Lambert et al. (1989) reported two affected French sisters, born of consanguineous parents originating from Algeria. Rouzier et al. (2006) provided a detailed clinical history and follow-up of the sisters. At age 3 years, the older sister developed painful contracture of the left fifth finger with a progressive extension to other fingers. Later, she presented with flexion contracture of the wrists, elbows, and shoulders. Lower limbs were also affected in a distal-to-proximal manner, and she was wheelchair-bound by age 10 years. Other features included a shortened trunk, coarse facial features, and thickened skin with hypertrichosis on the anterior sides of the legs and ankles. The younger sister had earlier onset at age 6 months and a more severe course. Reexamination of the sisters at ages 35 and 24 years, respectively, showed short stature, increased weight, flexion contractures of the large joints, kyphosis, and very small hands and feet. The skin was thin, and hypertrichosis in the older sister had disappeared. There were no cataracts and intellectual development was normal. Radiographic examination showed obvious progression of osteopenia with generalized cortical thinning, progressive osteolysis of the carpal and tarsal bones, resorptive deformities of the phalanges, and destruction of the interphalangeal and metacarpophalangeal joints. Other radiographic features included slender metatarsal diaphyses, ankylosed knee joints, incurved diaphyses of the femur and fibula, misshapen pelvis, marked excavation of the acetabulum, erosions of the articular surfaces of the hip joint, and biconcave aspect of the vertebral bodies and scoliosis. Rouzier et al. (2006) identified a homozygous in-frame deletion in the MMP2 gene in the two sisters.
Al-Mayouf et al. (2000) studied 10 patients (six females and four males) from six unrelated Saudi families with an autosomal recessive disorder characterized by simultaneous presentation of nodulosis, arthropathy, and osteolysis. All 10 patients had nodulosis and distal arthropathy. Eight of them presented with deformed hands and four with painful hands. The parents were first cousins in all cases, and three families had more than one affected child. Osteopenia and undertubulation of bones, distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial ends of the clavicles.
Al-Aqeel et al. (2000) studied a consanguineous Saudi family in which two affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life. The arthropathy eventually progressed to the proximal joints, resulting in crippling ankylosis and severe generalized osteopenia in both sibs. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Although Al-Aqeel et al. (2000) suggested that this form of multicentric osteolysis with autosomal recessive inheritance closely resembled the Torg osteolysis syndrome, a unique facial appearance, fibrocollagenous pads, and body hirsutism were not noted in the original description of Torg osteolysis syndrome.
Martignetti et al. (2001) described 11 patients affected with multicentric osteolysis, nodulosis, and arthropathy (MONA). These patients came from four consanguineous Saudi families originally studied by Al-Mayouf et al. (2000) and Al-Aqeel et al. (2000). All affected patients had multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies. Also they all were significantly growth restricted. Martignetti et al. (2001) mapped the disease locus to chromosome 16q12-q21. Haplotype analysis narrowed the critical region to a 1.2-cM region that spanned the gene encoding matrix metalloproteinase-2 (MMP2). They found no MMP2 enzymatic activity in serum or fibroblasts of affected family members.
Al-Mayouf (2007) undertook a retrospective review of children who presented with arthroptahy and a positive family history of a similar condition between 1990 and 2005 in a tertiary hospital in Saudi Arabia. Of the 62 patients identified, 15 (nine females, six males) were diagnosed with NAO Syndrome. These included patients that were used for haplotype analysis by Martignetti et al. (2001). The patients came from seven unrelated families. Parents of all patients were consanguineous, and five families had more than one affected child. All patients had mostly plantar nodulosis as well as arthropathy, with no evidence of inflammation. All patients also showed dysmorphic features with frontal bossing and hypertelorism. There was significant osteoporosis and progressive arthropathy complicated by joint deformity due to osteolysis.