Alternative titles; symbols
SNOMEDCT: 203476003; ORPHA: 86820;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.11 | Avascular necrosis of the femoral head | 608805 | Autosomal dominant | 3 | COL2A1 | 120140 |
A number sign (#) is used with this entry because of evidence that familial avascular necrosis of the femoral head-1 (ANFH1) is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.
Avascular necrosis of the femoral head (ANFH) is a debilitating disease that usually leads to destruction of the hip joint in the third to fifth decade of life. The disorder is characterized by progressive pain in the groin, mechanical failure of the subchondral bone, and degeneration of the hip joint. Nearly one-half of patients require hip replacement before 40 years of age. ANFH represents a specific form of the broader disease category of osteonecrosis (summary by Mont and Hungerford, 1995).
Genetic Heterogeneity of Primary Avascular Necrosis of the Femoral Head
ANFH2 is caused by mutation in the TRPV4 gene (605427) on chromosome 12q24.
Mutation in COL2A1 has also been found in Legg-Calves-Perthes disease (LCPD; 150600), a form of ANFH in growing children.
Chen et al. (2004) reported 2 large Taiwanese families segregating autosomal dominant idiopathic avascular necrosis of the femoral head over 4 generations (family A) and 5 generations (family B). In family A, 16 members were affected, including 11 females and 5 males, with an average age at onset of 26 years (range, 15-48 years). All presented with symptoms of pain in the groin. Examination revealed average stature and unremarkable musculoskeletal findings, with no evidence of chondrodysplasia. Using the Ficat system, 5 patients were classified as stage II and 7 were classified as stage IV (advanced lesions). In family B, 8 females and 8 males were affected, with an age at onset ranging from 12 to 37 years.
Liu et al. (2005) restudied the 2 families with ANFH previously reported by Chen et al. (2004) as well as another 3-generation Taiwanese family with 6 affected members (family C). Radiographs at age 21 years of a female twin from family A, who presented at age 16 years with groin pain, revealed stage II disease with cystic and sclerotic changes in both femoral heads. Examination of a core decompression specimen from the right femoral head showed several dead bony fragments mixed with necrotic marrow tissue and fat cells in the marrow space. Radiographs of a 34-year-old man from family A showed stage IV disease with joint space narrowing and involvement of the acetabula.
Kannu et al. (2011) reported a 40-year-old man who was diagnosed with ANFH at age 18 years and underwent bilateral hip replacement at age 33. He had generalized osteoporosis by DEXA scan and a normal skeletal survey, other than bilateral hip degeneration. He had no facial dysmorphism, and ophthalmologic and audiologic examinations were normal. The proband's 2 sisters, who were of average stature, had normal skeletal radiographs.
The transmission pattern of ANFH in the families reported by Chen et al. (2004) and Liu et al. (2005) was consistent with autosomal dominant inheritance.
In Taiwan, Chen et al. (2004) identified 2 families with ANFH showing autosomal dominant inheritance. By linkage analysis in a 4-generation family, they excluded linkage with PROC, PROS1, and PAI, which had been implicated in thrombophilia or hypofibrinolysis. Furthermore, by a genomewide scan, a significant 2-point lod score of 3.45 (theta = 0.0) was obtained between ANFH and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second family with ANFH, with replication of the linkage to D12S368. When an age-dependent penetrance model was applied, the combined multipoint lod score was 6.43 between D12S1663 and D12S85, a 15-cM region on 12q13.
It has been suggested that a common pathway of pathogenesis of ANFH involves the interruption of blood circulation to the anterior-superior-lateral part of the femoral head, leading to ischemic insult and bone collapse (Atsumi and Kuroki, 1992). The disease is aggravated by mechanical disruption, e.g., hip fracture (Bachiller et al., 2002); by external pressure on or damage to a vessel wall, e.g., vasculitis (Wang et al., 1988), radiation therapy (Massin and Duparc, 1995), and systemic lupus erythematosus (Abu-Shakra et al., 2003); arterial thrombosis or embolism, e.g., sickle cell disease (Milner et al., 1991); corticosteroid use (Fisher, 1978); and alcohol abuse (Wang et al., 2003).
Although a major proportion of individuals with ANFH have underlying risk factors and are classified as having secondary ANFH, 15 to 30% of patients showing no apparent risk factors are classified as having primary or idiopathic ANFH (Assouline-Dayan et al., 2002). Some ANFH previously considered idiopathic may actually represent a feature of hereditary thrombophilia (an increased tendency for intravascular thrombosis) or hypofibrinolysis (a reduced ability to lyse thrombi). Deficiency of activated protein C (PROC; 612283) or protein S (PROS1; 176880), resulting in thrombophilia (176860; 612336), has been reported to be associated with osteonecrosis of the hip in adults and with LCP in children. Hypofibrinolysis, mediated by high levels of plasminogen activator inhibitor (PAI; 173360), has been cited as a major cause of idiopathic osteonecrosis.
Liu et al. (2005) identified 3 families in which there was autosomal dominant inheritance of ANFH, with mapping of the phenotype to 12q13. They carried out haplotype analysis in the families, selected candidate genes in the critical interval for ANFH on 12q13, and sequenced the promoter and exonic regions of the type II collagen gene (COL2A1; 120140) from patients with inherited and sporadic forms of ANFH. The same gly1170-to-ser (120140.0043) mutation was found in 2 separate families, with the mutant allele occurring on different haplotype backgrounds. In the third family, a gly717-to-ser (120140.0044) mutation was detected. No mutation was found in the COL2A1 coding region in sporadic cases of ANFH. The authors pointed out that in families with ANFH, haplotype and sequence analysis of the COL2A1 gene can be used to identify carriers of the mutant allele before the onset of clinical symptoms, allowing the initiation of measures that may delay progression of the disease.
In a 40-year-old man with avascular necrosis of the femoral head who was negative for mutation in the COMP (600310), COL9A1 (120210), COL9A2 (120260), COL9A3 (120270), DTDST (606718), and MATN3 (602109) genes, Kannu et al. (2011) identified a heterozygous missense mutation in the COL2A1 gene (120140.0054) that was not found in unaffected family members or in 150 age-, sex-, and ethnicity-matched controls. One of the proband's 2 unaffected sisters had a daughter diagnosed radiographically with multiple epiphyseal dysplasia at 10 years of age who was negative for mutation in COL2A1 and 6 other candidate genes. Because most COL2A1 mutations are private, Kannu et al. (2011) suggested that complete COL2A1 analysis should be considered in individuals presenting with early-onset degenerative hip disease.
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