Genetic aspects of Sterno-costo-clavicular hyperostosis

Sternocostoclavicular hyperostosis (SCCH) is a relatively rare inflammatory
disorder of the axial skeleton presenting with pain, tenderness and swelling of
the sternum, medial ends of the clavicles and upper ribs, with the spine and
mandible being less commonly affected. The disease may start in early adulthood
and lasts several years with a natural course characterized by periods of
exacerbations and remissions. Pathophysiologically, the bone lesions are due to
a chronic sterile osteomyelitis of unknown aetiology leading to hyperostosis of
bone in the anterior chest wall. This reflects abnormal osteogenesis and is
radiologically manifested as sclerosis, with bony enlargement and increased
bone density. The mixture of destructive and proliferative components is
similar to classic psoriatic arthropathy and seronegative spondylarthropathies,
but the unusual locations and the variability of bone involvement leads to a
wide range of differential diagnoses including arthritis, osteomyelitis,
Paget*s disease of bone, primary bone tumors, and metastases. SCCH remains a
largely unrecognized syndrome, partly because of its limited manifestations as
it misses some of the essential components of the more severe form of chronic
sterile osteomyelitis of adults: the SAPHO syndrome (Synovitis, Acne,
Pustulosis, Hyperostosis and Osteitis), and partly because of its waxing and
waning natural course.

Although bone is the primary inflammation target, the disease has been
described in association with pustulosa-palmo-plantaris or other chronic
inflammatory disorders of the skin such as psoriasis and also with inflammatory
gut disorders such as Coeliac disease or Crohn*s disease (16). The
pathophysiology of SCCH and its more severe form SAPHO remains largely
enigmatic. Chronic Recurrent Multifocal Osteomyelitis (CRMO) is the childhood
form of chronic sterile osteomyelitis, characterized by multifocal bone
lesions, with multiple recurrent episodes of bone inflammation not responding
to prolonged antimicrobial therapy. The inflammatory bone lesions are not
confined to the axial skeleton like in SCCH or SAPHO but are typically located
at the metaphyses of tubular long bones. Recent evidence suggests that the
etiology of sporadic CRMO has a genetic component, including several reports of
affected siblings, affected parent and child duos, concordant monozygotic
twins, with a CRMO susceptibility locus mapped to human chromosome 18q21.3-
18q22. In addition, as many as half of patients have a first-degree
or second-degree family member who is affected by a chronic inflammatory
disorder, most commonly psoriasis. 2 The genes responsible for an autosomal
recessive rare form of chronic recurrent multifocal osteomyelitis (CRMO) with a
more severe phenotype (earlier presentation ~ 2 years of age, more frequent
recurrences, shorter remissions, poor linear growth and disease continuing in
adulthood) called Majeed syndrome (LPIN2), for cherubism (SH3BP2 and possibly
PTPN11), a hereditary chronic inflammatory disorder in which bone is also the
primary inflammatory target and for murine chronic multifocal osteomyelitis, an
autosomal recessive mouse model of CRMO with a locus mapped to a 21 cM region
of murine chromosome 18 (missense mutation in the pstpip2 gene) have also been
recently identified.

The role for genetic factors in SCCH is further supported by a fortuitously
discovered mouse model derived from a BALB/c.DBA/2 strain. The mice
spontaneously develop chronic multifocal aseptic osteomyelitis similar to the
bone lesions seen in humans with SAPHO syndrome. The susceptibility gene, which
is located on chromosome 18 (at a locus designated *cmo* for chronic multifocal
osteomyelitis) transmits the disease according to a recessive pattern. Analysis
of the cmo locus showed a missense mutation on gene pstpip2
(praline-serine-threonine phosphatase-interacting protein 2). The pstpip
proteins are involved in regulating the immune response via several mechanism
mediated by T cells and apoptosis. Several groups are currently investigating
the potential role for pstpip2 in a number of chronic inflammatory diseases,
including psoriasis. Not substantiated in a cohort of 89 patients with
non-bacterial osteitis which included patients with CRMO (Jansson 2007).
Furthermore, a study conducted in Germany in a cohort of 27 patients with
chronic recurrent multifocal osteomyelitis (a form of SAPHO) and their parents
suggests a role for a dominantly inherited gene with variable penetrance, also
located on chromosome 18q, near the D18S60 marker.

SCCH is a rare disease associated with significant morbidity that illustrates
the need for educational efforts aimed at improving the diagnosis and treatment
of affected patients and at accumulating knowledge on the disease. SCCH also
presents a unique model of a potential autoinflammatory disorder of the
skeleton, likely to be due to a genetically influenced disorder of innate
immunity. Unraveling the specific genetic factors involved in the pathogenesis
of this disorder would contribute to our understanding of the complex interface
of the immune system with the skeleton.

• To construct the pedigree of patients with SCCH with special attention to the
presence of other inflammatory disorders such as inflammatory bowel disease,
psoriasis, inflammatory arthritis in patients and kindreds.
• To identify the gene mutation responsible for the abnormal inflammatory
response in SCCH, starting with the already identified mutations in children
with CRMO, Cherubism and Majeed syndrome and the mutations identified in the
mice models of CRMO and in the TNF-alpha gene.

Open study design, with retrospective analysis of data at diagnosis of SCCH and
prospective pedigree construction and genetic analysis of DNA obtained at some
stage during the natural course of the disease.

Patients participation involves one visit to the outpatient departement of the
LUMC during which an interview of about one hour duration will be conducted,
following which blood will be collected and stored for future DNA analysis.
The above procedure can also be conducted at the patients home would she or he
so prefer.
No risks are involved.
Were indicated DNA will also be collected, based on the patient pedigree, from
relevant family members by appointment after singing informed consent.