zyxwvutsr zyxwvutsrq zyxwvu Clinical Genetics 1986: 30: 456-461 zyx Ehlers-Danlos features with progeroid facies and mild mental retardation Further delineation of the syndrome ALEJANDRO HERNANDEZ, M A R ~GUADALUPE A AGUIRRE-NEGRETE, SILVIAGONZALEZ-FLORES, MARTHA AND JOSB CELINAREYNOSO-LUNA, RUBENFRAGOSO,ZAMIRA NAZARA,GUADALUPE TAPIA-ARIZMENDI MAR~A CAN^ Divisiones de GenCtica y Neurobiologia, Subjefatura de Investigacion Centifica, Unidad de Investigacion Biomedica, Centro Mkdico de Occidente, Instituto Mexican0 del Seguro Social, Guadalajara, Jalisco, Mexico A syndrome characterized by progeroid facies, multiple nevi, mild mental retardation, skin hyperextensibility, bruisability, moderate skin fragility, joint hypermobility principally in digits, is described in two unrelated patients. Electron microscopy of the skin showed some fragmentation of the elastic fibers’ fibrous portion and moderate electrodensity in the amorphous portion. Since a practically identical constellation of clinical features was previously reported in three patients, the individualization of a distinct connective tissue disorder, probably autosomal dominant, with variable expressivity is concluded. zyxwvu zyxw Received 15 July 1985, revised, accepted for publication 30 June I986 Key words: Connective disorder; Ehlers-Danlos syndrome; genodermatosis; mental retardation; progeroid facies; short stature. Recently, Hernandez et al. (1979, 1981) described a distinct connective tissue disorder in three unrelated patients, and postulated that the condition was a variant of the Ehlers-Danlos syndrome (EDS). The present report concerns the clinical and histopathologic ultrastructural studies of two new cases permitting further delineation of the syndrome. Material and Methods (father) and 25 (mother) years at his birth. Birthweight and length were not recorded. From early infancy, severe delayed psychomotor development was observed and psychometric evaluation at 3 years of age revealed an IQ of 60. Physical examination (Fig. 1) at 8 years of age revealed the clinical data summarized in Table 1. Laboratory examinations, including blood cell count, urinalysis, urea, glucose, creatinine, serum protein, screening tests for metabolic defects (Phenistix, glucose oxidase, Millon, anthrone, ferric chloride, DNPH, nitrosonaphthol, acid albumin turbidity, CTA, methylmalonic acid, Benedict, cyanide nitroprusside), and karyotype yielded results within normal limits. zyxwvu Case 1: The male patient was born on February 19, 1973, following a full-term pregnancy and normal delivery. The non-consanguineous parents were normal, age 49 zyxwvut zyx A VARIANT OF EHLERS-DANLOS SYNDROME 457 Fig. 1. Case 1: a) note wrinkled facies, curly hair, scanty eyebrows and eyelashes, cryptorchidism, pes planus and short in stature. b) Right hand showing marked hypermobility of finger. Fig. 2. No alterations are observed in the collagen fibers, which appear negative stained (c). Lead citrate and uranyl acetate (5000 x ). 458 zyxwvutsr zyxwv HERNANDEZ ET AL. zyxwvutsrqpo Fig. 3. Slight disruption is depicted in the fibrous portion (arrows) of elastic fibers (e). M = mast cell; F=fibroblast. Lead citrate and uranyl acetate (2500 x ). Table 1 Comparative clinical data Features Father's age Sex Age (years) Height (cm) IQ Wrinkled facies Curly and fine hair Scanty eyebrows and eyelashes Telecanthus Periodontitis and multiple caries Low set and prominent ears Pectus excavatum Winged scapulae Mild aortic and pulmonary stenosis Cryptorchidism Inguinal hernia Hypospadias Pes planus Brachydactyly type E Skin hyperextensibility Joint hypermobility Dermatorrhesis, bruisability and papiraceous scars Multiple nevi Varicose veins Hernandez et al. (1979) A 0 55 M 15 145' 58 + + + + + + + + + + + + + + + + 33 M ia 149' 70 + + + + + + + + + + + + + + + + + M = male; *=below third percentile: Unfilled spaces = absent. Hernandez et al. (1981) 44 M 15 130' 70 + + + + + + + + + + + + + + + zyx Present cases Case 1 Case 2 49 M a ao* 60 + + + + + + + + + + + + + + + 43 M 15 162 70 + + + + + + + + + + + + + + + + + + zyxwvut zyx A VARIANT OF EHLERS-DANLOS SYNDROME 459 normal structural characteristics, except for -slight distension of intracellular spaces in the spinous layer. The dermal fibroblasts were normal and no significant alterations were seen in the collagen bundles (Fig. 2). The fibrous portion of elastic fibers showed some fragmentation whereas the amorphous portion appeared moderately electrodense (Fig. 3). The rest of connective tissue elements and the blood vessels examined were normal. There was no history of a similar pattern of anomalies in relatives up to the 4th degree. zyxw Case 2: The patient was born on August 9, 1969, following a fifth full-term pregnancy and normal delivery. Birthweight was 3.0 kg, length was not recorded. At birth, congenital inguinal hernia was present and surgically corrected at two years of age. Since early infancy psychomotor retardation was noted. He did not finish elementary school. At 14 years of age he received psychiatric treatment because of abnormal behaviour. Physical examination at 15 years old (Fig. 4 and 5 ) revealed weight 44 kg, height 162 cm, cephalic circumference 52 cm (weight below the third percentile for his age and sex). The clinical data are summarized in Table I. EEG was unremarkable. The cardiological and ophthalmological evaluations were normal. The same laboratory studies as in Case 1 yielded results within normal limits. X-ray studies disclosed shortness of third, fourth and fifth metacarpal bones bilaterally with apparently normal length of phalanges. zyxwvutsrq zyxwv Fig. 4. Case 2 at 15 years of age. Note similarity of facial features, right cryptorchidism and pes planus with Case 1. For ultrastructural studies, small fragments of skin including epidermis and the superficial portion of the dermis were immediately diced while immersed in cacodylate buffered 2.5% glutaraldehyde. The samples were post-fixed in OsO4 and embedded in Epon 812. Semithin sections were stained with toluidine blue and examined under a light microscope. Thin sections were contrasted with uranyl acetate and lead citrate and examined under a Zeiss EM-10 transmission electron microscope. No alterations were observed in dermal and epidermal elements at light microscopy level. With the electron microscope the epidermal cells showed their Discussion The clinical features of the two patients here described are summarized in Table 1 and compared with data from 3 other patients 460 zyxwvu zyxwv zyxwvuts HERNANDEZ ET A L Fig. 5. Case 2: A) Note curly and fine hair, scanty eyebrows and eyelashes, skin hyperextensibility. B) Wrinkled facies, multiple nevi. C) Winged scapulae, multiple nevi. D and E) Joint hyperrnobility. F) Varicose veins and papiraceous scars. G) Third, fourth and fifth metacarpals were short to some degree. with the syndrome (Hernandez et al. 1979, 1981). Features consist of wrinkled facies, curly and fine hair, scanty eyebrows and eyelashes, periodontitis and caries, cryptorchidism, multiple nevi and mild mental retardation. The variable stature, cardiac anomaly, cryptorchidism, inguinal hernia, hypospadias, and brachydactyly (type E) seem exceptional findings (Table I), suggesting variable expressivity of the syndrome. We stress the differential diagnosis with Noonan syndrome, which shows clinical resemblance. However, the most common data of EDS, including skin hyperextensibility, joint hypermobility, dermatorrhesis, bruisability, pectus excavatum, winged scapulae, varicose veins, and papiraceous scars, are present in all cases (Table 1). These clinical data of connective tissue are the most important differences for supporting EDS and ruling out Noonan syndrome. Also, in the differential diagnosis we include a seventeenth form of heterogeneous EDS actually recognized (McKusick 1983) and five others published in the literature (Beasley & Cohen 1979, MacFarlane et al. 1980, Cup0 et al. 1981, Friedman & Harrod 1982, Sulh et al. 1984) and compared by the clinical picture. A congenital defect in the structure of connective tissue, including incomplete or abnormal cross-linking of the type I col- zy zyxwv zyx zyxwvuts A VARIANT OF EHLERS-DANLOS S Y N D R O M E lagen fibers has been demonstrated in most patients with EDS. The structural alteration observed in Case 1 in which the fibrous portion of elastic fibers showed some fragmentation and the amorphous portion appeared moderately electrodense, supports a connective tissue dysplasia with minimal variations and its manifestations suggest a specific basic defect with primary action of the mutant gene in connective tissue. However, the study of other similar cases is necessary to have confirmatory results. Since all patients are sporadic and the paternal age is increased at the propositus’ birth, we can conclude a “de novo” autosoma1 dominant mutation for the origin of the entity (Table 1). Acknowledgments The authors wish to thank Armando ~ 1 raz for the art work, and Maria Eugenia Goiii for her secretarial assistance. infarction, panacinar emphysema and cerebral heterotopias. Am. J. Med. 71, 1051-1058. Friedman, J. M. & M. J. E. Harrod (1982). An unusual connective tissue disease in mother and son: a “new” type of Ehlers-Danlos syndrome? Clin. Genet. 21, 168-173. Hernandez, A., M. G. Aguirre-Negrete, S. Ramirez-Soltero, A. Gonzalez-Mendoza, R. Martinez y Martinez, A. Velazquez-Cabrera & J. M. Cantu (1979). A distinct variant of the Ehlers-Danlos syndrome. Clin. Genet. 16, 335-339. Hernandez, A., M. G. Aguirre-Negrete, J. C. Liparoli & J. M. Cantu (1981). Third case of a distinct variant of the Ehlers-Danlos syndrome. Clin. Genet. 20, 222-224. MacFarlane, J. D., D. W. Hollister, D. D. Weaver, K. D. Brandt, L. L. Luzzatti & A. A. Biegel (1980). A new Ehlers-Danlos syndrome with skeletal dysplasia. Am. J. Hum. Genet. 32, 118A. McKusick, V. A. (1983). Mendelian Inheritance in Man, 6th Edit. Baltimore, Johns Hopkins University Press. Sulh, ~ H.~ M. -B., B. Steinmann, R. Velidi, G. Dudin, J. Abu Zeid, M. Slim & V. der Kaloustian (1984). Ehlers-Danlos syndrome type IV D: an autosomal recessive disorder. Clin. Genet. 25, 278-287. References Beasley, R. P. & M. M. Cohen, Jr (1979). A new presumably autosomal recessive form of the Ehlers-Danlos syndrome. Clin. Genet. 16, 19-24. Cupo, L. N., R. E. Pyeritz, J. L. Olson, G. M. Hutchins & V A. McKusick (1981). EhlersDanlos syndrome with abnormal collagen fibrils, sinus of valsalva aneurysms, miocardial 461 Address: Dr. A. Hernandez Tellez Institutu Mexico Del Seguro Social Division de Genetica Apartado Postal 1-3838 Guadalajara, Jalisco Mexico