The radiological findings of osteopoikilosis consist of multiple, well-circumscribed round or oval opacities, each 1–10 mm in diameter. They are usually found in the epiphyses and metaphyses of long bones and the pelvis, but are also frequent in the spongiosa of the phalanges, carpal and tarsal bones. The ribs, skull and spine are very rarely affected, which is helpful in excluding other osteocondensing conditions such as metastases, mastocytosis and tuberous sclerosis .
Osteopoikilosis is of no pathological significance and is usually an incidental finding, found in 12 of 211,000 radiographs in one series . It can occur in the fetus, but usually takes many years to develop and may not be detectable before the late adolescent or adult period. Familial osteopoikilosis in the absence of skin changes has been described .
Buschke–Ollendorff syndrome usually remains a benign disorder throughout life, as exemplified by a woman who gave birth to eight affected children . Rarely, muscle fibrosis and contractures may complicate the disorder  and several associations have been described [11,41], most of which are likely to be purely coincidental. One exception to this is the association with otosclerosis [5,23,42,43], possibly as a consequence of a generalized connective tissue disorder.
Differential Diagnosis and Treatment.
History, careful clinical examination and appropriate radiological investigations of the patient and whole family are essential to identify BOS. Indeed, the differential diagnosis of the cutaneous findings is quite large (Box 145.1). In the absence of bone changes in any member of the family, a biopsy will differentiate BOS from other connective tissue naevi.
Box 145.1 Differential Diagnosis of Cutaneous Elastoma in the Buschke–Ollendorff Syndrome
- Shagreen patch (tuberous sclerosis)
- Pseudo-xanthoma elasticum
- Lichen myxoedematosus
- Dermal nodules of Hunter syndrome
- Smooth muscle hamartoma
The lesions of BOS remain asymptomatic and rarely cause cosmetic problems, so no treatment is necessary. Informing close relatives of the diagnosis is advisable to avoid misinterpretation of incidental radiographs and allow genetic counselling of this autosomal dominant syndrome.
Papular elastorrhexis is a rare variant of connective tissue naevus in which there is normal collagen and a decreased amount of elastic fibres. The disorder, appearing in adolescence, has been described in three single patients [44,45]. In these non-familial cases, the cutaneous findings were distinct from papular acne scars and not associated with extracutaneous abnormalities. Although some believe that most connective tissue naevi-like lesions, including papular elastorrhexis, in adults are papular acne scars , it seems that the distinctive histology of papular elastorrhexis clearly separates the condition from other entities . Less than 15 cases were published in 2008 .
Schirren et al. described three members of one family presenting with non-follicular, distributed, white papules on the trunk and extremities . The clinical appearance with absence of osteopoikilosis and the histological findings (decreased, fragmented elastic fibres and normal collagen) were compatible with papular elastorrhexis. However, on the basis of the genetic background, the authors believed that papular elastorrhexis was an abortive form of the Buschke–Ollendorff syndrome and suggested that connective tissue naevi with the most prominent alterations in the elastic tissue should be classified under the term elastic tissue naevi.
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17 Marguery MC, Samalens G, Pieraggi MT et al. Conjunctive nevus of the disseminated elastic type without osteopoikilosis or Weidman juvenile elastoma. Ann Dermatol Venereol 1991;118:465–8.
18 Huilgol SC, Griffiths WA, Black MM. Familial juvenile elastoma. Australas J Dermatol 1994;35:87–90.
19 Woodrow S, Pope F, Handfield-Jones S. The Buschke–Ollendorff syndrome presenting as familial elastic tissue naevi. Br J Dermatol 2001;144:890–3.
20 Ramme K, Kolde G, Stadler R. Dermatofibrosis lenticularis disseminata with osteopoikilosis. Buschke–Olldendorff syndrome. Hautarzt 11993;44:312–14.
21 Dahan S, Bonafe JL, Laroche M et al. Iconography of Buschke Ollendorff syndrome: X ray computed tomography and nuclear magnetic resonance of osteopoikilosis. Ann Dermatol Venereol 1989;116:225–30.
22 Roberts NM, Langtry JA, Branfoot AC et al. Case report: osteopoikilosis and the Buschke–Ollendorff syndrome. Br J Radiol 1993;66:468–70.
23 Schnur RE, Grace K, Herzberg A. Buschke–Ollendorff syndrome, otosclerosis, and congenital spinal stenosis. Pediatr Dermatol 1994;11:31–4.
24 Thieberg MD, Stone MS, Siegfried EC. What syndrome is this? Buschke–Ollendorff syndrome. Pediatr Dermatol 1993;10:85–7.
25 Trattner A, David M, Rothem A et al. Buschke–Ollendorff syndrome of the scalp: histologic and ultrastructural findings. J Am Acad Dermatol 1991;24:822–4.
26 Ghomrasseni S, Dridi M, Bonnefoix M et al. Morphometric analysis of elastic fibres from patients with: cutis laxa, anetoderma, pseudoxanthoma elasticum, and Buschke–Ollendorff and Williams–Beuren syndromes. J Eur Acad Dermatol Venereol 2001;15:305–11.
27 Al Attia H, Sherif A. Buschle–Ollendorff syndrome in a grande multipara: a case report and short review of the literature. Clin Rheumatol 1998;17:172–5.
28 Hellemans J, Preobradzhenska O, Willaet A et al. Loss-of-function mutations in LEMD3 result in ostoepoikilosis, Buschke–Ollendorff syndrome and melorheostosis. Nat Genet 2004;36:1213–18.
29 Mumm S, Wenkert D, Zhang X et al. Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke–Ollendorff syndrome, but not sporadic melorheostosis. J Bone Min Res 2007;22:243–50.
30 Debeer P, Pykels E, Lammens J et al. Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family. Am J Med Genet 2003;119:188–93.
31 Happle R. Segmentale Type-2-Manifestation autosomal dominanter Hautkrankheiten. Hautarzt 2001;52:283–7.
32 Ehrig T, Cockerell CJ. Bushke–Ollendorff syndrome: report of a case and interpretation of the clinical phenotype as a type 2 segmental manifestation of an autosomal dominant skin disease. J Am Acad Dermatol 2003;49:1163–6.
33 Gass JK, Hellemans J, Mortier G et al. Buschke–Ollendorff syndrome: a manifestation of a heterozygous nonsense mutation in the LEMD3 gene. J Am Acad Dermatol 2008;58:s103–4.
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35 Hess W. Roentgenologische und pathologisch–anatomische Beobachtungen bei einem Fall von Osteopoikilie. Fortschr Geb Roentgenstr 1940;62:252–8.
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38 Jonasch E. 12 Faelle von Osteopoikilie. Fortrschr Roentgenstr 1955;82:344–53.
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41 Reid EM, Baker BL, Stees MA et al. Buschke–Ollendorff syndrome: a 32-month-old boy with elastomas and craniosynostosis. Pediatr Dermatol 2008;25:349–51.
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44 Bordas X, Ferrandis C, Ribera M et al. (Papular elastorrhexis: a variety of nevus anelasticus? Arch Dermatol 1987;123:433–4.
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Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue due to the abnormal expression of fibrillin-1 and is characterized by manifestations in the cardiovascular, musculoskeletal and ophthalmic systems (Table 145.1). The syndrome also shows striking pleiotropism and clinical variability.
In 1896, the French paediatrician Marfan described a 5-year-old girl with tall stature and disproportionately long limbs and fingers . He used the term ‘dolichostenomelia’ which is now referred to as the marfanoid habitus. A few years later, Marfan’s original patient developed scoliosis . Another clinically similar patient was described by Achard, who introduced the word ‘arachnodactyly’ to describe the associated long, slender fingers . Following reports of associated dislocation of the lens (ectopia lentis) and mitral valve regurgitation with the disorder, Weve, in 1931, proposed the name ‘dystrophica mesodermalis congenita, typus Marfanis’ . This was condensed to Marfan syndrome in 1938 by Apert . In 1956, McKusick, a major contributor to the characterization of MFS, suggested that elastic fibres or a component intimately associated with elastic fibres was defective in MFS. Studies initially focused on collagens, elastin and other connective tissue components and it was only in the late 1980s that fibrillin was identified as a molecule tightly linked with elastic fibres [6,7]. In a very short time, both the positional cloning approach and the candidate gene strategy resulted in the cloning and localization of two fibrillin genes [8–12]. As seen in Table 145.1, mutations in the fibrillin-1 gene (FBN1, located on chromosome 15) were identified in patients with both MFS and autosomal dominant ectopia lentis ; mutations in the fibrilin-2 gene (FBN2, on chromosome 5) are linked to the MFS-related disorder called congenital contractural arachnodactyly (CCA) .
Finally, two anecdotes in the MFS saga are worth mentioning: it is likely that Marfan’s original patient did not have MFS but rather CCA , and there is quite an interest in knowing whether US President Abraham Lincoln was affected by MFS [16,17].
Fibrillin, an acidic glycoprotein with an estimated molecular mass of 350 kDa, is a major constituent of the 10 nm microfibrils of the extracellular matrix. Its primary structure is characterized by several cysteine-rich motifs, reminiscent of the epidermal growth factor (EGF) peptide module that also has six similarly spaced cysteinyl residues [6,18,19]. The role of fibrillin as the underlying cause of MFS is supported by three independent lines of experimental evidence: firstly, antisera to fibrillin showed a decreased amount of microfibrils in MFS tissue samples [20,21]; secondly, defective synthesis and secretion of fibrillin by dermal fibroblasts were demonstrated in 26 probands with MFS ; thirdly, linkage and mutational analysis of several affected kindred confirmed a genetic homogeneity between MFS and the fibrillin gene .
Functionally, the 10 nm microfibrils, including fibrillin, serve at least three functions: as a link between elastin and other matrix structures (i.e. the basement membrane at the dermoepidermal junction); as a scaffolding upon which elastin is deposited (i.e. in the tunica media of the aorta); and as a structural component in tissues that do not contain elastin (i.e. the ciliary zonule) .
The pathogenic role of fibrillin in MFS was thought to be principally structural, causing a defective connective tissue. Recently, a second pathogenic role was described for fibrillin-1 deficient mice , which involves a metabolic pathway since these mice have marked dysregulation of transforming growth factor-β (TGF-β) activation and signalling. This is in keeping with the fact that families with variant MFS syndrome showed mutations on the TGF-β receptor genes.
Genetic analysis provided precise insights into the structural and functional features of fibrillin. Initially, however, such studies failed to define predictable genotype/phenotype correlations. This was highly in keeping with the variable expression of MFS features in affected individuals of the same family and implied that other factors are involved in the development of the clinical phenotype. Indeed, the same mutation (P1148A) was shown in individuals with MFS, isolated ectopia lentis (EL) and the MFS-related but clinically distinct Shprintzen–Goldberg syndrome . The first clinicopathological correlations have now emerged through the analysis of 803 pathogenic mutations found in 1013 probands . These correlations among different mutation types and clinical manifestations might be explained by different underlying genetic mechanisms (dominant-negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus as a mediator of TGF-β signalling).
The clinical expression of MFS is highly variable, ranging from congenital presentation and death before a few months of life to long-term survival. Severe cases are often sporadic rather than familial and a few have a recessive mode of inheritance with homozygous mutations.
Dolichostenomelia is the characteristic skeletal abnormality in MFS . It includes tall stature, decreased upper to lower segment ratio (US/LS, a value <0.85 in adults is significant), dolichocephaly and arachnodactyly of fingers and toes (Fig. 145.2). Pectus excavatum/carinatum can be present at birth or develop as a result of excessive longitudinal growth. Scoliosis or kyphoscoliosis occurs in 30–60% of MFS individuals. Ligamentous laxity and generalized hypermobility are common and can cause spinal pain, arthralgia, ligament injury or other musculoskeletal symptoms in up to three-quarters of children and in nearly all adults with MFS .
These are responsible for the shortened lifespan of MFS individuals. Multivalvular incompetence predominates in childhood whereas most adults suffer from degenerative complications of the aorta. Dilation of the aorta is due to typical cystic medial necrolysis and provokes aortic aneurysms, often before the age of 40 years. Aortic regurgitation, which correlates with the aortic root diameter, is the most common valvular complication (as high as 70% in adults). Mitral valve prolapse is the next most frequent finding.
Ectopia lentis (EL) is usually bilateral and occurs in 50–80% of MFS individuals. The lens displacement is usually upward. Although EL is the most frequent ocular manifestation in MFS, visual loss more often results from secondary myopia, retinal detachment, glaucoma or iritis [30–32].
These are minor findings in MFS. Striae atrophicae are the most common cutaneous manifestations of MFS and are usually found on the deltoid, pectoral and lumbar regions [33–35]. They can be found in two-thirds of MFS individuals and their number increases with age . Histologically, they do not differ from striae in the normal population .
Skin hyperextensibility is also found in two-thirds of MFS patients, regardless of their age, and significantly correlates with joint laxity . The combination of a marfanoid habitus and skin hyperextensibility, but apparently without MFS, has been described .
Easy bruising can be a complaint of MFS patients, this being due not to impaired coagulation but rather as a consequence of thin skin, decreased subcutaneous fat and increased tendency to contusions as a result of joint laxity and poor visual acuity.
Papyraceous scars can occur but are not a typical feature of MFS patients whose cutaneous incisions or lacerations usually heal promptly, in contrast to those with Ehlers–Danlos syndrome .
Finally, isolated reports include the association of MFS with poliosis , LEOPARD syndrome , Ehlers–Danlos syndrome , neurofibromatosis , PHACE syndrome , elastosis perforans serpiginosa  and vermiculate atrophoderma .
The diagnosis of MFS is mainly clinical  and relies on the presence of cardinal manifestations (Box 145.2). Helpful and simple screening tests include the thumb sign (Fig. 145.3), the wrist sign (positive if the thumb and little finger overlap when wrapped around the opposite wrist) and the US/LS ratio. A severe infantile form of the disorder is recognized .
Box 145.2 Criteria for the Diagnosis of Marfan Syndrome. Modified from Judge 2005 
- If the family/genetic history is not contributory, major criteria in two or more different organ systems and involvement of a third organ system.
- If a mutation known to cause Marfan syndrome in others is identified, one major criterion in an organ system and involvement of a second organ system.
Relative of an Index Case Who Independently Meets these Strict Diagnostic Criteria
Presence of a major criterion in the family history, one major criterion in an organ system, and involvement of a second organ system.
A major criterion requires at least four of the following: pectus carinatum; pectus excavatum needing surgery; reduced upper-to-lower segment ratio or arm span-to-height ratio ≥1.05; positive wrist and thumb signs; reduced extension of the elbows (≤170°); medial displacement of the medial malleolus causing pes planus; protrusio acetabulae of any degree.
Involvement is defined by the presence of two of the preceding features or the presence of one of the preceding features and two of the following minor criteria: pectus excavatum not requiring surgery; joint hypermobility; high-arched palate with crowding of teeth; facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures).
A major criterion is defined by ectopia lentis.
Involvement is defined by the presence of at least two of the following minor criteria: flat cornea; increased axial length of globe; hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis.
A major criterion is defined by either dissection of the ascending aorta or dilation of the ascending aorta, with or without aortic regurgitation, and involving at least the sinuses of Valsalva.
Involvement requires the presence of at least one of the following minor criteria: mitral valve prolapse with or without mitral regurgitation; dilation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis, under the age of 40 years; calcification of the mitral annulus under the age of 40 years; dilation or dissection of the descending thoracic or abdominal aorta under the age of 50 years.
No major criterion.
Involvement is defined by at least one of the following minor criteria: spontaneous pneumothorax; radiological evidence of apical blebs.
Skin and Integument
No major criterion.
Involvement is defined by at least one of the following minor criteria: striae atrophicae; a recurrent or incisional hernia.
A major criterion is the presence of lumbosacral dural ectasia.
No minor criterion.
A major criterion is defined by one of the following: having a parent, child or sibling who meets these diagnostic criteria independently; presence of a mutation of FBN1 which is known to cause Marfan syndrome; presence of a haplotype around the FBN1 locus, inherited by descent, known to be associated with unequivocally diagnosed Marfan syndrome in the family.
No minor criterion.
A marfanoid habitus is found in two rarer fibrillin disorders (see Table 145.1). Congenital contractural arachnodactyly (CCA) presents with joint contractures and abnormalities of the external ears but without cardiovascular or ocular manifestations [14,15]. The marfanoid-craniosynostosis syndrome (Shprintzen–Goldberg) is a clinically distinct variant of MFS, reported in only 11 individuals and characterized by additional findings such as craniofacial abnormalities, mental retardation, hypotonia and congenital abdominal wall weakness [27,47].
Other differential diagnoses include homocystinuria, Stickler syndrome (hereditary arthrophthalmopathy), annuloaortic ectasia (Erdheim disease) and mitral valve prolapse syndrome [48,49].
The dermatologist will rarely need to be involved in multidisciplinary teams managing MFS. In recent years, the increased lifespan and decreased morbidity in MFS have mainly been achieved through the improvement of cardiovascular, orthopaedic and ocular surgery [32,50–52]. β-blockers are useful to reduce/delay aortic dilation [53,54]. Pregnancy remains a problem, due to the high risk of ruptured aneurysms, but can be managed in women with minimal cardiovascular findings [55–57].
A breakthrough in therapy came from the finding that selected manifestations of MFS reflect excessive signalling by the TGF-β family of cytokines. Promising results have been seen with angiotensin II-receptor blockers on aortic root dilation .
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