It was named “osteopetrosis” in 1926. Ocular symptoms are primarily caused by overgrowth of the skull and orbital bones.

Epidemiology

Autosomal dominant osteopetrosis (ADO): Most common. Frequency is 1 in 20,000 newborns.
Autosomal recessive osteopetrosis (ARO): Severe type. Frequency is 1 in 250,000 births. High frequency in Costa Rica.
Infantile malignant osteopetrosis (IMO): A subtype of ARO. Frequency is 1 in 200,000 to 1 in 300,000. ¹⁾

Main Types

ADO (Dominant Type)

Age of onset: Adolescence to adulthood. Relatively mild.

Also known as: Albers-Schönberg disease. Mainly caused by CLCN7 mutations.

Main problems: fractures, hearing loss, facial nerve palsy, osteomyelitis.

ARO (autosomal recessive osteopetrosis)

Onset: immediately after birth. Severe type.

Genes: TCIRG1 (approximately 50%), CLCN7, SNX10, OSTM1, etc.

Main problems: pancytopenia, hepatosplenomegaly, optic atrophy, nystagmus. Untreated, usually fatal within 10 years. ⁴⁾

Other types

Intermediate type: onset in childhood. Presents with short stature, fractures, osteomyelitis, anemia, dental abnormalities, facial nerve palsy, hearing loss.

CA II deficiency: associated with renal tubular acidosis.

X-linked type: NEMO/IKBKG mutation. Rarest.

Q What types of marble bone disease exist?

It is broadly classified into three types: autosomal dominant (ADO), autosomal recessive (ARO), and X-linked. There are also subtypes such as the intermediate type (childhood onset) and carbonic anhydrase II deficiency with renal tubular acidosis. ADO is relatively mild, while ARO is severe and requires early treatment intervention.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Progressive vision loss and blindness: Caused by compressive optic neuropathy due to excessive bone growth in the optic canal. One of the main symptoms of the infantile malignant type. In cases with RANKL mutation, progressive painless vision loss in both eyes starting at age 9, eventually leading to only light perception, has been reported. ²⁾
Proptosis: Due to overgrowth of orbital bones. Often occurs in both eyes.
Diplopia: Occurs when multiple cranial nerves (III, IV, VI) are compressed as they pass through the superior orbital fissure.

Clinical Findings (Findings Confirmed by Physician Examination)

Compressive optic neuropathy: Caused by optic canal stenosis. Regular monitoring of optic canal diameter by CT is necessary. Severe stenosis of the skull base canals (internal auditory canal, bilateral orbital apices, optic canal) is confirmed on CT. ²⁾
Optic atrophy: Observed on fundus examination as bilateral optic disc pallor. ²⁾ Severe cases with non-recordable flash VEP have also been reported.
Exophthalmos: In cases with RANKL mutation, Hertel exophthalmometry measured 27 mm in the right eye and 29 mm in the left eye. ²⁾
Restriction of extraocular muscle movement: Particularly limited upward gaze (5 to 10 degrees). ²⁾
Strabismus: Both exotropia and esotropia have been reported. ^2,3)
Nystagmus: May appear from infancy. A case of nystagmus onset at 7 months of age has been reported. ^3,4)
Papilledema: Caused by impaired venous return due to osteosclerosis, leading to cerebrospinal fluid accumulation.
Cranial nerve palsy: Narrowing of neural foramina due to bone proliferation. Cranial nerves III, IV, and VI (via the superior orbital fissure) are affected. Facial nerve palsy (cranial nerve VII) causes lagophthalmos.
Hypertelorism: Increased interorbital distance.
Retinal atrophy: Reported in some cases.
Conductive hearing loss: Complication due to narrowing of the internal auditory canal. In a case with a RANKL mutation, bilateral conductive hearing loss of 40 dB on the right and 32 dB on the left was observed. ²⁾

Q Why does vision loss occur in osteopetrosis?

Due to impaired bone resorption by osteoclasts, immature bone tissue compresses neural canals (optic canal, superior orbital fissure, skull base foramina). The optic canal gradually narrows, causing sustained mechanical compression of the optic nerve, leading to compressive optic neuropathy. If left untreated, optic atrophy and blindness can result. For details, see the “Pathophysiology and Detailed Mechanism” section.

3. Causes and Risk Factors

Osteopetrosis is caused by genetic mutations affecting osteoclast formation and function, with 23 genes identified to date. The inheritance pattern and responsible gene significantly influence treatment suitability.

Main causative genes

The causative genes of osteopetrosis are broadly classified into two types: those in which osteoclasts are formed but do not function (osteoclast-rich type) and those in which osteoclasts themselves are not formed (osteoclast-poor type).

Gene	Type	Frequency in ARO
TCIRG1	osteoclast-rich	Approximately 50%⁴⁾
CLCN7	osteoclast-rich (also a main cause of ADO-2)	13–16%³⁾
SNX10	osteoclast-rich	about 4%¹⁾
OSTM1	osteoclast-rich	2–6%³⁾
TNFSF11 (RANKL)	osteoclast-poor	Rare²⁾
TNFRSF11A (RANK)	osteoclast-poor	Rare³⁾

TCIRG1: Encodes the a3 subunit of V-ATPase, involved in acidification of the bone resorption lacuna by osteoclasts.
CLCN7: Encodes the voltage-gated chloride channel 7. It is also the main cause of ADO-2 (dominant form). When CLCN7 mutations are associated with neurodegeneration, HSCT may not improve the condition.³⁾
TNFSF11 (RANKL): A growth factor essential for osteoclast differentiation and activation. HSCT is ineffective for this mutation, making molecular diagnosis indispensable. ²⁾
Risk factors: Consanguineous marriage increases the risk of autosomal recessive types. ²⁾

4. Diagnosis and Testing Methods

Early diagnosis and identification of the genotype directly determine the treatment strategy.

Imaging Tests

X-ray: Diffuse osteosclerosis is characteristic. Findings include “bone-within-a-bone” appearance (spine, phalanges) and “sandwich vertebrae” (sclerotic bands at vertebral endplates). ^1,2)
CT scan: Used to monitor optic canal diameter, allowing quantification of nerve compression. Confirms severe narrowing of skull base canals (internal auditory canal, bilateral orbital apices, optic canal). ²⁾
DEXA scan: Quantifies bone mineral density. Even in the mildest cases, the BMD Z-score is reported to be ≥5 SD. In ADO-2 cases, lumbar L1-L4 BMD of 2,381 g/cm² (Z-score=12.1) has been reported. ⁵⁾

Genetic Testing

Identification of the causative gene by whole exome sequencing (WES) is essential for determining treatment strategy. ^2,3,4)

Essential for determining HSCT eligibility. HSCT is ineffective in TNFSF11 (RANKL) and OSTM1 mutations, requiring prior genetic diagnosis for exclusion. ^2,3)
Screening for mutations in TCIRG1, CLCN7, SNX10, RANKL, etc., is performed.

Ophthalmic Examination

VEP (Visual Evoked Potentials): Non-recordable flash VEP suggests severe optic neuropathy. ⁴⁾
Fundus Examination: Check for optic disc pallor (atrophy) and papilledema. ²⁾
Exophthalmometry (Hertel exophthalmometer): Serial monitoring of proptosis. ²⁾

Blood Tests

Pancytopenia (anemia, thrombocytopenia, leukocyte abnormalities), elevated ALP, and elevated LDH are observed. ^1,3,4)

Differential Diagnosis

Congenital cytomegalovirus infection presents with hepatosplenomegaly, pancytopenia, and optic nerve abnormalities, so caution is required. Genetic testing is necessary for a definitive diagnosis. ⁴⁾

Q Why is genetic testing necessary?

Because the indication for HSCT differs depending on the causative gene. HSCT is ineffective or harmful in cases of RANKL (TNFSF11) or OSTM1 mutations, and performing transplantation without confirming the genotype exposes the patient to unnecessary risk. It is important to identify the causative gene through whole-exome sequencing and determine the treatment strategy.

5. Standard Treatment

Hematopoietic Stem Cell Transplantation (HSCT)

This is the only curative treatment for infantile malignant osteopetrosis (IMO). Early intervention increases the likelihood of preserving or restoring vision.

In a review of 34 cases with SNX10 mutations, HSCT was performed in 16 cases, and 12 survived. ¹⁾
Untreated IMO typically leads to death within 10 years. ⁴⁾

When HSCT is not effective:

In OSTM1 mutations and some CLCN7 mutations (with neurodegeneration), neurological symptoms do not improve after HSCT. ³⁾
HSCT is ineffective for TNFSF11 (RANKL) mutations. Genetic screening is essential. ^2,3)

Exceptional Treatment for TNFSF11 Mutations

In osteopetrosis caused by TNFSF11 (RANKL) gene mutations, administration of recombinant RANKL protein is a treatment option. Since HSCT is ineffective in this type, personalized treatment based on molecular diagnosis is required.

Optic Nerve Decompression

As symptomatic treatment, surgery to decompress the optic canal by removing bone tissue. Early intervention in the infantile malignant form has been reported to prevent vision deterioration. Early diagnosis is important to slow the progression of neurological symptoms.

Symptomatic Treatment and Multidisciplinary Collaboration

Management of bone marrow failure: Red blood cell transfusion, iron chelation therapy (deferiprone 30 mg/kg/day). ⁵⁾
Treatment of osteomyelitis: Surgical debridement, hyperbaric oxygen therapy, antibiotic therapy (ciprofloxacin + clindamycin). ²⁾
Continuous ophthalmologic monitoring: CT follow-up of optic canal diameter, VEP, fundus examination.
Fracture management, infection management, and dental management: Regular follow-up by a multidisciplinary team is required.

Q Is hematopoietic stem cell transplantation effective for all types of osteopetrosis?

No, it is not. HSCT is effective for infantile malignant osteopetrosis (ARO/IMO), but it is ineffective for some genotypes such as RANKL (TNFSF11) mutations or OSTM1 mutations. For cases with RANKL mutations, administration of recombinant RANKL protein is an option. Genetic diagnosis before treatment is essential.

6. Pathophysiology and Detailed Mechanism of Onset

Osteoclast Dysfunction

The basic pathology of osteopetrosis is impaired bone resorption due to defective osteoclast formation or function. Unresorbed defective bone tissue accumulates, leading to brittle and overly dense bone structure. When bone marrow cavities are invaded by bone, hematopoietic space decreases, resulting in extramedullary hematopoiesis in the liver and spleen (causing hepatosplenomegaly). ⁶⁾

Osteoclast-rich type

Main causative genes: TCIRG1, CLCN7, OSTM1, SNX10, etc.

Mechanism: Osteoclasts are present but bone resorption does not function.

TCIRG1: V-ATPase a3 subunit defect → impaired acidification of the resorption lacuna → inability to resorb bone. ³⁾

CLCN7: Cl⁻/H⁺ exchange dysfunction → loss of coordination with hydrogen ion transport by TCIRG1. ³⁾

Osteoclast-poor type

Main causative genes: TNFSF11 (RANKL), TNFRSF11A (RANK).

Mechanism: Osteoclast differentiation and activation themselves are impaired.

RANKL: A growth factor essential for osteoclast differentiation and activation. It binds not only to the receptor RANK but also to LGR4, suppressing osteoclast differentiation via the GSK3-β pathway. ²⁾

Therapeutic significance: HSCT is ineffective. Recombinant RANKL protein is a treatment option.

Mechanism of Ocular Symptoms

The fundamental cause is the accumulation of immature bone due to impaired bone resorption, which narrows the neural canals.

Optic canal stenosis: Mechanical compression of the optic nerve → compressive optic neuropathy → optic atrophy → blindness
Superior orbital fissure stenosis: Compression of cranial nerves III, IV, and VI → ophthalmoplegia and diplopia
Reduced orbital volume: Overgrowth of orbital bones → exophthalmos
Venous drainage impairment: Venous outflow obstruction due to bone sclerosis → cerebrospinal fluid accumulation → papilledema

Q Why does impaired osteoclast function affect the eyes?

During fetal and infant bone development, openings such as the optic canal and superior orbital fissure are formed and maintained at appropriate sizes through bone resorption by osteoclasts. When osteoclasts do not function, immature bone tissue is not resorbed and accumulates, gradually narrowing these openings. Narrowing of the optic canal compresses the optic nerve, leading to compressive optic neuropathy, optic atrophy, and blindness.

7. Latest Research and Future Prospects (Reports at the Research Stage)

Gene Therapy

Autologous hematopoietic stem cell gene therapy is attracting attention as an alternative to allogeneic HSCT. It may avoid complications from conditioning regimens and the risk of GVHD (graft-versus-host disease). ⁴⁾

Xian et al. (2020) successfully generated gene-corrected osteoclasts from osteopetrosis iPSCs. Moscatelli et al. (2020) demonstrated proof of concept for phenotypic reversal in a preclinical research review of gene therapy for IMO. ⁴⁾

Identification of Novel Gene Mutations

Currently, 23 causative genes have been identified, and reports of novel mutations continue to emerge.

SNX10 c.61C>T (p.Gln21Ter): First report from China. An IMO case caused by a homozygous mutation. ¹⁾
TNFSF11 (RANKL) c.842T>G (p.Phe281Cys): First report from a Thai family. It showed a relatively mild phenotype. ²⁾
Novel mutations in TCIRG1: Two novel mutations, c.242dup and c.1020+1_1021+5dup, were identified. ⁴⁾
Novel mutations in CLCN7: c.1555C>T, c.286-9G>A, and c.1025T>C were reported. ³⁾

8. References

Zhou T, Zeng C, Xi Q, et al. SNX10 gene mutation in infantile malignant osteopetrosis: A case report and literature review. J Cent South Univ (Med Sci). 2021;46(1):108-112.
Lertwilaiwittaya P, Suktitipat B, Khongthon P, et al. Identification of novel mutation in RANKL by whole-exome sequencing in a Thai family with osteopetrosis; a case report and review of RANKL osteopetrosis. Mol Genet Genomic Med. 2021;9(8):e1727.
Liang H, Li N, Yao R, et al. Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis. Mol Genet Genomic Med. 2021;9(11):e1815.
Jin X, Wang W, Pan Z, et al. Osteopetrosis misdiagnosed as congenital cytomegalovirus infection: A case report and literature review. Medicine. 2025;104(45):e45583.
Lu K, Cheng B, Shi Q, et al. Anterior cruciate ligament rupture in a patient with Albers-Schonberg disease. BMC Musculoskelet Disord. 2022;23(1):719.
Khsiba A, Nasr S, Hamzaoui L, et al. Osteopetrosis: a rare case of portal hypertension. Future Sci OA. 2022;8(10):FSO817.

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