New form of idiopathic osteolysis: Nodulosis, arthropathy and osteolysis (NAO) syndrome

Abstract

We describe 10 patients (6 females and 4 males) from 6 unrelated families with an autosomal recessive disease characterized by simultaneous presentation of nodulosis, arthropathy and osteolysis. They were followed up regularly at King Faisal Specialist Hospital and Research Center in Saudi Arabia for clinical evaluation, serial blood work-up, and evaluating radiological changes. Nodulosis and arthropathy were the clinical criteria for inclusion in this study, and the ten patients fulfilled these criteria. All patients had nodulosis and distal arthropathy. Eight patients (80%) presented with deformed hands and four (40%) with painful hands. All patients had parents who were first cousins and three families had more than one affected child, the finding suggesting autosomal recessive inheritance. 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 clavicles. This novel phenotype should be considered in the differential diagnosis of chronic arthritis. Familial arthropathies are more often seen in communities where interfamilial marriage is common. Such a collection of patients is ideal for homozygosity mapping of the disease locus.

Characterization of the Distinct Collagen Binding, Helicase and Cleavage Mechanisms of Matrix Metalloproteinase 2 and 14 (Gelatinase A and MT1-MMP)

“…Mmp2 knockout mice, though smaller at birth than wild-type littermates, develop normally without any apparent deficits in collagen turnover (53). However, in humans the Mmp2 gene mutations, R101H and Y244X, in three consanguineous families leads to a deficiency in MMP-2 expression (54) with afflicted individuals displaying severe growth restrictions and many skeletal defects (55,56). This indicates that in humans, MMP-2 is critical for the balance of bone matrix protein synthesis and degradation, in which type I collagen is the major structural element.…”

Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development

“…Humans null for MMP2 have severe osteolytic syndromes, whereas Mmp2 -/-mice have only mild skeletal defects (Itoh et al, 1997;Al Aqeel et al, 2000;Al-Mayouf et al, 2000;Martignetti et al, 2001;Zankl et al, 2005;Inoue et al, 2006;Rouzier et al, 2006). The spontaneous occurrence of a low penetrance, runted phenotype with abnormal craniofacial features in our Mmp2 -/-mouse colony led us to hypothesize that there were genetic modifiers of Mmp2.…”

“…3A). Humans with MMP2-null mutations suffer from osteolytic lesions in their long bones that can be so debilitating that they become wheel-chair-bound (Al-Mayouf et al, 2000). Microcomputed tomography (micro-CT) analysis of Mmp2 -/-;Col1a1 r/r mice showed reduced trabecular bone density in tibiae, indicating osteopenia ( Fig.…”

“…Inactivating mutations in human MMP2 are the cause of rare but severe skeletal defect syndromes in patients born from consanguineous marriages (Martignetti et al, 2001;Zankl et al, 2005;Rouzier et al, 2006). The clinical findings in these MMP2-null patients include hyperextension of metacarpophalangeal joints, flexion contractures of large joints, dysmorphic faces, significant growth restrictions and, surprisingly, loss of bone mass with osteolysis (Al Aqeel et al, 2000;Al-Mayouf et al, 2000;Zankl et al, 2005;Rouzier et al, 2006). In contrast to MMP2-null humans, Mmp2 -/-mice have mild skeletal defects and no focal osteolysis (Inoue et al, 2006).…”

Cyclic intravenous pamidronate treatment in children with nodulosis, arthropathy and osteolysis syndrome

“…The lower serum urate values in women of reproductive age compared with their male counterparts have been ascribed to lower renal postsecretory uric acid reabsorption. 1 An increase in ratios of testosterone to oestradiol has been reported to be associated with hyperuricaemia. 2 The oestrogen receptor gene is located at chromosome 6q25.1 and has a thymine-adenine (TA) dinucleotide repeat polymorphism 1174 bp upstream from exon 1.…”