- Email: [email protected]
Dyskeratosis congenita: An autosomal dominant disorder
Dyskeratosis congenita: An autosomal dominant disorder Ping-K T c h o u , M . D . , F . R . C . P . ( C ) , and Thomas Kohn, M.D.
Quebec, Quebec, Canada Dyskeratosis congenita is a mesoectodermal disorder classically presenting with leukokeratosis of the mucous membrane, dystrophy of the nails, and reticulate hyperpigmentation of the skin. In this report, we describe a family in which this syndrome is transmitted in an autosomal dominant fashion and in which multisystemic involvement is well illustrated. (J AM ACAD DERMATOL 6: 1034-1039, 1982.)
A large French-Canadian family with five female and one male m e m b e r affected with dyskeratosis congenita will be described. This s y n d r o m e is reported to be either X-linked recessive or autosomal dominant. W e believe the inheritance in this family is autosomal dominant. Dyskeratosis c o n g e n i t a is a mesoectodermal congenital dermatosis. T h e first report o f this disease was in 1906 by Zinser, 1 who described the disorder in two brothers with hyperpigmentation of the skin, leukoplakia o f the oraI mucosa, and nail dystrophy. In 1926, Cole et al 2 presented three similar cases, all male. It was not until 1930 that Cole et al "~''~ p r o p o s e d calling the s y n d r o m e " d y s k e r a t o s i s congenita with pigmentation, dystrophia unguis and leukokeratosis o r i s . " The s y n d r o m e has been reported to date in approximately sixty-six patients, seven of w h o m were female. The first f e m a l e patients were described by S o r r o w and H i t c h ) Sirinavin and Trowbridge, 6 and D. Rosenthal in personal communication regarding two patients at the Canadian Dermatology Meeting in June, 1979. W e saw this syndrome in a family with five affected female and one affected male member.
Aceepted for publication Oct. 22, 1981. Reprint requests to: Dr. Thomas Kolm, 11 Cote du Palais, Quebec, Quebec G IR 2J6, Canada.
1034
CASE REPORTS Case 1 C 18 was a 48-year-old woman who had been hospitalized at the Hotel-Dieu Hospital in Quebec on two occasions. She had been followed by several family physicians since the age of 18 for a reticulate hyperpigmentation, darkest on her neck (otherwise asymptomatic). She had dental caries in most of her teeth and was edentulous by the age of 18. She also had diffuse graying of her hair since the age of 18, and at one time had an episode of alopecia totalis, which was followed by spontaneous regrowth. She complained of fatigue for many years and was investigated on multiple occasions for anemia. No definite diagnosis was made, and she was treated with iron. Her most persistent and bothersome problem was recurrent urinary tract infections, seven to eight per year. Her surgical history included a cholecystectomy, hysterectomy for benign disease, and cholesteatoma removal (in 1978). She was gravida VI, para III, abortus Ill. Pregnancies were complicated by eclampsia and nephritis. Her complaints also consisted of dysphagia for the preceding 12 months, primarily with solid foods. Physical examination revealed a 48-year-old pale female patient appearing considerably older than her stated age. The skin on her neck (Figs. 2 and 3), inguinal area, and breast had a tan to brown reticulate hyperpigmentation surrounding small islands of slightly atrophic hypopigmented skin. On the scalp there was diffuse thinning of the hair, which was completely gray. She had brown eyes and pale conjunctivae, and was myopic. Teeth were absent, and the tongue had punctate areas of 0190-9622/82/061034+06500.60/0
© 1982 Am Acad Dermatol
Volume 6 Number 6 June, 1982
Dyskeratosis congenita
AD " l
1035
O
B
1
10
2
11
12
c
1
2
3
4
5
6
7
8
9
10
11
12
LEGEND [ ] male C) female [ ] O Dyskeratosis Congenita [] probable Oyskeratosis Congenita IRI Blindness [] Cancer [] Incertain c a s e s
13
14
~ 1
2
20
21
22
3
Fig. 1. Family pedigree.
Figs. 2 and 3. Case 1. Skin on the neck, showing a tan to brown reticulate hyperpigmentation surrounding small islands of slightly atrophic hypopigmented skin.
noninfiltrated leukoplakia (Fig. 4). Two of her fingernails had longitudinal ridging, and pitting of other nails was present (Fig. 5). There was no lymphadenopathy or hepatosplenomegaly. Neurologic examination was normal. Evaluation for dysphagia revealed no abnormalities. Pelvic examination was remarkable only for pale atrophic mucosa. Rectal examination revealed tonismus of the inner sphincter, but no other abnormalities. Laboratory examination. Skin biopsy from the left side of her neck showed an area of thinning of the epidermis, and Fontana's stain showed melanophores in the upper dermis (Fig. 6).
The laboratory studies over the 6-year period showed: hemoglobin, 9.8-10.4 gm/dl (normal, 12.3-16.2 gin/ dl); hematocrit, between 28% and 31%; white blood cell count, 3800-3900, of which 40%-80% were potymorphonuclear leukocytes, 30%-38% lymphocytes, and 14% eosinophils. Platelets were between 270,000 and 305,000/mm a. T celI percentage by the sheep red blood cell (SRBC) rosette assay was elevated as 82%; mean corpuscular volume was 114/xm ~ (normal, 8 2-97/zma); serum folate, 36.5 mg/dl (normal, up to 13.2 mg/dl); B12, 170 U (normal, 200-870 U); reticulocyte count, between 1.7% and 4.5%; serum iron, within normal limits on both examinations; IgA, 660 mg/dl (normal);
1036
Journal of the American Academy of Dermatology
Tchou and Kohn
Fig. 5. Longitudinal ridging of two nails and pitting of other nails of Patient 1.
Fig. 4. Pnnctate areas of noninfiltrated leukoplakia on the tongue of Patient 1. IgM, 37 (normal); sedimentation rate (Westergren method), 100 mm/hr in I973, 108 mm/hr in 1979 (normal, less than 10). The following tests were normal or negative: uric acid, Shilling test, Coombs' test, haptoglobin test, lupus erythematosus cell prep, antinuclear antibody, T3, and T4. HLA-B27 was absent. Bone marrow aspiration in 1972 showed normal cellularity, but in 1979 showed evidence of severe hypoplasia. Only one of four urinary cultures showed significant Escherichia coli, Papanicolaou smear t'rom the cervix was normal. Intradermal skin tests for acetone, purified protein derivative, streptokinase-streptodornase, and candidin showed a slight positive reaction only to candidin. Chromosomal analysis was normal and showed no breakage. Case 2 D 1 was a 24-year-old woman and a daughter of Patient 1. Her parents were not related. Since the age of 18, she noted a brown reticulate pattern on both sides of
her neck, which had become progressively darker and more extensive. For the preceding year she had experienced a sensation of burning in these areas. Scalp hair had been graying since the age of 18. She had also been treated with iron unsuccessfully for anemia. She was gravida I, para I. Examination revealed a 24-year-old woman who appeared to be her stated age. Her hair was diffusely gray. Skin on both sides of her neck showed a reticulate hyperpigmentation pattern, similar to her mother's. The anterior portion of the tongue revealed leukoplakia in the center with a bluish discoloration at the margins. Dentition was normal. There was longitudinal ridging of the left index fingernail. The rest of the physical examination was unremarkable. Laboratory examination. Laboratory studies showed: hemoglobin, 12.3 gm/dl; hematocrit, 37.4%; white blood cell count, 11,200 with 65% polymorphonuclear leukocytes and 17% lymphocytes (normal, 4.311.6); sedimentation rate, 30 mm/hr (Westergren method) (normal, less than 10); platelet count, 260,000/ mm :~ (normal, 150,000-400,000/mma; mean corpuscular volume, 106 /xm3 (normal, 82-97 /xm3); SMA 12, 60 (normal); serum iron, 47 /xg/dl (normal). Case 3 D2, the eldest son of Patient 1, was 22 years of age and had had a macrocytic anemia for 5 to 6 years. He had not noticed any cutaneous lesions. On physical examination, no cutaneous lesions were found. He was very pale and looked his stated age. Laboratory examination. Laboratory studies showed: hemoglobin, 9.7 gm/dl (normal, 12.3-16.2 gm/dl); white blood cell count, 3900 (normal, 4,30011,600); platelets, 85,000/ram ~ (normal, 150,000-
Volume 6 Number 6 June, 1982
Dyskeralosis congenita
1037
Fig. 6. Skin biopsy from the left side of the neck of Patient 1 shows an area of thinning of the epidermis, and Fontana's stain shows melanophores in the upper dermis.
400,000/mma); reticulocyte count, 1.8% (normal, less than 1.5%); mean corpuscular volume, 17/zm :~(normal, 82-97 /xma); mean corpuscular hemoglobin concentration, 40 gm/dl (normal, 32-36 gm/dl; differential count: 54% polymorphonuclear leukocytes, 0%-2% stabs, 1% eosinophils, 30% lymphocytes, 6% monocytes; haptoglobin: 336 mg/dl (normal, 100-300 mg/dl); ferritin, 140 mg/dl (normal, 30-269 mg/dl); iron saturatiori, 31% (normal, 20%-60%); SMA 12, 60 (normal). The patient had become progressively more pancytopenic since 1976 when his bone marrow biopsy confirmed the diagnosis of aplastic anemia.
Case 4 C4 was a 42-year-old female cousin of Patient 1. She had reticulate hyperpigmentation about the inguinal area but no hair loss, leukoplakia, or nail changes.
Case 5 C20, the oldest living brother, was 46 years of age and had been edentulous since his early years. He had also been noted to have pitting of his nails and reticulate hyperpigmentation of his skin on the neck and in the intertriginous area. He had diffuse alopecia.
Case 6 The youngest brother, C22, had an unknown type of anemia. He also had sparse hair on his scalp and acanthosis nigricans in each axilla.
Case 7 C17, a 50-year-old woman and sister of Patient 1, had normal hair and reticulate hyperpigmentation of the neck. She also had an anemia, type undetermined. Case 8 C21, a 46-year-old white woman and sister of Patient 1, had similar lesions to that of the propositus and also had sparse hair. The family pedigree is shown in Fig. 1. The grandparents were first cousins with no known dermatologic problems. The patient's nine uncles and aunts were also said to be unaffected. One of her uncles, B3, married his first cousin, B4. Their sons, C1, C2, and C3, were legally blind; type of blindness was unspecified. These patients were not seen by us. The other children, C5, C6, C7, and C8, were not seen because they were not bothered by any skin lesions. C18's parents, B8 and B9, were second cousins. Eight of their thirteen children were alive at the time of writing. C9 died of Hodgkin's disease at 59 years of age. C12 died of an anesthetic complication while undergoing tonsillectomy at 9 years of age. C13 died of diphtheria at 2 years of age. C 14 died of tuberculosis at 25 years of age, and C15, of cancer of the pancreas at 50 years of age. The patient, C10, had been wearing dentures since her youth and had sparse hair, but no ectodermal defects. C l l , 61 years of age, had had dentures since
1038
Journal of the American Academy of Dermatology
T~hou and Kohn
Table I
Case
No
Reticulated hyperplgmentatton
1
+
2 3 4 5 6
+
7 8
+ +
+ +
Nail dystrophy
Leukoplakm
+ +
+ +
Extensive caries and early dental loss
Alopecm
Anemia
+
+
+ + +
+
early adolescence and had been noted to have acanthosls mgncans in both axlllae She had no other ectodermaI problems C16 had no ectodermal signs, but was treated m 1976 for a tumor of the spinal cord (type unspecified) DISCUSSION
T h e m a n l f e s t a h o n s o f dyskeratosls congenlta are k n o w n to be multtsystemac The &sease rev o l v e s m a i n l y the e c t o d e r m with a reticulate hyp e r p l g m e n t a t l o n o f the skin, had dystrophy, and l e u k o p l a k m of the m u c o u s membranes Slrmavln and T r o w b r l d g e , ~ as well as other authors, r-j~ s u m m a r i z e multiple assocmted findings which ine l u d e d skin a t r o p h y , hyperhldrosls of the palms and soles, hyperkeratos~s of the palms and soles, on bullae f o r m a t i o n , acrocyanosxs, e p l p h o n a , low m t e l h g e n c e , h e p a t o m e g a l y , splenomegaly, extensive c a n e s and early dental loss, alopecla, dysphagla, anemia a2-14 (usually aplastlc m a y b e acc o m p a m e d by l e u k o p e m a and thrombocytopenla), l e u k o p e m a , and c h r o m c refection T h e last six o f these w e r e present m o u r proposltus It ~s interesting to n o t e that one cousin, one brother, and t w o s~sters o f the proposltus, as well as her daughter, h a d slrmlar skin h y p e r p l g m e n t a tlon (see T a b l e I) In addition, an incomplete s y n d r o m e s e e m s to be present m several f a m d y m e m b e r s , w~th the a n e m m in her son and her y o u n g e s t brother It is interesting also to speculate on the increased mcadence of cancer m the family of this paUent and the relatlonshxp of th~s to a possable xmmunologlc cell-medmted defect as e w -
+
-i+
Leukopenla
Chronic refection
+
+
+
+ +
±
denced by an increased mcldence of cancer and Infections present m the syndrome The major compllcatton of dyskeratosls congenata has been an increased incidence of malignant tumors which usually develop in areas of leukoplakla W e intend to follow our patients for possible appearance of these tumors We are also very interested to see what will happen to the presently uninvolved family members, especially the two who have only anemm The three bhnd cousins may also represent an Incomplete syndrome Are they going to develop other manifestations of dyskeratosls congenlta9 The relataonshxp of acanthosas nlgncans to the syndrome remains an emgma REFERENCES
1 Zmser F Atrophla Cutm Retlculatum Pxgmentataon, Dystrophla Ungmm et Leukoplakla Ons Ikonographla Dermatologlca Hyoto 5 219-223, 1970 2 Cole HW, Cole HW Jr, Lascheld WP Dyskeratosls congenlta Arch Dermatol 76 702-719, 1957 3 Cole HW, Rauschkolb JE, Toomey J Dyskeratosls congemta with p~gmentatlon dystrophia unguls and leukokeratosls ons Arch Dermatol 21 71-99, 1930 4 Rauschkolb HN, Toomey J Dyskeratosls congemta with p~gmentat~on dystrophia ungu~m and leukokeratos~s orls Arch Dermatol 71 451-450, 1955 5 Sorrow JM Jr, Hitch JM Dyskeratosls congemta First report of its occurrence in a female and a review of the literature Arch Dermatol 88 340-347, 1963 6 Smnavln C, Trowbrldge AA Dyskeratosls congemta Chnlcal features and genetic aspects Report of a family and review of the hterature J Med Genet 12 339-354, 1975 7 Sato SI, Hanmbal JE Jr Ectodermal defect Dyskeratosls congemta with pigmentation, dystrophla ungulm and
Volume 6 Number 6 June, 1982
leukokeratosis oris. Arch Dermatol 86:114-115, 1962. 8. Costello M J, Bnncke CM: Dyskeratosis congenita. Arch Dermatol 73:123-132, 1956. 9. Engman MF: A unique case of reticular pigmentation of the skin with atrophy. Arch Derrnatol 13:685-687, 1926. 10. Engman MF Jr: Congenital atrophy of the skin with reticular pigmentation: Report of two cases. ]'AMA 105:1252-1256, 1933. i 1. Garb J: Dyskeratosis congenita with pigmentation, dystrophia unguim and leukoplakia oris. Arch Dermatol 55: 242-250, 1947.
Dyskeratosis congenita
1039
12. Bolalski J, Defecinska E, Judiewicz E, Pacanowski M: Fanconi's anemia and dyskeratosis congenita as a syndrome. Dermatologica 127:330-342, 1963. 13. Bryan HG, Wiron RK: Dyskeratosis congenita and familial pancytopenia. JAMA 192:203-208, 1965. 14. Texier L, Maleville 3: La symptomatologie cutante de l'an~mie perniciosiforme de Fanconi. Rapports avec la dysk&atose cong~nitale de Zinsser-Cole-Engman. Ann Dermatol Syphilol 90:553-568, 1963.
Quebec, Quebec, Canada Dyskeratosis congenita is a mesoectodermal disorder classically presenting with leukokeratosis of the mucous membrane, dystrophy of the nails, and reticulate hyperpigmentation of the skin. In this report, we describe a family in which this syndrome is transmitted in an autosomal dominant fashion and in which multisystemic involvement is well illustrated. (J AM ACAD DERMATOL 6: 1034-1039, 1982.)
A large French-Canadian family with five female and one male m e m b e r affected with dyskeratosis congenita will be described. This s y n d r o m e is reported to be either X-linked recessive or autosomal dominant. W e believe the inheritance in this family is autosomal dominant. Dyskeratosis c o n g e n i t a is a mesoectodermal congenital dermatosis. T h e first report o f this disease was in 1906 by Zinser, 1 who described the disorder in two brothers with hyperpigmentation of the skin, leukoplakia o f the oraI mucosa, and nail dystrophy. In 1926, Cole et al 2 presented three similar cases, all male. It was not until 1930 that Cole et al "~''~ p r o p o s e d calling the s y n d r o m e " d y s k e r a t o s i s congenita with pigmentation, dystrophia unguis and leukokeratosis o r i s . " The s y n d r o m e has been reported to date in approximately sixty-six patients, seven of w h o m were female. The first f e m a l e patients were described by S o r r o w and H i t c h ) Sirinavin and Trowbridge, 6 and D. Rosenthal in personal communication regarding two patients at the Canadian Dermatology Meeting in June, 1979. W e saw this syndrome in a family with five affected female and one affected male member.
Aceepted for publication Oct. 22, 1981. Reprint requests to: Dr. Thomas Kolm, 11 Cote du Palais, Quebec, Quebec G IR 2J6, Canada.
1034
CASE REPORTS Case 1 C 18 was a 48-year-old woman who had been hospitalized at the Hotel-Dieu Hospital in Quebec on two occasions. She had been followed by several family physicians since the age of 18 for a reticulate hyperpigmentation, darkest on her neck (otherwise asymptomatic). She had dental caries in most of her teeth and was edentulous by the age of 18. She also had diffuse graying of her hair since the age of 18, and at one time had an episode of alopecia totalis, which was followed by spontaneous regrowth. She complained of fatigue for many years and was investigated on multiple occasions for anemia. No definite diagnosis was made, and she was treated with iron. Her most persistent and bothersome problem was recurrent urinary tract infections, seven to eight per year. Her surgical history included a cholecystectomy, hysterectomy for benign disease, and cholesteatoma removal (in 1978). She was gravida VI, para III, abortus Ill. Pregnancies were complicated by eclampsia and nephritis. Her complaints also consisted of dysphagia for the preceding 12 months, primarily with solid foods. Physical examination revealed a 48-year-old pale female patient appearing considerably older than her stated age. The skin on her neck (Figs. 2 and 3), inguinal area, and breast had a tan to brown reticulate hyperpigmentation surrounding small islands of slightly atrophic hypopigmented skin. On the scalp there was diffuse thinning of the hair, which was completely gray. She had brown eyes and pale conjunctivae, and was myopic. Teeth were absent, and the tongue had punctate areas of 0190-9622/82/061034+06500.60/0
© 1982 Am Acad Dermatol
Volume 6 Number 6 June, 1982
Dyskeratosis congenita
AD " l
1035
O
B
1
10
2
11
12
c
1
2
3
4
5
6
7
8
9
10
11
12
LEGEND [ ] male C) female [ ] O Dyskeratosis Congenita [] probable Oyskeratosis Congenita IRI Blindness [] Cancer [] Incertain c a s e s
13
14
~ 1
2
20
21
22
3
Fig. 1. Family pedigree.
Figs. 2 and 3. Case 1. Skin on the neck, showing a tan to brown reticulate hyperpigmentation surrounding small islands of slightly atrophic hypopigmented skin.
noninfiltrated leukoplakia (Fig. 4). Two of her fingernails had longitudinal ridging, and pitting of other nails was present (Fig. 5). There was no lymphadenopathy or hepatosplenomegaly. Neurologic examination was normal. Evaluation for dysphagia revealed no abnormalities. Pelvic examination was remarkable only for pale atrophic mucosa. Rectal examination revealed tonismus of the inner sphincter, but no other abnormalities. Laboratory examination. Skin biopsy from the left side of her neck showed an area of thinning of the epidermis, and Fontana's stain showed melanophores in the upper dermis (Fig. 6).
The laboratory studies over the 6-year period showed: hemoglobin, 9.8-10.4 gm/dl (normal, 12.3-16.2 gin/ dl); hematocrit, between 28% and 31%; white blood cell count, 3800-3900, of which 40%-80% were potymorphonuclear leukocytes, 30%-38% lymphocytes, and 14% eosinophils. Platelets were between 270,000 and 305,000/mm a. T celI percentage by the sheep red blood cell (SRBC) rosette assay was elevated as 82%; mean corpuscular volume was 114/xm ~ (normal, 8 2-97/zma); serum folate, 36.5 mg/dl (normal, up to 13.2 mg/dl); B12, 170 U (normal, 200-870 U); reticulocyte count, between 1.7% and 4.5%; serum iron, within normal limits on both examinations; IgA, 660 mg/dl (normal);
1036
Journal of the American Academy of Dermatology
Tchou and Kohn
Fig. 5. Longitudinal ridging of two nails and pitting of other nails of Patient 1.
Fig. 4. Pnnctate areas of noninfiltrated leukoplakia on the tongue of Patient 1. IgM, 37 (normal); sedimentation rate (Westergren method), 100 mm/hr in I973, 108 mm/hr in 1979 (normal, less than 10). The following tests were normal or negative: uric acid, Shilling test, Coombs' test, haptoglobin test, lupus erythematosus cell prep, antinuclear antibody, T3, and T4. HLA-B27 was absent. Bone marrow aspiration in 1972 showed normal cellularity, but in 1979 showed evidence of severe hypoplasia. Only one of four urinary cultures showed significant Escherichia coli, Papanicolaou smear t'rom the cervix was normal. Intradermal skin tests for acetone, purified protein derivative, streptokinase-streptodornase, and candidin showed a slight positive reaction only to candidin. Chromosomal analysis was normal and showed no breakage. Case 2 D 1 was a 24-year-old woman and a daughter of Patient 1. Her parents were not related. Since the age of 18, she noted a brown reticulate pattern on both sides of
her neck, which had become progressively darker and more extensive. For the preceding year she had experienced a sensation of burning in these areas. Scalp hair had been graying since the age of 18. She had also been treated with iron unsuccessfully for anemia. She was gravida I, para I. Examination revealed a 24-year-old woman who appeared to be her stated age. Her hair was diffusely gray. Skin on both sides of her neck showed a reticulate hyperpigmentation pattern, similar to her mother's. The anterior portion of the tongue revealed leukoplakia in the center with a bluish discoloration at the margins. Dentition was normal. There was longitudinal ridging of the left index fingernail. The rest of the physical examination was unremarkable. Laboratory examination. Laboratory studies showed: hemoglobin, 12.3 gm/dl; hematocrit, 37.4%; white blood cell count, 11,200 with 65% polymorphonuclear leukocytes and 17% lymphocytes (normal, 4.311.6); sedimentation rate, 30 mm/hr (Westergren method) (normal, less than 10); platelet count, 260,000/ mm :~ (normal, 150,000-400,000/mma; mean corpuscular volume, 106 /xm3 (normal, 82-97 /xm3); SMA 12, 60 (normal); serum iron, 47 /xg/dl (normal). Case 3 D2, the eldest son of Patient 1, was 22 years of age and had had a macrocytic anemia for 5 to 6 years. He had not noticed any cutaneous lesions. On physical examination, no cutaneous lesions were found. He was very pale and looked his stated age. Laboratory examination. Laboratory studies showed: hemoglobin, 9.7 gm/dl (normal, 12.3-16.2 gm/dl); white blood cell count, 3900 (normal, 4,30011,600); platelets, 85,000/ram ~ (normal, 150,000-
Volume 6 Number 6 June, 1982
Dyskeralosis congenita
1037
Fig. 6. Skin biopsy from the left side of the neck of Patient 1 shows an area of thinning of the epidermis, and Fontana's stain shows melanophores in the upper dermis.
400,000/mma); reticulocyte count, 1.8% (normal, less than 1.5%); mean corpuscular volume, 17/zm :~(normal, 82-97 /xma); mean corpuscular hemoglobin concentration, 40 gm/dl (normal, 32-36 gm/dl; differential count: 54% polymorphonuclear leukocytes, 0%-2% stabs, 1% eosinophils, 30% lymphocytes, 6% monocytes; haptoglobin: 336 mg/dl (normal, 100-300 mg/dl); ferritin, 140 mg/dl (normal, 30-269 mg/dl); iron saturatiori, 31% (normal, 20%-60%); SMA 12, 60 (normal). The patient had become progressively more pancytopenic since 1976 when his bone marrow biopsy confirmed the diagnosis of aplastic anemia.
Case 4 C4 was a 42-year-old female cousin of Patient 1. She had reticulate hyperpigmentation about the inguinal area but no hair loss, leukoplakia, or nail changes.
Case 5 C20, the oldest living brother, was 46 years of age and had been edentulous since his early years. He had also been noted to have pitting of his nails and reticulate hyperpigmentation of his skin on the neck and in the intertriginous area. He had diffuse alopecia.
Case 6 The youngest brother, C22, had an unknown type of anemia. He also had sparse hair on his scalp and acanthosis nigricans in each axilla.
Case 7 C17, a 50-year-old woman and sister of Patient 1, had normal hair and reticulate hyperpigmentation of the neck. She also had an anemia, type undetermined. Case 8 C21, a 46-year-old white woman and sister of Patient 1, had similar lesions to that of the propositus and also had sparse hair. The family pedigree is shown in Fig. 1. The grandparents were first cousins with no known dermatologic problems. The patient's nine uncles and aunts were also said to be unaffected. One of her uncles, B3, married his first cousin, B4. Their sons, C1, C2, and C3, were legally blind; type of blindness was unspecified. These patients were not seen by us. The other children, C5, C6, C7, and C8, were not seen because they were not bothered by any skin lesions. C18's parents, B8 and B9, were second cousins. Eight of their thirteen children were alive at the time of writing. C9 died of Hodgkin's disease at 59 years of age. C12 died of an anesthetic complication while undergoing tonsillectomy at 9 years of age. C13 died of diphtheria at 2 years of age. C 14 died of tuberculosis at 25 years of age, and C15, of cancer of the pancreas at 50 years of age. The patient, C10, had been wearing dentures since her youth and had sparse hair, but no ectodermal defects. C l l , 61 years of age, had had dentures since
1038
Journal of the American Academy of Dermatology
T~hou and Kohn
Table I
Case
No
Reticulated hyperplgmentatton
1
+
2 3 4 5 6
+
7 8
+ +
+ +
Nail dystrophy
Leukoplakm
+ +
+ +
Extensive caries and early dental loss
Alopecm
Anemia
+
+
+ + +
+
early adolescence and had been noted to have acanthosls mgncans in both axlllae She had no other ectodermaI problems C16 had no ectodermal signs, but was treated m 1976 for a tumor of the spinal cord (type unspecified) DISCUSSION
T h e m a n l f e s t a h o n s o f dyskeratosls congenlta are k n o w n to be multtsystemac The &sease rev o l v e s m a i n l y the e c t o d e r m with a reticulate hyp e r p l g m e n t a t l o n o f the skin, had dystrophy, and l e u k o p l a k m of the m u c o u s membranes Slrmavln and T r o w b r l d g e , ~ as well as other authors, r-j~ s u m m a r i z e multiple assocmted findings which ine l u d e d skin a t r o p h y , hyperhldrosls of the palms and soles, hyperkeratos~s of the palms and soles, on bullae f o r m a t i o n , acrocyanosxs, e p l p h o n a , low m t e l h g e n c e , h e p a t o m e g a l y , splenomegaly, extensive c a n e s and early dental loss, alopecla, dysphagla, anemia a2-14 (usually aplastlc m a y b e acc o m p a m e d by l e u k o p e m a and thrombocytopenla), l e u k o p e m a , and c h r o m c refection T h e last six o f these w e r e present m o u r proposltus It ~s interesting to n o t e that one cousin, one brother, and t w o s~sters o f the proposltus, as well as her daughter, h a d slrmlar skin h y p e r p l g m e n t a tlon (see T a b l e I) In addition, an incomplete s y n d r o m e s e e m s to be present m several f a m d y m e m b e r s , w~th the a n e m m in her son and her y o u n g e s t brother It is interesting also to speculate on the increased mcadence of cancer m the family of this paUent and the relatlonshxp of th~s to a possable xmmunologlc cell-medmted defect as e w -
+
-i+
Leukopenla
Chronic refection
+
+
+
+ +
±
denced by an increased mcldence of cancer and Infections present m the syndrome The major compllcatton of dyskeratosls congenata has been an increased incidence of malignant tumors which usually develop in areas of leukoplakla W e intend to follow our patients for possible appearance of these tumors We are also very interested to see what will happen to the presently uninvolved family members, especially the two who have only anemm The three bhnd cousins may also represent an Incomplete syndrome Are they going to develop other manifestations of dyskeratosls congenlta9 The relataonshxp of acanthosas nlgncans to the syndrome remains an emgma REFERENCES
1 Zmser F Atrophla Cutm Retlculatum Pxgmentataon, Dystrophla Ungmm et Leukoplakla Ons Ikonographla Dermatologlca Hyoto 5 219-223, 1970 2 Cole HW, Cole HW Jr, Lascheld WP Dyskeratosls congenlta Arch Dermatol 76 702-719, 1957 3 Cole HW, Rauschkolb JE, Toomey J Dyskeratosls congemta with p~gmentatlon dystrophia unguls and leukokeratosls ons Arch Dermatol 21 71-99, 1930 4 Rauschkolb HN, Toomey J Dyskeratosls congemta with p~gmentat~on dystrophia ungu~m and leukokeratos~s orls Arch Dermatol 71 451-450, 1955 5 Sorrow JM Jr, Hitch JM Dyskeratosls congemta First report of its occurrence in a female and a review of the literature Arch Dermatol 88 340-347, 1963 6 Smnavln C, Trowbrldge AA Dyskeratosls congemta Chnlcal features and genetic aspects Report of a family and review of the hterature J Med Genet 12 339-354, 1975 7 Sato SI, Hanmbal JE Jr Ectodermal defect Dyskeratosls congemta with pigmentation, dystrophla ungulm and
Volume 6 Number 6 June, 1982
leukokeratosis oris. Arch Dermatol 86:114-115, 1962. 8. Costello M J, Bnncke CM: Dyskeratosis congenita. Arch Dermatol 73:123-132, 1956. 9. Engman MF: A unique case of reticular pigmentation of the skin with atrophy. Arch Derrnatol 13:685-687, 1926. 10. Engman MF Jr: Congenital atrophy of the skin with reticular pigmentation: Report of two cases. ]'AMA 105:1252-1256, 1933. i 1. Garb J: Dyskeratosis congenita with pigmentation, dystrophia unguim and leukoplakia oris. Arch Dermatol 55: 242-250, 1947.
Dyskeratosis congenita
1039
12. Bolalski J, Defecinska E, Judiewicz E, Pacanowski M: Fanconi's anemia and dyskeratosis congenita as a syndrome. Dermatologica 127:330-342, 1963. 13. Bryan HG, Wiron RK: Dyskeratosis congenita and familial pancytopenia. JAMA 192:203-208, 1965. 14. Texier L, Maleville 3: La symptomatologie cutante de l'an~mie perniciosiforme de Fanconi. Rapports avec la dysk&atose cong~nitale de Zinsser-Cole-Engman. Ann Dermatol Syphilol 90:553-568, 1963.