Key points
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Ehlers-Danlos syndromes are a heterogeneous group of disorders characterized by abnormal formation of collagen or molecules related to collagen synthesis, abnormalities in the matrix glycoprotein tenascin, and probably fibronectin.
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Parry-Romberg (or Romberg) syndrome is, in most cases, a sporadic disorder characterized by slow progressive atrophy or shrinkage of facial tissues including skeletal muscle, skin, eyes, hair, and frequently bone of, in most instances, half of the face.
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Witkop syndrome, also known as tooth-nail or nail dysgenesis–hypodontia syndrome, is an autosomal dominant type of ectodermal dysplasia with an estimated incidence of 1 to 2 in 10,000.
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Ectodermal dysplasias are a group of heterogeneous inherited developmental disorders affecting structures that develop directly from the ectoderm.
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Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber syndrome) is characterized by the presence of multiple arteriovenous malformations that lack intervening capillaries and result in direct connection between arteries and veins.
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Ascher syndrome is characterized by blepharochalasis, double lip, and nontoxic thyroid enlargement.
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Initially described as the combination of ocular inflammation and orogenital ulcerations, Behçet syndrome, or Behçet disease, is a multisystem immunodysregulation disorder of unknown etiology, possibly triggered by environmental antigens, including bacteria and viruses, and characterized by vasculitis of small and large arteries and veins.
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Felty syndrome occurs in patients who have a long history of seropositive rheumatoid arthritis, and is characterized by the development of moderate to severe leukopenia, neutropenia, and, in most instances, splenomegaly.
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Reactive arthritis is a form of seronegative spondyloarthritis characterized by inflammatory back pain, additive or migratory oligoarthritis and extra-articular symptoms that typically follow a gastrointestinal or urogenital infection by a minimum of 1 to a maximum of 3 to 6 weeks.
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Stevens-Johnson syndrome and toxic epidermal necrolysis are conditions in the spectrum of severe cutaneous adverse reactions affecting the skin and mucosal membranes.
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There is a range of diseases characterized by accelerating aging, such as Hutchinson-Gilford progeria syndrome, Werner syndrome, Cockayne syndrome, trichothiodystrophy, and ataxia-telangiectasia.
Ehlers-Danlos syndromes
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of disorders characterized by abnormal formation of collagen or molecules related to collagen synthesis, abnormalities in the matrix glycoprotein tenascin, and probably fibronectin. According to the Villefranche Classification there are 7 major types of EDS, 6 with subtypes that relate to specific collagen defects and a seventh that represents a collection of all other variants that are generally rare forms. For the purposes of this article the most frequent types are presented, in addition to forms with oral manifestations.
Clinical manifestations
Classic EDS (EDS I and EDS II)
Eighty percent of patients with EDS have either EDS I (Gravis type) or the more severe form EDS II (Mitis type). Both are autosomal dominant and are characterized by mutations in the COL5A1 that controls packing of collagen type 1 fibrils. Clinical features include:
- 1.
Extreme joint hypermobility ( Fig. 1 ) that can cause poor joint stability and dislocations leading to premature osteoarthritis
Fig. 1 Extreme joint hypermobility in a patient with EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 2.
Hyperelastic velvety ( Fig. 2 ) and friable skin that heals with formation of often pigmented cigarette paper–like scars ( Fig. 3 )
Fig. 2 Ehlers Danlos syndrome: Hyperelasticity of facial skin.( From Neville BW, Damm DD, Allen CM, et al. Oral and maxillofacial pathology. 3rd edition. Philadelphia: Saunders, an Imprint of Elsevier; 2009. Fig. 16-32; with permission.)Fig. 3 Pigmented cigarette paper–like scars in a patient with EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 3.
Connective tissue fragility associated with easy bruising
- 4.
Oral mucosal fragility with delayed healing but without scar formation, early periodontal disease ( Fig. 4 ) because of easily traumatized gingiva, subluxation of the temporomandibular joint (TMJ), and ability in 50% of patients to touch their nose with the tongue (Gorlin sign; only seen in the 8%–10% of the general population) ( Fig. 5 )
Fig. 4 Early periodontal disease as seen in EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.)Fig. 5 The Gorlin sign in Ehlers-Danlos syndrome.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 5.
Dental abnormalities including hypoplastic enamel and dentin, high cusps with deep occlusal fissures, and deformed roots with pulp stones. Multiple keratocysts have been described in a patient with EDS II
- 6.
Epicanthic folds, myopia, strabismus, eversion of the upper eyelids, and, less often, blue sclera
- 7.
Prolapse of mitral valve and (occasionally) tricuspid valve
Familial hypermobility EDS (EDS III)
This autosomal dominant type is seen in approximately 10% of the patients, and in most patients is caused by mutations in TNXB (tenascin-X), COL3A1 , and, less often, COL1A2 . Clinically there is remarkable joint hypermobility while the skin properties are within normal limits. Peripheral neuropathy has been described. Supernumerary teeth have been reported.
Vascular (ecchymotic) EDS (EDS IV and EDS V)
Six percent of patients with EDS have EDS IV, whereas EDS V is very rare and is not discussed here. EDS IV can be a life-threating disorder because patients may suffer catastrophic bleeding from arterial rupture (intracranial and renal artery aneurysms) early in their lives, hence the shortened life span encountered in most patients. Both autosomal dominant and recessive modes of inheritance can occur, and multiple COL3A1 mutations have been described. Clinically, EDS IV is characterized by:
- 1.
Thin translucent skin with visible veins, ecchymoses after only minor trauma over knees and shins, and dark pigmented scars ( Fig. 6 )
Fig. 6 Ecchymoses caused by connective tissue fragility in EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 2.
Acrogeric facies (prominent eyes, protruding ears, pinched nose, thin lips)
- 3.
Early tooth loss attributable to periodontal destruction
EDS type VIII
EDS VIII is characterized by early-onset periodontal disease and pretibial skin ecchymoses.
Differential diagnosis
The different types of EDS should be distinguished from other inherited disorders that can present with hyperelastic skin (cutis laxa syndromes), gerodermia osteodysplastica, vascular fragility syndromes, and familial generalized articular hypermobility.
Treatment considerations for the oral and maxillofacial surgeon
Patients with EDS experience low oral health–related quality of life that includes muscle pain, hypermobility of the TMJ, hematomas in the mouth, gingival fragility, and loss of periodontal support. Encouraging results have been reported with placement of implants that lend periodontal support in patients with tooth loss. Arthroscopic surgery can alleviate EDS-associated temporomandibular disorders, especially in type III.
Ehlers-Danlos syndromes
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of disorders characterized by abnormal formation of collagen or molecules related to collagen synthesis, abnormalities in the matrix glycoprotein tenascin, and probably fibronectin. According to the Villefranche Classification there are 7 major types of EDS, 6 with subtypes that relate to specific collagen defects and a seventh that represents a collection of all other variants that are generally rare forms. For the purposes of this article the most frequent types are presented, in addition to forms with oral manifestations.
Clinical manifestations
Classic EDS (EDS I and EDS II)
Eighty percent of patients with EDS have either EDS I (Gravis type) or the more severe form EDS II (Mitis type). Both are autosomal dominant and are characterized by mutations in the COL5A1 that controls packing of collagen type 1 fibrils. Clinical features include:
- 1.
Extreme joint hypermobility ( Fig. 1 ) that can cause poor joint stability and dislocations leading to premature osteoarthritis
Fig. 1 Extreme joint hypermobility in a patient with EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 2.
Hyperelastic velvety ( Fig. 2 ) and friable skin that heals with formation of often pigmented cigarette paper–like scars ( Fig. 3 )
Fig. 2 Ehlers Danlos syndrome: Hyperelasticity of facial skin.( From Neville BW, Damm DD, Allen CM, et al. Oral and maxillofacial pathology. 3rd edition. Philadelphia: Saunders, an Imprint of Elsevier; 2009. Fig. 16-32; with permission.)Fig. 3 Pigmented cigarette paper–like scars in a patient with EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 3.
Connective tissue fragility associated with easy bruising
- 4.
Oral mucosal fragility with delayed healing but without scar formation, early periodontal disease ( Fig. 4 ) because of easily traumatized gingiva, subluxation of the temporomandibular joint (TMJ), and ability in 50% of patients to touch their nose with the tongue (Gorlin sign; only seen in the 8%–10% of the general population) ( Fig. 5 )
Fig. 4 Early periodontal disease as seen in EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.)Fig. 5 The Gorlin sign in Ehlers-Danlos syndrome.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 5.
Dental abnormalities including hypoplastic enamel and dentin, high cusps with deep occlusal fissures, and deformed roots with pulp stones. Multiple keratocysts have been described in a patient with EDS II
- 6.
Epicanthic folds, myopia, strabismus, eversion of the upper eyelids, and, less often, blue sclera
- 7.
Prolapse of mitral valve and (occasionally) tricuspid valve
Familial hypermobility EDS (EDS III)
This autosomal dominant type is seen in approximately 10% of the patients, and in most patients is caused by mutations in TNXB (tenascin-X), COL3A1 , and, less often, COL1A2 . Clinically there is remarkable joint hypermobility while the skin properties are within normal limits. Peripheral neuropathy has been described. Supernumerary teeth have been reported.
Vascular (ecchymotic) EDS (EDS IV and EDS V)
Six percent of patients with EDS have EDS IV, whereas EDS V is very rare and is not discussed here. EDS IV can be a life-threating disorder because patients may suffer catastrophic bleeding from arterial rupture (intracranial and renal artery aneurysms) early in their lives, hence the shortened life span encountered in most patients. Both autosomal dominant and recessive modes of inheritance can occur, and multiple COL3A1 mutations have been described. Clinically, EDS IV is characterized by:
- 1.
Thin translucent skin with visible veins, ecchymoses after only minor trauma over knees and shins, and dark pigmented scars ( Fig. 6 )
Fig. 6 Ecchymoses caused by connective tissue fragility in EDS.( Courtesy of the collection of Robert J. Gorlin, DDS.) - 2.
Acrogeric facies (prominent eyes, protruding ears, pinched nose, thin lips)
- 3.
Early tooth loss attributable to periodontal destruction
EDS type VIII
EDS VIII is characterized by early-onset periodontal disease and pretibial skin ecchymoses.
Differential diagnosis
The different types of EDS should be distinguished from other inherited disorders that can present with hyperelastic skin (cutis laxa syndromes), gerodermia osteodysplastica, vascular fragility syndromes, and familial generalized articular hypermobility.
Treatment considerations for the oral and maxillofacial surgeon
Patients with EDS experience low oral health–related quality of life that includes muscle pain, hypermobility of the TMJ, hematomas in the mouth, gingival fragility, and loss of periodontal support. Encouraging results have been reported with placement of implants that lend periodontal support in patients with tooth loss. Arthroscopic surgery can alleviate EDS-associated temporomandibular disorders, especially in type III.
Parry-Romberg syndrome
Parry-Romberg (or Romberg) syndrome (PRS) is, in most cases, a sporadic disorder characterized by slow progressive atrophy or shrinkage of facial tissues including skeletal muscle, skin, eyes, hair, and frequently bone of, in most instances, half of the face ( Fig. 7 ). It is accompanied very often by contralateral Jacksonian epilepsy and trigeminal neuralgia. Bilateral manifestations occur in 5% to 10% of cases, and ipsilateral involvement of the rest of the body is rare. The cause is unknown; however, alterations in the peripheral trophic sympathetic system, cerebral disturbance of fat metabolism, trauma, autoimmunity, and, recently, Borrelia spp infection have been considered as possible causes. It is more common in females, and in many studies the left side of the face seems to be more frequently affected.
Clinical manifestations
PRS appears usually during the first decade, with the overlying skin of the affected side becoming darkly pigmented. When the facial bones are affected the disease starts earlier. The progression of the disease can be as long as 9 to 10 years, and it becomes stationary for life. Hair involvement precedes that of skin, with the affected side of the scalp characterized by focal areas of complete alopecia, loss of eyelashes, and the median portion of eyebrows. Some patients have a scar-like demarcation on the forehead near the midline known as linea scleroderma or en coup de sabre (strike of the sword). Histopathologically there is atrophy of the epidermis, dermis, and adnexal elements and vessels, in addition to inflammation. These characteristics are also present in patients with linear scleroderma.
Oral manifestations
Hemiatrophy of the tongue can be an early finding ( Fig. 8 ). Atrophy of half of the upper lip and tongue may lead to exposure of maxillary teeth of the affected side. Delayed eruption, root dilaceration, root hypoplasia ( Fig. 9 ), and resorption are rarely described. Alteration in the development of the mandible, which leads to malocclusion, is also reported ( Fig. 10 ).
Ophthalmologic manifestations
The most common manifestation is enophthalmos resulting from loss of periorbital fat ( Fig. 11 ). Loss of the underlying bone may cause the outer canthus to be displaced downward. Other ocular stigmata include atrophy of the eyelid, uveitis, retinal vasculitis, glaucoma, and retinal pigmentations. The contralateral eye may be also affected.
Neurologic manifestations
Epileptic seizures are the most common neurologic manifestation, often of the Jacksonian type (motor cortex–related seizures spreading from the distal limb to the face), followed by cerebellar and cerebral hemiatrophy, calcifications, and, less often, vascular abnormalities.
Differential diagnosis
PRS should be differentiated from localized linear scleroderma en coup de sabre (LSCS). There is considerable debate regarding whether the 2 entities represent 2 distinct conditions or if they are variations of the same disorder (ie, scleroderma). The difficulty exists because both have the same age onset and a slow progressive course, affect women more often, and have common neurologic and ophthalmologic manifestations. However, patients with PRS more often have central nervous system manifestations. In PRS there is inflammation appreciated, which is not regarded as a feature in LSCS. Rasmussen encephalitis presents neurologic manifestations essentially similar to those of PRS. Congenital facial hypoplasia is diagnosed at birth, and there is diminution of the teeth of the affected side. The oculo-auriculo-vertebral spectrum of malformations should also be included in the differential diagnosis. However, this group of conditions is related to anomalies of the first and second branchial arches.
Treatment considerations for the oral and maxillofacial surgeon
The main aim is to halt the disease and to improve symptoms and facial appearance. Immunosuppressive medications have been used for cerebellar involvement. After the condition is stabilized, the restoration of the symmetry with corrective esthetic surgery should be attempted, including facial recontouring with volumetric regeneration.
Witkop syndrome
Witkop syndrome (WS), also known as tooth-nail or nail dysgenesis–hypodontia syndrome, is an autosomal dominant type of ectodermal dysplasia (ED) with an estimated incidence of 1 to 2 in 10,000. It affects 2 ectodermal derivatives, namely teeth and nails. It is caused by nonsense mutations of the MSX1 at 4p16.1. Isolated cases, without family history, have been described.
Clinical manifestations
Teeth and nails are affected without involvement of sweat glands and the characteristic facies seen in EDs. Most patients report normal heat tolerance and normal sweating. Occasionally, hair may be thin and slow growing but without microscopic abnormalities.
Oral manifestations
There is hypodontia ( Fig. 12 ), less often oligondontia, and in rare extreme cases anodontia. The most frequently missing teeth are the maxillary incisors, second molars, maxillary canines, and, less often, the premolars. The permanent dentition is usually more severely affected. Moreover the tooth shape varies, with teeth being conical and having narrow crowns.
