Multicentric Carpotarsal Osteolysis Syndrome

A number sign (#) is used with this entry because of evidence that multicentric carpotarsal osteolysis syndrome (MCTO) is caused by heterozygous mutation in the MAFB gene (608968) on chromosome 20q12.

Description

Multicentric carpotarsal osteolysis syndrome is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bone usually occurs and other bones may also be involved. Chronic renal failure is a frequent component of the syndrome. Mental retardation and minor facial anomalies have been noted in some patients. Autosomal dominant inheritance has been documented in many families (Pai and Macpherson, 1988).

See also Torg-Winchester syndrome (259600), an autosomal recessive multicentric osteolysis syndrome.

Clinical Features

Shurtleff et al. (1964) observed a family in which 11 persons in 3 generations had osteolysis of the carpal bones with nephropathy. Osteolysis of the carpal bones led to disappearance of these bones in older subjects. Deformity of the hands suggesting arthritis also occurred in severe cases. Hypertension and renal failure resulting from arteriolar thickening were internal complications.

Caffey (1961) described affected father and son. The father died of uremia (McKusick, 1970).

Torg et al. (1969) suggested that sporadic cases such as that of Lagier and Rutishauer (1965) and that of Torg and Steel (1968) represent a separate disorder. It seems that they are indistinguishable (except quantitatively in terms of severity of renal disease) from the inherited cases and may represent new dominant mutations.

Gluck and Miller (1972) reported a family with males affected with osteolysis in 3 successive generations. Nephropathy and hypertension were not present.

Kohler et al. (1973) described a father and 3 sibs with hereditary osteolysis. The osteolysis was most severe in the carpal and tarsal bones. The osteolysis was also present and spreading in adjacent areas. All the affected showed arthritic symptoms in childhood, painless deformities of the wrists and feet, and a Marfan-like appearance. Mild deterioration of the elbow was present in the children. No hypertension or renal involvement was seen. These patients demonstrated an elevated alkaline phosphatase reflecting the process of bone destruction.

Whyte et al. (1978) described affected father and son. Both had micrognathia and hypotelorism and were exceptionally tall during the symptomatic stage of their disease. Urinary hydroxyproline was increased. Whyte et al. (1978) suggested that multicentric osteolysis with nephropathy is an entity separate from hereditary multicentric osteolysis.

Bennett et al. (1980) described a female patient with onset of puffy and tender feet and wrists at age 21 months. She was 135 cm tall at the age of 13. At age 14 cloudiness of the lower portion of both corneas was discovered. Proteinuria and white cells in the urine with no bacteria were discovered at age 16. Then and at age 18 and 20, blood pressure was normal. At the age of 22, the patient presented with a blood pressure of 240/140; however, hypertensive retinopathy was not seen. The patient died soon afterwards with azotemia. The kidneys weighed 55 grams each. Microscopy showed proliferation of vascular intima and medial hypertrophy of renal vessels of all sizes. Nephropathy in this condition typically appears several years after osteolysis has occurred, and the reverse sequence has, it seems, not been seen.

After diagnosing carpotarsal osteolysis in a man hospitalized for nephropathy, Fryns (1982) diagnosed the same disorder in his 6-month-old son.

Hardegger et al. (1985) reported an isolated case and reviewed the various forms of osteolysis including the monocentric massive osteolysis which goes by the name of Gorham (Gorham and Stout, 1955) and appears to be nonmendelian.

Carnevale et al. (1987) pointed out that clinical manifestations begin in early childhood with arthritis-like episodes involving ankles and wrists, progressive deformities, radiologic osteolytic changes, and variable degrees of disability. They emphasized the triangular shape of the face, protruding eyes, and micrognathia.

Pai and Macpherson (1988) reported 2 sporadic cases. One of the patients was described as having a 'peculiar, chubby cheek, doll-like facial appearance' in spite of a generally cachectic appearance. Similar facial changes were noted in the review by Carnevale et al. (1987). The second patient of Pai and Macpherson (1988) was an 11-year-old black boy referred for the management of end-stage renal disease. Proteinuria had first been detected during a preschool examination at age 5.

Patients with onset of symptoms in adulthood may represent a subgroup in which ribs, clavicles, sternum, and mandible may be involved (Renie and Pyeritz, 1981; Tookman et al., 1985). It is not clear whether this is genetically determined or whether it is the same disorder as the childhood-onset condition.

Shinohara et al. (1991) described a 5-year-old girl with osteolysis of the carpal bones as well as other parts of the skeleton and nephropathy. She also had corneal clouding and valvular pulmonary stenosis, leading Shinohara et al. (1991) to conclude that the disorder was distinctive.

Urlus et al. (1993) reported the cases of affected father and daughter and provided an extensive review of the literature.

Zankl et al. (2012) studied 11 simplex probands and 2 multigenerational pedigrees with multicentric carpotarsal osteolysis. Each affected individual had classic radiographic features of MCTO, with complete destruction of carpal bones but relatively well-preserved metacarpals and phalanges. Of the 11 simplex cases, 5 had undergone renal transplantation and 3 had markedly impaired renal function but did not yet require dialysis; the remaining 3 patients, who showed no evidence of renal dysfunction, were all under 7 years of age. The affected individuals from the 2 families with MCTO showed no evidence of renal dysfunction, with the exception of 1 patient who 'at a very old age' developed renal dysfunction of unknown etiology.

Inheritance

Male-to-male transmission in several cases of osteolysis of carpal bones with nephropathy (e.g., Caffey, 1961, Whyte et al., 1978, Fryns, 1982) confirmed autosomal dominant inheritance.

Molecular Genetics

In 5 probands with multicentric carpotarsal osteolysis, Zankl et al. (2012) performed whole-exome sequencing followed by quality filtering and identified heterozygosity for missense mutations in the MAFB gene (see, e.g., 608968.0001-608968.0003 and 608968.0005) in all 5 patients. Analysis of MAFB in an additional 6 unrelated simplex cases revealed heterozygosity for missense mutations in all of them (see, e.g., 608968.0003 and 608968.0004). In 2 families with autosomal dominant inheritance of MCTO, Zankl et al. (2012) identified heterozygosity for another missense mutation that segregated with disease in both families (608968.0006). Noting that affected individuals from these 2 families, many of whom were adults, did not manifest renal disease, the authors concluded that MAFB mutations are also responsible for MCTO in the absence of renal disease.