American J o u r n a l of Medical Genetics 39:338-341 (1991)
New Clinical Aspects of Hereditary Mucoepithelial Dysplasia M.D. Urban, R. Schosser, W. Spohn, W.O. Wentling, and M. Robinow Department of Pediatrics (M.D.U., W.S., W.O. W., M.R.), Wright State University School of Medicine, Dayton, Ohio; Department of Dermatology (R.S.1, University of Arkansas for Medical Sciences, Little Rock
Hereditary mucoepithelial dysplasia (HMD) is a multiepithelial disorder. It is transmitted as an autosomal dominant trait (McKusick: Mendelian Inheritance in Man-Catalogs of A u tosomal Dominant, A utosomal Recessive, and X-Linked Phenotypes, 8th edition. Baltimore: The Johns Hopkins University Press, pp 499, 1988). HMD is characterized by variable combinations of lesions of skin, hair, orificial mucosa, gingiva, eyes, and lungs. In some previously described patients, the corneal and pulmonary lesions were progressive and led to blindness, recurrent pneumonia, and/or premature death. On light microscopy, the lesion is characterized by dyskeratosis and, on electron microscopy,by a paucity of gap junctions and desmosomes. Here, we describe a new 5-generation kindred in which affected individuals had the same histologic characteristics but a somewhat different clinical spectrum and a more benign course. HMD should be considered in the differential diagnosis of childhood alopecia, follicular hyperkeratosis, keratoconjunctivitis, juvenile cataracts, gingival hyperemia, restrictive lung disease, and esophageal stenosis or webs.
INTRODUCTION In 1978 and again in 1979,1980, and 1982, Witkop et al. described a 4 generation kindred with a previously unrecognized disorder which they termed hereditary mucoepithelial dysplasia (HMD). Affected individuals presented with follicular hyperkeratosis, intermittent alopecia, fiery red gums, severe keratoconjunctivitis, cataracts, and progressive, often fatal lung disease. Light microscopy of skin, vaginal, and oral mucosa showed a distinct type of dyskeratosis, while electron microscopy documented a paucity of gap junctions and desmosomes. Witkop et al. [1979] recognized the same condition in a family which had been described previously by Okamoto et al. [1977] under the term of “chronic mucocutaneous moniliasis” and a sporadic case of HMD was reported by Sheman et al. [1989]. We are reporting a new 5-generation kindred with identical histological findings but a somewhat different spectrum of clinical manifestations and a more benign course.
CLINICAL REPORT The proposita (Fig. 1, IV-19) was a g5/ia year-old girl, referred for alopecia. She was born a t term with a weight of 3.2 k g and length of 53 cm. Growth and development were normal. Her general health was good except for repeated “eye infections.” She had also been treated a t ages 3 and a t 4 years for “thrush.” Her skin had always been rough and dry and her hair was dry and brittle. At age 6 years she gradually lost all of her scalp hair. After KEY WORDS: new kindred, phenotypic varia few months the hair grew back but more sparsely than ability, esophageal stenosis, before. Combing and brushing caused excessive hair benign course, autosomal loss. dominant inheritance Physical examination showed a slightly obese prepubertal girl whose height was 140.5 cm (75th centile), weight 45 kg (one kg above the 95th centile). Her skin was rough and dry with pronounced follicular hyperkeratosis (Fig. 21, particularly on the trunk and the Received for publication April 20, 1990; revision received July extensor surfaces. Her cheeks were flushed; the lips 30, 1990. were dry with mild angular fissuring. The scalp hair Address reprint requests to Maria D. Urban, M.D., Department was sparse and wiry. Body hair was scant and brittle. of Pediatrics, Wright State University School of Medicine, Dayton, Finger and toe nails appeared normal. The gingiva and OH 45435. adjacent areas of the hard palate were fiery red (Fig. 3). A preliminary report: “Hereditary mucoepithelial dysplasia-A These areas were sharply demarcated from the normal new kindred?” was presented a t the 1986 David W. Smith Workshop a t Burlington, VT and published in the Proceedings of the pink color of the rest of the palate and buccal mucosa. There was no dental or periodontal disease. The tongue Greenwood Genetic Center 1986, pp. 120-121.
0 1991 Wiley-Liss, Inc.
Hereditary Mucoepithelial Dysplasia
339
I I
21
1
V Fig. 1. Pedigree ofthe familyOO(thin hair);BO(cataract);QOlesophagealweb);QO (red gingiva).
was deeply fissured. The eyes showed fine corneal vascularization and, on slit lamp examination, there were early cataracts consisting of minute opacities scattered throughout all layers of the lenses. Vision was 20120.
Laboratory Studies Urinalysis, complete blood count, serum electrolytes, calcium, phosphorus, blood urea nitrogen, thyroxine, and thyroid-stimulating hormone levels were normal, and serum thyroid, adrenal, and parietal cell antibodies were not present. Pulmonary function studies documented mild obstructive but no restrictive lung disease. A radiographic study of the esophagus was reported as normal. However, 3 years later, she developed difficulties swallowing solid food and a repeat radiographic study documented a small area of stenosis and beginning web formation. Biopsies of gingival lesions were obtained. The results will be described below. Family Study The pedigree (Fig. 1) shows the affected and unaffected individuals and their major manifestations.
Fig. 2. Pronounced follicular hyperkeratosis of the skin (IV-19).
Eleven relatives, 7 affected and 4 normal, were examined by one or more of the authors. Unfortunately, no affected male was available for study. Historical information on the remaining relatives was consistent and seemed reliable. The clinically involved areas were, as follows. Skin. Only the index case (IV-19) had follicular hyperkeratosis (Fig. 2). Hair. Non-scarring alopecia, varying from diffusely sparse and thin hair to alopecia totalis, including loss of sexual hair in adults, had occurred in all affected individuals. In most cases, the hair loss was at first intermittent but became permanent with advancing age. Teeth and nails were not affected in any relative. Orificial mucosa and gingiva. The most conspicuous manifestation of HMD was the fiery red coloration of the gingiva and adjacent hard palate (Fig. 3). The deep red areas were sharply demarcated from the normal pink of the remaining palate and buccal mucosa. These oral lesions were completely asymptomatic. They
Fig. 3. Mouth of IV-19 showing fiery red gingiva and adjacent areas of the hard palate. These areas are sharply demarcated from the normal pink color of the rest of the palate and buccal mucosa.
340
Urban et al. TABLE I. HMD in 3 Families* Witkop et al. Follicular keratosis Alopecia Fiery red gums Mucocutaneous moniliasis Keratoconjunctivitis Cataracts hlmonarv disease Esophageal stenosisiwebs Females more severely affected
* + , common; ( + 1, uncommon;
- , absent;
Okamoto et al.
Present Familv
+ + 0 + + +
+(?I -
~
+ (?)
-
0, no information;
seemed constant rather than episodic as was the alopecia. One individual (111-21)had vaginal discharge and vulvovaginal leukoplakia for many years. A hysterectomy seems to have been curative. The index patient had oral candidiasis past infancy on 2 occasions. Eyes. Mild corneal vascularization was found in 2 individuals (111-20, IV-16). Tearing and photophobia were not complaints, although the index case was reported to have had frequent eye infections. Cataracts developed in almost all affected individuals. They began in childhood or early adult age. In most cases cataract surgery became necessary around age 30 years. Lungs. None of our patients gave a history of pneumonia. Only 2 members (IV-29, IV-22) reported frequent attacks of bronchitis. One patient (111-20) had undergone a lobectomy for a benign tumor. Pulmonary function studies on 5 other affected members showed normal vital capacity, normal total lung capacity, mild obstructive lung disease in some, but none with evidence of restrictive lung disease. Esophagus. Esophageal webs, requiring dilatation andlor resection, occurred in the index patient and 3 other female relatives (11-4, 111-20, 111-21). Genetics. The pedigree of our kindred (Fig. 1)documents autosomal dominant inheritance. Penetrance appears to be complete, although clinical manifestations may not be apparent in early childhood. Expressivity is variable. Females tend to be more severely affected than males.
Histopathology Biopsies of the reddened oral mucosa were taken from 3 affected individuals. Specimens for light microscopy were fixed in formalin, imbedded in paraffin, and stained with hematoxylin-eosin. Transmission electron micrographs were prepared by the Electron Microscopy Laboratory, University of Dayton, and the Dean A. McGee Eye Institute, Oklahoma City. All slides were examined by one of the authors (R.H.S.). All biopsies from the oral lesions showed disrupted epithelial maturation. Basal and parabasal cells were vacuolated and their nuclei varied in size, shape, and chromatin density. Dyskeratotic cells were seen in the mid-spinous layer. Patchy thin layers of hyperkeratotic material were seen on the surface. Electron microscopic findings were less consistent. Initial preparations did not show any abnormalities. However, a repeat gingival biopsy of
+ (?), uncertain.
the index case documented reduced numbers of desmosomes, debris-filled intercellular spaces and bundles of tonofilaments.
DISCUSSION Although the histopathologic findings in our patients were similar to those described by Witkop et al. [1980, 1978, 1979, 19821 and consistent with the diagnosis of HMD, there were significant clinical differences between our kindred and those previously published (Table I). Only the index case in our kindred had follicular hyperkeratosis, a change present in all of Witkop et a1.k [1980,1978,1979,1982]cases. Our patients did not have tearing and photophobia which were prominent symptoms in the patients reported by Witkop et al. [1980, 1978, 1979, 19821 and Okamoto et al. [1977]. In our kindred, only mild obstructive lung disease was found in some relatives, unlike the patients described by Witkop et al. [1979] in whom repeated pneumonia, hemoptysis, restrictive lung disease, and, ultimately, cor pulmonale were the most serious health problems. The cause of these differences is not readily apparent. They are not likely to be the result of sampling bias or random variation. We think that i t is more likely that the disorder in our patients represents a more benign allele with a somewhat different phenotype. Studies on additional families should resolve this point. ACKNOWLEDGMENTS We are grateful to Dr. Carl J. Witkop, University of Minnesota, School of Dentistry, who kindly reviewed the slide histopathology and electron micrographs. We also wish to thank Karen Smith and Donna WachnowskyDiakiw for preparation of the manuscript. REFERENCES McKusick VA (1988):#15831-Mucoepithelial Dysplasia, Hereditary. In McKusick VA (ed):“Mendelian Inheritance in Man-Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes,” 8th edition. Baltimore: The Johns Hopkins University Press, 499-500. Okamoto GA, Hall JG, Ochs H, Jackson C, Rodaway K, Chandler J (1977):New syndrome of chronic mucocutaneous candidiasis. Birth Defects 3b:117-125. Sheman AJ, Ray DJ, Witkop CJ, Jr, Dahl MV (1989): Hereditary mucoepithelial dysplasia: case report and review of the literature. J Am Acad Dermatol 21(No 2, Part 2):351-357. Witkop CJ, Jr (1980): Disorders affecting cellular communications in oral tissues: gap junctions. Birth Defects XVI/2:197-209.
Hereditary Mucoepithelial Dysplasia Witkop CJ, Jr, White JG, King RA, Dahl MV, Young WG, Sauk JJ, Jr (1979): Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation. Am J Hum Genet 31:414-427. WitkoD CJ, Jr, White JG, Sauk J J , Jr, King RA (1978): Clinical, histologic, cytologic, and ultrastructural characteristics of the oral le~~
341
sions from hereditary mucoepithelial dysplasia. Oral Surg Oral Med Oral Pathol 46:645-657. Witkop cJ, Jr, White JG, Waring GO (1982): Hereditary mucoepithelial dysplasia, a disease of gap junction and desmosome formation. Birth Defects XVIII/6:493-511.
New Clinical Aspects of Hereditary Mucoepithelial Dysplasia M.D. Urban, R. Schosser, W. Spohn, W.O. Wentling, and M. Robinow Department of Pediatrics (M.D.U., W.S., W.O. W., M.R.), Wright State University School of Medicine, Dayton, Ohio; Department of Dermatology (R.S.1, University of Arkansas for Medical Sciences, Little Rock
Hereditary mucoepithelial dysplasia (HMD) is a multiepithelial disorder. It is transmitted as an autosomal dominant trait (McKusick: Mendelian Inheritance in Man-Catalogs of A u tosomal Dominant, A utosomal Recessive, and X-Linked Phenotypes, 8th edition. Baltimore: The Johns Hopkins University Press, pp 499, 1988). HMD is characterized by variable combinations of lesions of skin, hair, orificial mucosa, gingiva, eyes, and lungs. In some previously described patients, the corneal and pulmonary lesions were progressive and led to blindness, recurrent pneumonia, and/or premature death. On light microscopy, the lesion is characterized by dyskeratosis and, on electron microscopy,by a paucity of gap junctions and desmosomes. Here, we describe a new 5-generation kindred in which affected individuals had the same histologic characteristics but a somewhat different clinical spectrum and a more benign course. HMD should be considered in the differential diagnosis of childhood alopecia, follicular hyperkeratosis, keratoconjunctivitis, juvenile cataracts, gingival hyperemia, restrictive lung disease, and esophageal stenosis or webs.
INTRODUCTION In 1978 and again in 1979,1980, and 1982, Witkop et al. described a 4 generation kindred with a previously unrecognized disorder which they termed hereditary mucoepithelial dysplasia (HMD). Affected individuals presented with follicular hyperkeratosis, intermittent alopecia, fiery red gums, severe keratoconjunctivitis, cataracts, and progressive, often fatal lung disease. Light microscopy of skin, vaginal, and oral mucosa showed a distinct type of dyskeratosis, while electron microscopy documented a paucity of gap junctions and desmosomes. Witkop et al. [1979] recognized the same condition in a family which had been described previously by Okamoto et al. [1977] under the term of “chronic mucocutaneous moniliasis” and a sporadic case of HMD was reported by Sheman et al. [1989]. We are reporting a new 5-generation kindred with identical histological findings but a somewhat different spectrum of clinical manifestations and a more benign course.
CLINICAL REPORT The proposita (Fig. 1, IV-19) was a g5/ia year-old girl, referred for alopecia. She was born a t term with a weight of 3.2 k g and length of 53 cm. Growth and development were normal. Her general health was good except for repeated “eye infections.” She had also been treated a t ages 3 and a t 4 years for “thrush.” Her skin had always been rough and dry and her hair was dry and brittle. At age 6 years she gradually lost all of her scalp hair. After KEY WORDS: new kindred, phenotypic varia few months the hair grew back but more sparsely than ability, esophageal stenosis, before. Combing and brushing caused excessive hair benign course, autosomal loss. dominant inheritance Physical examination showed a slightly obese prepubertal girl whose height was 140.5 cm (75th centile), weight 45 kg (one kg above the 95th centile). Her skin was rough and dry with pronounced follicular hyperkeratosis (Fig. 21, particularly on the trunk and the Received for publication April 20, 1990; revision received July extensor surfaces. Her cheeks were flushed; the lips 30, 1990. were dry with mild angular fissuring. The scalp hair Address reprint requests to Maria D. Urban, M.D., Department was sparse and wiry. Body hair was scant and brittle. of Pediatrics, Wright State University School of Medicine, Dayton, Finger and toe nails appeared normal. The gingiva and OH 45435. adjacent areas of the hard palate were fiery red (Fig. 3). A preliminary report: “Hereditary mucoepithelial dysplasia-A These areas were sharply demarcated from the normal new kindred?” was presented a t the 1986 David W. Smith Workshop a t Burlington, VT and published in the Proceedings of the pink color of the rest of the palate and buccal mucosa. There was no dental or periodontal disease. The tongue Greenwood Genetic Center 1986, pp. 120-121.
0 1991 Wiley-Liss, Inc.
Hereditary Mucoepithelial Dysplasia
339
I I
21
1
V Fig. 1. Pedigree ofthe familyOO(thin hair);BO(cataract);QOlesophagealweb);QO (red gingiva).
was deeply fissured. The eyes showed fine corneal vascularization and, on slit lamp examination, there were early cataracts consisting of minute opacities scattered throughout all layers of the lenses. Vision was 20120.
Laboratory Studies Urinalysis, complete blood count, serum electrolytes, calcium, phosphorus, blood urea nitrogen, thyroxine, and thyroid-stimulating hormone levels were normal, and serum thyroid, adrenal, and parietal cell antibodies were not present. Pulmonary function studies documented mild obstructive but no restrictive lung disease. A radiographic study of the esophagus was reported as normal. However, 3 years later, she developed difficulties swallowing solid food and a repeat radiographic study documented a small area of stenosis and beginning web formation. Biopsies of gingival lesions were obtained. The results will be described below. Family Study The pedigree (Fig. 1) shows the affected and unaffected individuals and their major manifestations.
Fig. 2. Pronounced follicular hyperkeratosis of the skin (IV-19).
Eleven relatives, 7 affected and 4 normal, were examined by one or more of the authors. Unfortunately, no affected male was available for study. Historical information on the remaining relatives was consistent and seemed reliable. The clinically involved areas were, as follows. Skin. Only the index case (IV-19) had follicular hyperkeratosis (Fig. 2). Hair. Non-scarring alopecia, varying from diffusely sparse and thin hair to alopecia totalis, including loss of sexual hair in adults, had occurred in all affected individuals. In most cases, the hair loss was at first intermittent but became permanent with advancing age. Teeth and nails were not affected in any relative. Orificial mucosa and gingiva. The most conspicuous manifestation of HMD was the fiery red coloration of the gingiva and adjacent hard palate (Fig. 3). The deep red areas were sharply demarcated from the normal pink of the remaining palate and buccal mucosa. These oral lesions were completely asymptomatic. They
Fig. 3. Mouth of IV-19 showing fiery red gingiva and adjacent areas of the hard palate. These areas are sharply demarcated from the normal pink color of the rest of the palate and buccal mucosa.
340
Urban et al. TABLE I. HMD in 3 Families* Witkop et al. Follicular keratosis Alopecia Fiery red gums Mucocutaneous moniliasis Keratoconjunctivitis Cataracts hlmonarv disease Esophageal stenosisiwebs Females more severely affected
* + , common; ( + 1, uncommon;
- , absent;
Okamoto et al.
Present Familv
+ + 0 + + +
+(?I -
~
+ (?)
-
0, no information;
seemed constant rather than episodic as was the alopecia. One individual (111-21)had vaginal discharge and vulvovaginal leukoplakia for many years. A hysterectomy seems to have been curative. The index patient had oral candidiasis past infancy on 2 occasions. Eyes. Mild corneal vascularization was found in 2 individuals (111-20, IV-16). Tearing and photophobia were not complaints, although the index case was reported to have had frequent eye infections. Cataracts developed in almost all affected individuals. They began in childhood or early adult age. In most cases cataract surgery became necessary around age 30 years. Lungs. None of our patients gave a history of pneumonia. Only 2 members (IV-29, IV-22) reported frequent attacks of bronchitis. One patient (111-20) had undergone a lobectomy for a benign tumor. Pulmonary function studies on 5 other affected members showed normal vital capacity, normal total lung capacity, mild obstructive lung disease in some, but none with evidence of restrictive lung disease. Esophagus. Esophageal webs, requiring dilatation andlor resection, occurred in the index patient and 3 other female relatives (11-4, 111-20, 111-21). Genetics. The pedigree of our kindred (Fig. 1)documents autosomal dominant inheritance. Penetrance appears to be complete, although clinical manifestations may not be apparent in early childhood. Expressivity is variable. Females tend to be more severely affected than males.
Histopathology Biopsies of the reddened oral mucosa were taken from 3 affected individuals. Specimens for light microscopy were fixed in formalin, imbedded in paraffin, and stained with hematoxylin-eosin. Transmission electron micrographs were prepared by the Electron Microscopy Laboratory, University of Dayton, and the Dean A. McGee Eye Institute, Oklahoma City. All slides were examined by one of the authors (R.H.S.). All biopsies from the oral lesions showed disrupted epithelial maturation. Basal and parabasal cells were vacuolated and their nuclei varied in size, shape, and chromatin density. Dyskeratotic cells were seen in the mid-spinous layer. Patchy thin layers of hyperkeratotic material were seen on the surface. Electron microscopic findings were less consistent. Initial preparations did not show any abnormalities. However, a repeat gingival biopsy of
+ (?), uncertain.
the index case documented reduced numbers of desmosomes, debris-filled intercellular spaces and bundles of tonofilaments.
DISCUSSION Although the histopathologic findings in our patients were similar to those described by Witkop et al. [1980, 1978, 1979, 19821 and consistent with the diagnosis of HMD, there were significant clinical differences between our kindred and those previously published (Table I). Only the index case in our kindred had follicular hyperkeratosis, a change present in all of Witkop et a1.k [1980,1978,1979,1982]cases. Our patients did not have tearing and photophobia which were prominent symptoms in the patients reported by Witkop et al. [1980, 1978, 1979, 19821 and Okamoto et al. [1977]. In our kindred, only mild obstructive lung disease was found in some relatives, unlike the patients described by Witkop et al. [1979] in whom repeated pneumonia, hemoptysis, restrictive lung disease, and, ultimately, cor pulmonale were the most serious health problems. The cause of these differences is not readily apparent. They are not likely to be the result of sampling bias or random variation. We think that i t is more likely that the disorder in our patients represents a more benign allele with a somewhat different phenotype. Studies on additional families should resolve this point. ACKNOWLEDGMENTS We are grateful to Dr. Carl J. Witkop, University of Minnesota, School of Dentistry, who kindly reviewed the slide histopathology and electron micrographs. We also wish to thank Karen Smith and Donna WachnowskyDiakiw for preparation of the manuscript. REFERENCES McKusick VA (1988):#15831-Mucoepithelial Dysplasia, Hereditary. In McKusick VA (ed):“Mendelian Inheritance in Man-Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes,” 8th edition. Baltimore: The Johns Hopkins University Press, 499-500. Okamoto GA, Hall JG, Ochs H, Jackson C, Rodaway K, Chandler J (1977):New syndrome of chronic mucocutaneous candidiasis. Birth Defects 3b:117-125. Sheman AJ, Ray DJ, Witkop CJ, Jr, Dahl MV (1989): Hereditary mucoepithelial dysplasia: case report and review of the literature. J Am Acad Dermatol 21(No 2, Part 2):351-357. Witkop CJ, Jr (1980): Disorders affecting cellular communications in oral tissues: gap junctions. Birth Defects XVI/2:197-209.
Hereditary Mucoepithelial Dysplasia Witkop CJ, Jr, White JG, King RA, Dahl MV, Young WG, Sauk JJ, Jr (1979): Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation. Am J Hum Genet 31:414-427. WitkoD CJ, Jr, White JG, Sauk J J , Jr, King RA (1978): Clinical, histologic, cytologic, and ultrastructural characteristics of the oral le~~
341
sions from hereditary mucoepithelial dysplasia. Oral Surg Oral Med Oral Pathol 46:645-657. Witkop cJ, Jr, White JG, Waring GO (1982): Hereditary mucoepithelial dysplasia, a disease of gap junction and desmosome formation. Birth Defects XVIII/6:493-511.
