Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified.

Source: GeneReviews — "CLCN7-Related Osteopetrosis"

Penetrance

Penetrance ranges from 60% to 90% in families with ADOII .

Source: GeneReviews — "CLCN7-Related Osteopetrosis"

Diagnostic Criteria

The spectrum of CLCN7-related osteopetrosis includes the following: • Autosomal recessive osteopetrosis (ARO; infantile malignant CLCN7-related autosomal recessive osteopetrosis) • Intermediate autosomal osteopetrosis (IAO) • Autosomal dominant osteopetrosis type II (ADOII; Albers-Schnberg disease) Suggestive Findings A CLCN7-related osteopetrosis should be suspected in individuals with osteosclerosis noted on radiographs, which may be accompanied by hypocalcemia and resulting convulsions, anemia, thrombocytopenia, visual impairment, and/or central nervous system involvement. Table 1. Diagnostic Features of the Subtypes of CLCN7-Related Osteopetrosis Finding | Subtype of CLCN7-Related Osteopetrosis

Source: GeneReviews — "CLCN7-Related Osteopetrosis"

Differential Diagnosis

Pathogenic variants in CLCN7 account for 13% of the infantile autosomal recessive osteopetrosis (ARO), 40% of the recessive intermediate autosomal osteopetrosis (IAO), 60% of the dominant IAO, and 99% of the autosomal dominant osteopetrosis type II (ADOII) [Authors, personal observation]. ARO Table 3. Other Types of Autosomal Recessive Osteopetrosis

Management Guidelines

General guidelines for diagnosis, therapy, and follow up are available for all forms of osteopetrosis; see . Due to the difference in severity, the evaluation, treatment, and surveillance recommendations for infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO) and CLCN7-related autosomal dominant osteopetrosis type II (ADOII) differ. The CLCN7-related intermediate autosomal osteopetrosis (IAO) phenotype lies between these two forms and has variable manifestations and prognosis. Therefore, management options for CLCN7-related IAO must be evaluated on an individual basis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ARO, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

System/Concern | Evaluation | Comment

Osteosclerosis

| Baseline radiographic skeletal survey |

Choanal stenosis

| Otorhinolaryngologic exam to evaluate for choanal stenosis assoc w/sclerosis of skull base |

Hypocalcemia

secondary hyper-

parathyroidism | Calcium concentrations in blood urine |

Anemia

thrombocytopenia | CBC w/reticulocyte count |

Abdominal ultrasound | Evaluate for hepatosplenomegaly assoc w/extrameduallry hematopoeisis.

Neurologic

Source: GeneReviews — "CLCN7-Related Osteopetrosis"

Clinical Guidance

ADOII

• Activities with high fracture risk should be avoided.

• Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.

Source: GeneReviews — "CLCN7-Related Osteopetrosis"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "CLCN7-Related Osteopetrosis"

Surveillance Guidelines

Table 9. Recommended Surveillance for Individuals with Infantile Malignant CLCN7-Related Autosomal Recessive Osteopetrosis (ARO)

Source: GeneReviews — "CLCN7-Related Osteopetrosis"