Multicentric Osteolysis Nodulosis And Arthropathy

Clinical characteristics.

Multicentric osteolysis nodulosis and arthropathy (MONA) is a skeletal dysplasia characterized by progressive osteolysis (particularly of the carpal and tarsal bones), osteoporosis, subcutaneous nodules on the palms and soles, and progressive arthropathy (joint contractures, pain, swelling, and stiffness). Other manifestations include coarse facies, pigmented skin lesions, cardiac defects, and corneal opacities. Onset is usually between ages six months and six years (range: birth to 11 years).

Diagnosis/testing.

The diagnosis of MONA is established in a proband with characteristic clinical and radiographic findings and either biallelic pathogenic variants in MMP2 or decreased activity of the enzyme matrix metalloproteinase 2.

Management.

Treatment of manifestations: Treatment is supportive only and can include physical therapy (which may slow the rate of development of contractures and prolong mobility). Pain medications may not provide relief. Congenital heart defects are managed as per routine.

Surveillance: Annual reviews by a rheumatologist for pain management and joint assessments.

Genetic counseling.

MONA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the MMP2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk are possible.

Suggestive Findings

MONA should be suspected in individuals with the following clinical and radiographic findings:

Clinical

• Joint disease manifest predominantly as pain, swelling, and contractures of the small joints of the hands and feet in early childhood (Figure 1, Figure 2)
• Subcutaneous nodules, usually on the palms and soles (Figure 2)
• Coarse facial features
• Gingival hypertrophy

Figure 1.

Hands of different children with MONA showing joint contractures and swelling of the digits at age 4 years (A), 5 years (B), 7 years (C,D), 9 years (E), 10 years (F), 13 years (G,H), and 15 years (I). From Bhavani et al [2016]; republished with permission (more...)

Figure 2.

Feet of different individuals with MONA at ages 5 years (A), 6 years (B,C), 7 years (D,E), 9 years (F), 10 years (G), 13 years (H,I), and 15 years (J). Subcutaneous nodules are seen in A, B, C, F, G (arrows). From Bhavani et al [2016]; republished with (more...)

Radiographic

• Progressive osteopenia and osteolysis with early and predominant involvement of the bones of the hands (Figure 4) and feet (Figure 5). The carpal and tarsal bones, which are initially well formed, slowly show thinning of the cortices, osteopenia, and finally osteolysis, becoming small and irregular or disappearing completely.
• Thin cortices of the long bones (Figure 6). The metacarpals, metatarsals, and phalanges are most affected.
• Milder and similar changes in other bones

Figure 4.

Radiographs of the hands of different children with MONA at age 4 years (A), 5 years (B), 6 years (C,D), 7 years (E), 9 years (F), 10 years (G), 11 years (H), and 13 years (I,J). All have diffuse osteopenia and cortical thinning, most striking in the (more...)

Figure 5.

Radiographs of the feet of affected individuals at ages 5 years (A), 6 years (B), 7 years (C), 9 years (D), and 13 years (E). All cases demonstrate diffuse osteopenia. Small tarsal bones for age with irregular margins, particularly in (C) and (E), are (more...)

Figure 6.

Radiographs of the long bones of the upper extremities in affected individuals at ages 6 years (A, B) and 13 years (C, D, E). All cases demonstrate decreased bone mineralization with cortical thinning. From Bhavani et al [2016]; republished with permission (more...)

Establishing the Diagnosis

The diagnosis of MONA is established in a proband with characteristic clinical and radiographic findings by identification of biallelic pathogenic variants in MMP2 on molecular genetic testing (see Table 1) or decreased activity of the enzyme matrix metalloproteinase 2 by gelatin zymography.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of MMP2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes MMP2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes MMP2) fails to confirm a diagnosis in an individual with features of MONA. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Analysis of matrix metalloproteinase 2 enzyme activity can be performed by the electrophoretic technique gelatin zymography on body fluids and/or cell or tissue extracts [Martignetti et al 2001, Azzollini et al 2014]. In contrast to controls, affected individuals show complete loss of enzyme activity.

Clinical Description

Multicentric osteolysis nodulosis and arthropathy (MONA) is a skeletal dysplasia characterized by progressive osteolysis (particularly of the carpal and tarsal bones), osteoporosis, subcutaneous nodules on the palms and soles, and progressive arthropathy (contractures, pain, joint swelling/stiffness). Other manifestations include pigmented lesions on the skin, coarse facies, corneal opacities, and cardiac defects.

Most affected children are apparently normal at birth. Onset is usually between ages six months and six years [Azzollini et al 2014]; the range is from birth to 11 years [Castberg et al 2013, Bhavani et al 2016].

Joints. Peripheral joints are more involved than proximal joints. Small joints of the hands and feet are the most obvious sites of involvement. Progressive bone destruction leads to pain, swelling, stiffness, and later flexion contractures (Figure 1, Figure 2). Foot and hand deformities and progressive shortening of digits occur with age.

Knees show swelling and contractures in the majority (Figure 3); hip involvement is less severe [Bhavani et al 2016].

Figure 3.

Swollen knee joints in children with MONA at age 6 years (A), 7 years (B), and 13 years (C,D). Note serpiginous hyperpigmented skin lesions in C and D. From Bhavani et al [2016]; republished with permission of John Wiley and Sons

Wrists, ankles, and elbows are also involved.

Over time all affected individuals need assistance with mobility. Those with more severe manifestations are wheelchair bound between ages three and 12 years [Zankl et al 2005, Rouzier et al 2006, Temtamy et al 2012].

Face. Coarsening of facial features, bulbous nose, proptosis, strabismus, and gingival hypertrophy have been observed in several affected individuals [Bhavani et al 2016].

Skin. Subcutaneous, firm, palpable nodules in the palms and soles are noted in the majority of (but not all) affected individuals (Figures 2B and 2C). The presence of subcutaneous nodules may be age dependent. To date it has not been possible to determine if these nodules are painful as affected individuals have pain in their hands and feet due to osteopenia, fractures, contractures, limitation of movement, and sometimes inflammation.

Other cutaneous manifestations include hyperpigmentation and thickening. Serpiginous hyperpigmented cutaneous lesions are present in a few individuals (Figures 3C and 3D) [Zankl et al 2005, Azzollini et al 2014, Bhavani et al 2016].

In some individuals excessive skin folds in the hands and feet have resulted from destruction of underlying bones (Figure 1I).

Heart. Congenital heart defects (transposition of great arteries, atrial septal defect, ventricular septal defect, bicuspid aortic valve, and mitral valve prolapse) have been observed in one third of individuals reported to date [Tuysuz et al 2009, Castberg et al 2013, Bhavani et al 2016].

Other

• Most individuals have short stature [Castberg et al 2013]. Stature is normal in early in childhood; progressive bone and joint deformities could be the cause of short stature.
• Scoliosis and kyphosis are observed in very few individuals [Temtamy et al 2012, Azzollini et al 2014, Bhavani et al 2016].
• Low bone density and osteoporosis may lead to an increased risk of fracture of long bones and vertebrae [Jeong et al 2010, Temtamy et al 2012].
• Corneal opacities are occasionally observed; however, vision is preserved.
• Intellect is normal.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Nomenclature

In addition to MONA, this phenotype has been reported in the literature as Torg syndrome, Winchester-Torg (or Torg-Winchester) syndrome, and nodulosis-arthropathy-osteolysis (NAO) syndrome. All of these conditions have been shown to be caused by biallelic pathogenic variants in MMP2 with no discernable genotype-phenotype correlation. The term MONA is therefore used throughout this GeneReview to refer to all of these conditions.

Prevalence

The prevalence for this rare skeletal dysplasia is not available at present. To date 44 individuals (from 27 families) with molecularly proven MONA have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multicentric osteolysis nodulosis and arthropathy (MONA), the following evaluations are recommended:

• Complete skeletal survey
• Evaluation by an orthopedic surgeon, rheumatologist, and physical therapist to assess joint range of motion
• Cardiac evaluation, including echocardiogram
• Eye examination
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is supportive.

Osteopenia and osteolysis

• At present no specific therapy can alleviate the progressive osteopenia.
• Assure that daily requirements of vitamin D and calcium are met.
• Pamidronate is probably not effective [Phadke et al 2007].
• Steroids and immunosuppressants have been used without much benefit and are best avoided given their side effects [Al-Mayouf et al 2000, Zankl et al 2007, Tuysuz et al 2009, Castberg et al 2013, Ekbote et al 2014].

Joints

• Physical therapy may slow the rate of development of contractures and prolong mobility.
• Surgical release of contractures may not help [Author, personal observation].
• Aids to ensure mobility (wheelchair and walking aids) may be needed as the disease progresses.
• Nonsteroidal anti-inflammatory drugs may not provide sufficient relief. Referral to a rheumatologist or pain clinic may be beneficial to develop an individual pain management plan.

Cardiac manifestations. Provide medical or surgical interventions as appropriate.

Surveillance

The following are appropriate:

• Annual assessment of joints by a rheumatologist or orthopedic surgeon
• Follow up of congenital heart defects as per the treating cardiologist

Agents/Circumstances to Avoid

Avoid physical trauma to reduce the risk of fractures.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No information on pregnancy management and outcomes is available.

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.