May 24, 1990 - Medicine, University of South Florida, Box 15-G, 12901 Bruce B. Downs Blvd., Tampa, FL 33612-4799. 0 1990 Wiley-Liss, Inc. types. Patients ...
American J o u r n a l of Medical Genetics 37:465-470 (1990)
Phenotypic Overlap of Ehlers-Danlos Syndrome Types IV and VIII James K. Hartsfield, Jr., and Boris G. Kousseff University of South Florida College of Medicine, Department of Pediatrics, Diuision of Medical Genetics, Tampa
An 18-year-old Caucasian woman has been followed since age 12 years for Ehlers-Danlos syndrome (EDS) with easy bruisability and “cigarette paper scars.” Her chief complaint at age 17 years was tooth mobility, especially in the anterior mandible, necessitating the removal of the four incisors. Initial biochemical analysis of cultured skin fibroblasts indicated the presence of pepsin-sensitive type I11 collagen. Subsequent analysis of cultured skin fibroblasts by the same laboratory and another laboratory found no abnormality in the type I11 collagen with or without protease treatment. This is in distinction to the finding of abnormal type I11 collagen in the only two reported patients with EDS and early-onset periodontitis who have had collagen analyses. One of them was diagnosed as EDS type IV and the other as EDS type VIII, although the defects of type III collagen were consistent with EDS type IV. The defect in type I11 collagen in some patients with early periodontitis and the considerable overlap of the clinical manifestations of EDS types IV and VIII point out the need for further studies of collagen formation and maturation in any patient who has early periodontitis and who has been classified with EDS type IV or VIII. KEY WORDS: differential diagnosis, periodontitis, collagen INTRODUCTION Nine types of Ehlers-Danlos syndrome (EDS) have been delineated, with the biochemical defect known in a few (Table I). Clinical experience shows that there are many patients who do not easily fit into one of these Received for publication February 27, 1989; revision received May 24, 1990. Address reprint requests to Dr. James K. Hartsfield, Jr., Division of Medical Genetics, Department of Pediatrics, College of Medicine, University of South Florida, Box 15-G, 12901 Bruce B. Downs Blvd., Tampa, FL 33612-4799.
0 1990 Wiley-Liss, Inc.
types. Patients with EDS type IV have hyperextensibility of skin, ecchymotic pretibial lesions, easy bruisability, cigarette paper scars, joint hypermobility of digits, pes planus, and arterial and intestinal rupture, the latter two being major characteristics for diagnosis and prognosis. This type is heterogeneous with a t least five subtypes having a defect of type I11 collagen [McKusick, 1990; Beighton et al., 1988; Pope et al., 19881. Patients with EDS type VIII have been reported to show early periodontal disease, variable hyperextensibility of the skin, ecchymotic pretibial lesions, minimal bruising, minimum to moderate joint hypermobility of the digits, cigarette paper scars, and autosomal dominant inheritance (Table 11).The finding of early-onset periodontitis in a female patient with signs that otherwise would fit into either EDS type IV or VIII led to a review ofthe literature and to reappraisal of the classification of similar patients diagnosed with EDS type IV or VIII.
CLINICAL REPORT Patient M.C. has been followed since age 12 years in the genetics clinic a t the University of South Florida. The initial diagnosis of EDS type IV was based on increased skin fragility with minimal stretchability, atrophic (“cigarettepaper”) scars, mild joint laxity mostly in the digits, kyphoscoliosis, easy bruisability with normal clotting, and pretibial ecchymotic lesions. Her ethnic background is Italian, German, and American Indian. The patient’s mother is 167.6 cm tall (80th centile) and healthy. The maternal half-sister and paternal halfbrother are healthy. The father is 185.4 cm (95th centile) and has a history of asthma. Atrophic scars, pretibia1 ecchymotic lesions, and early periodontitis are not present in the mother and were not reported in any other relative. The patient was the product of the first pregnancy of the 23-year-old mother. The term gestation was uneventful. Birth was spontaneous from a vertex position. Birth weight was 2.9 kg (15th centile), and length was 53.3 cm (90th centile). No anomalies were noted a t birth. She rolled over a t 3.5 months, had her first tooth a t 5 months, sat at 6 months, stood a t 8.5 months, walked a t 10 months, and said her first words a t age 1year. During infancy, slightly elevated sweat chloride was found and
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TABLE I. Classification of Ehlers-Danlos Syndrome*
Type--
~~
~
~-
__
~.
I Gravis I1 Mitis I11 Hypermobile IV Vascular IV-A Acrogeric IV-B Acrogeric IV-C Ecchymotic IV-D Others V X-linked VI Ocular-scoliotic VI-A VI-B (?) VII Arthrochalasis multiplex congenita VII-A VII-B VII-c (?) VIII Periodontitis IX Vacant, formally occipital horn syndrome or X-linked cutis laxa; now categorized as a disorder of copper transport" X Fibronectin type XI Vacant, formally familial joint instability; now categorized with the familial articular hypermobility svndromes
Inheritance AD AD AD AD AR AD AD,AR (?) XLR AR
____
Biochemical Disorder .~
__
~
~
~~
-
Unknown Unknown Unknown All forms have a defect of type 111 collagen Unknown Decreased lysyl hydroxylase Normal lysyl hydroxylase
AD AD AR AD
Structural defect of pro-alpha l(1j Structural defect of pro-alpha 2(1j Procollagen N-proteinase deficiency Unknown
AR
Plasma fibronectin abnormality
*Adapted from Beighton et al. [19881. "Byers I19891 included this disorder in his review
TABLE I1 Fkported Patients With EDS Type VlII
_
_
_
_
_
_
_
McKusick _ -[19721 _ _
Number of cases Precocious periodontitis Pretibial lesions Joint hypermobility in the digits Bruising Skin hyperextensibility
y+
Cigarette paper scarring
+
-
Linch and Hollister Nelson and Stewart et a1 Acton et a1 King [1979] _ [19771 _ _ ~ ~ ~ ~ [19801 - -~ ~[19811 3 1 4" 7 3' +d 4 +e 3 + Minimum + Moderate Moderate Moderate Minimum Minimum + Minimum + Moderate to marked 3 + i 7 + ~~~
Lapiere and Nusgens 119811 ~1
+f 7
Moderate 7
+ ?g
~
"In addition to the family apparently reported by Stewart et al. 119771. 'Described as "resorptive periodontosis." 'Periodontal pathology was reported to be like that seen in Papillon-LeFevre syndrome. dPattern led to a tentative diagnosis of juvenile destructive periodontitis. 'Diffuse bone loss became evident in late teens with focal areas in the mandibular anterior and maxillary right first molar areas "'A very severe periodontitis" at age 12 years of age. K"Skinfragility" without specific mention of scarring.
cystic fibrosis was excluded. Prior to age 5 years, the skin had been noted to be thin and wrinkled, particularly on the palms and soles. The gingiva was described a s friable and edematous, with bleeding after tooth brushing and minor trauma since age 2 years. Epistaxis and easy bruisability have been noted since age 5 years. Superficial wounds healed adequately, but with thin, atrophic scars. On a couple of occasions, sutures were necessary, but did not hold in the skin. There was a history of joint laxity with hyperextensibile interphalangeal joints and ability to place the feet behind her head. At age 9 years, orthodontic therapy with fixed
appliances was begun and continued for 5 years. Results of audiometry were normal. Onset of menarche was a t 10 years, with subsequent heavy, irregular periods and painful cramps. Recently, the severity of the cramping has decreased. Orthopedic evaluation a t 12 years demonstrated a left thoracolumbar scoliosis (30"from T7 to L3), dorsal kyphosis (57'1, mild joint laxity, hyperextension of the arms a t the elbows and knees, and hip flexion contractures (30") bilaterally with hamstring spasm. Ophthalmological examination was unremarkable; drusen or angioid streaks were not present. At a chronological age
Ehlers-Danlos Syndrome
of 152/izyears the bone age was 16 years. She returned to the clinic a t age 17 years with the chief complaint of loose teeth and had the four mandibular incisors extracted because of bone loss without complication. Physical examination a t age 17 years showed a white girl with dry, thin skin, interphalangeal joint laxity, and slightly increased skin stretchability (Fig. 1).Her weight was 54.3 kg (30th centile) and height was 175.4 crn (95th centile). Head circumference was 55.2 cm (50th centile). The outer canthal distance measured 8.0 cm (15th centile), and innercanthal distance was 2.8 cm (35th centile). Right and left ear lengths were 5.8 cm (40th centile). Twenty-seven permanent teeth were present. Inflamed gingiva and bleeding were noted on probing. Approximately 1mm (grade I) tooth mobility of the posterior teeth and 2-3 mm of mobility (grades 11-111) of the mandibular anterior teeth were present. Radiographs showed alveolar bone loss, especially around the mandibular anterior teeth (Fig. 2) and right mandibular first molar (Fig. 3). Gingival recession around the maxillary right first premolar and the mandibular anterior teeth was noted (Figs. 4,5). The palate was The were The left hand length was 17.5 cm (40th centile), and the third finger length was 7.5 cm (90th centile). The right hand length was also 17.5 cm (40th centile), and the third finger length was 7.2 cm (30 centile). The middle left finger as a percentage of the total hand length was 43 (55th centile). The middle right finger a s a percentage of the total hand length was 41 (15th centile). The hand length/ height ratio was 9.9% (>11% denotes arachnodactyly). The left foot length was 24.5 cm (70th centile). The right foot length was 25.5 cm (85th centile). The right foot lengthlheight ratio was 14.5% (>15% denotes arachnodactyly). Pes planus was present, as were a large number of creases on the palms and soles. Persistent
467
Fig. 2. Alveolar bone loss around the mandibular anterior teeth.
Fig. 3. Alveolar bone loss around the mandibular right first molar.
Fig. 1. The 18-year-old proposita.
Fig. 4. Variable gingival recession on the left side.
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Fig. 5. Variable gingival recession on the right side.
ecchymotic discoloration of the shins was still present (Fig. 6), although less than before. Dermatoglyphics showed nine ulnar loops and one radial loop, with the left axial triradius in t position (atd angle = 45") and the right axial triradius in t-t' position (atd angle = 51").
LABORATORY RESULTS Bleeding time (Ivy) was 3 minutes (norm, 2-10 minutes). Activated clot time was 107 seconds (norm, 70-130 seconds). Prothrombin time was 11.5 seconds (norm, 10-13 seconds). Activated partial thromboplastin time was 30.7 seconds (norm,
