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) and mobility aids. Pain medications may not provide relief unless the pain is due to secondary osteoarthritis/contractures. Daily recommended supplementation of vitamin D and calcium; standard management of congenital heart defects; management of scoliosis and kyphosis per orthopedist.

Surveillance: Annual joint assessment by a rheumatologist or orthopedic surgeon. Evaluation with cardiologist as needed for follow up of congenital heart disease. Annual assessment for scoliosis and kyphosis.

Agents/circumstances to avoid: Physical trauma to reduce the risk of fractures.

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 and preimplantation genetic testing for a pregnancy at increased risk are possible.

Suggestive Findings

MONA should be suspected in individuals with the following clinical findings, radiographic findings, and family history.

Clinical findings

• Joint disease manifest predominantly as pain, swelling, and contractures of the small joints of the hands and feet in early childhood (See Figure 1 and Figure 2.)
• Subcutaneous nodules, usually on the palms and soles (See 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 findings

• Progressive osteopenia and osteolysis with early and predominant involvement of the bones of the hands (see Figure 4) and feet (see 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 (see 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...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis

Establishing the Diagnosis

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

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic MMP2 variants of uncertain significance (or of one known MMP2 pathogenic variant and one MMP2 variant of uncertain significance) does not establish or rule out the diagnosis.

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].

To date, 51 individuals have been identified with biallelic pathogenic variants in MMP2 [Martignetti et al 2001, Zankl et al 2005, Rouzier et al 2006, Phadke et al 2007, Zankl et al 2007, Tuysuz et al 2009, Gok et al 2010, Jeong et al 2010, Temtamy et al 2012, Castberg et al 2013, Azzollini et al 2014, Ekbote et al 2014, Bader-Meunier et al 2016, Bhavani et al 2016, Pichler et al 2016, Kröger et al 2019, Elsebaie et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Joint manifestations. 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].

Osteopenia. 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].

Short stature. Most individuals have short stature [Castberg et al 2013]. Stature is normal in early childhood; progressive bone and joint deformities could be the cause of short stature.

Facial features. 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].

Intellect is normal.

Other

• Scoliosis and kyphosis are observed in some individuals [Temtamy et al 2012, Azzollini et al 2014, Bhavani et al 2016, Kröger et al 2019].
• Corneal opacities are occasionally observed; however, vision is preserved.

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 discernible genotype-phenotype correlation. The term MONA is therefore used throughout this GeneReview to refer to all of these conditions.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], MONA is referred to as MMP2-related multicentric osteolysis, nodulosis, and arthropathy and is included in the osteolysis group.

Prevalence

The prevalence for this rare skeletal dysplasia is not available at present. To date 51 individuals (from 31 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 evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is supportive.

Surveillance

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.

Mode of Inheritance

Multicentric osteolysis nodulosis and arthropathy (MONA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one MMP2 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MMP2 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an MMP2 pathogenic variant, each sib of an affected individual has at conception 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.
• The age of onset and manifestations may vary in sibs with the same biallelic MMP2 pathogenic variants [Kröger et al 2019].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with MONA are obligate heterozygotes (carriers) for an MMP2 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an MMP2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the MMP2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the MMP2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MMP2 encodes metalloproteinase-2 enzyme (MMP2), a type IV collagenase protein also known as gelatinase. MMP2 consists of four functional domains: signal peptide, propeptide domain, catalytic domain, and hemopexin domain.

Pathogenic variants include deletions and missense, nonsense, and splice site variants. Most pathogenic variants are private and homozygous. Most MMP2 pathogenic variants lead to loss of gelatinolytic activity of the enzyme MMP2 [Azzollini et al 2014].

The study of osteoblast cell lines from Mmp2-null mice showed that the loss of Mmp2 protein leads to decreased bone mineralization, destruction of articular cartilage, joint erosion, and defects in osteoblast and osteoclast growth [Mosig et al 2007].

Mechanism of disease causation. Loss of function

Cancer and Benign Tumors

Somatic MMP2 pathogenic variants that result in abnormal MMP2 expression are associated with cancers (e.g., gastric, colorectal, ovarian, melanoma, breast, and lung cancers). The COSMIC (Catalogue of Somatic Mutations in Cancer) database shows 192 unique MMP2 variants in tissues associated with cancers.

Author Notes

Dr Katta M Girisha, MD, DM is a clinical geneticist with special interest in skeletal dysplasia and genomic diagnosis of rare diseases.

Website: kmcmedicalgenetics.in

Acknowledgments

Indian Council of Medical Research – Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects (BMS 54/2/2013)

Department of Science and Technology – Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development (SB/SO/HS/005/2014)

Revision History

• 30 March 2023 (sw) Revision: "MMP2-Related Multicentric Osteolysis, Nodulosis, and Arthropathy" added as a synonym; Nosology of Genetic Skeletal Disorders: 2023 Revision [Unger et al 2023] added to Nomenclature
• 9 September 2021 (sw) Comprehensive update posted live
• 14 July 2016 (bp) Review posted live
• 22 February 2016 (kmg) Original submission

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