MISCELLANEOUS GENODERMATOSES: BECKWITH-WIEDEMANN SYNDROME, BIRT-HOGG-DUBE SYNDROME, FAMILIAL ATYPICAL MULTIPLE MOLE MELANOMA SYNDROME, HEREDITARY TYLOSIS, INCONTINENTIA PIGMENTI, AND SUPERNUMERARY NIPPLES
Philip R. Cohen, MD, and Razelle Kurzrock, MD
This article includes some genodermatoses in which patients have developed internal malignancies. For each of these genoder- matoses, preliminary studies suggest that the patients have an inherited increased risk for developing cancer. Whether all of these con- ditions represent bona fide genodermatoses with malignant potential or the coincidental detection of neoplasm in those patients re- mains to be determined.
BECKWITH-WIEDEMANN SYNDROME
At the annual meeting of the Western Soci- ety for Pediatric Research, on November 11, 1963, Beckwith“ described a constellation of autopsy findings and questioned whether
these represented “another syndrome.” Sub- sequently, at the June 16-18, 1964 annual meeting of the American Pediatric Society, Beckwith et al reported that their findings on autopsy of three unrelated children were those of “a newly recognized syndrome.” Independently, Wiedemann130 noted an asso- ciation between umbilical hernia and macro- glossia in two of three siblings with omphalo- cele whose parents were consanguineous and published his observation in 1964. Because the most common clinical manifestations of Beckwith-Wiedemann syndrome are exom- phalos (omphalocele), macroglossia, and gi- gantism, the disorder is also referred to as EMG syndrome.35 Beckwith-Wiedemann syn- drome is currently considered to be a condi- tion composed of multiple potential congeni- tal anomalies (including prevalent cutaneous
From the Departments of Dermatology and Pathology, The University of Texas-Houston Medical School (PRC); and the Department of Medical Specialties (Section of Dermatology) (PRC) and the Division of Medicine (Section of Biologic Studies, Department of Clinical Investigation) (RK), The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| Major clinical findingst Abdominal wall defects: diastasis recti, omphalocele, and umbilical hernia (72%) | Minor clinical findings Cardiac anomalies Diaphragmatic anomalies (7%) Gastrointestinal anomalies |
|---|---|
| Advanced bone age | |
| Craniofacial dysmorphia: maxillary underdevelopment, mid-face hypoplasia, prominent occiput | Head circumference (9%) Inguinal hernia (6%) |
| Ear/earlobe anomalies: creases, pits | Mental retardation Microcephaly Skeletal anomalies |
| Genitourinary anomalies: clitoromegaly, cryptorchidism, enlarged labia, hypospadias | |
| Gigantism: prenatal, postnatal | Laboratory findings§ |
| Hemihypertrophy (somatic asymmetry) | Hypercholesterolemia Hypertriglyceridemia |
| Increased birth weight | |
| Macroglossia (82%) | Hypocalcemia |
| Muscular hypertrophy | Hypoglycemia, neonatal (30%) |
| Nevus flammeus (facial) Seizures, apnea, cyanosis Visceromegaly: hepatomegaly, nephromegaly, splenomegaly | Polycythemia, neonatal (20%) |
*Data summarized from references 35 and 98.
+Estimated frequency between 20% and 40%, unless otherwise noted.
Estimated frequency between 12% and 16%, unless otherwise noted. §Estimated frequency below 5%, unless otherwise noted.
and mucosal features, as summarized in Ta- ble 1) in which there is a risk for the develop- ment of childhood tumors (Table 2)32, 34, 35, 37, 72, 82, 98, 117, 118, 131, 133; therefore, we consider this syndrome to represent, perhaps previously unrecognized, a genodermatosis with malig- nant potential.
Most cases of Beckwith-Wiedemann syn- drome are sporadic. The most frequent cyto- genetic abnormality that has been described is duplication of 11p15 (trisomy 11p15). Inter- estingly, in all of the cases of sporadic chro- mosomal duplication, the 11p15 duplication is always of paternal origin.15 In these cases, a possible role of genomic imprinting has been suggested.15
Yet, up to 15% of cases of Beckwith-Wiede-
| Benign hamartomas | Malignant neoplasms Adrenocortical carcinoma Appendiceal carcinoid Extra-abdominal neuroblastoma Glioblastoma |
| Adrenal adenoma | |
| Extra-adrenal cortical | |
| adenoma | |
| Fibrous hamartoma | |
| of the heart | |
| Gastric teratoma | Gonadoblastoma |
| Lumbar lipoma | Hepatoblastoma |
| Mammary | Lymphoma |
| fibroadenoma | Nodular renal blastoma |
| Placental | Pancreatoblastoma |
| hemangioma | Rhabdomyosarcoma |
| Retroperitoneal ganglioneuroma Umbilical myxoma | Wilms' tumor |
*Data from references 32, 34, 37, 72, 82, 98, 117, 118, 131, and 133.
mann syndrome are inherited in an autoso- mal dominant pattern, with low penetrance and variable expressivity. In these patients, linkage analysis has demonstrated that the disease locus maps to the 11p15.5 region of the genome.15, 98 Because the inherited cases of Beckwith-Wiedemann syndrome are only manifested when the defective gene is inher- ited from the mother, it has also been sug- gested that the pattern of inheritance for Beckwith-Wiedemann syndrome includes au- tosomal dominant inheritance with premuta- tion such that only “carrier” female subjects can produce the first generation of affected offspring (similar to the mode of inheritance of fragile-X syndrome and myotonic syn- drome).15
Insulin-like growth factor 2 (which is also called somatomedin) is likely to have a pri- mary or secondary role in the pathogenesis of Beckwith-Wiedemann syndrome. The insu- lin-like growth factor 2 gene is located on the short arm of chromosome 11; it has been considered responsible for various forms of giantism. Also, in some of the children with Beckwith-Wiedemann syndrome, increased circulating insulin-like growth factor 2 activ- ity has been reported.35, 98
Mucosal and Skin Manifestations
Macroglossia, anomalies of the ears, and facial nevus flammeus are the mucocutaneous features described in Beckwith-Wiedemann syndrome.35, 37, 72, 82, 98 Macroglossia is fre-
quently present at birth in newborns with Beckwith-Wiedemann syndrome; in larger se- ries of Beckwith-Wiedemann syndrome pa- tients, a large tongue has been observed in 82%35 to 100%82 of infants. Indeed, some au- thors advocate that the detection of macro- glossia in a newborn warrants further investi- gation to rule out Beckwith-Wiedemann syndrome.82
Clinically, macroglossia appears as a uni- form enlargement of the tongue with protru- sion from the mouth (Fig. 1)35 (additional ex- amples of macroglossia in patients with Beckwith-Wiedemann syndrome are shown in references 37, 72, and 82). Microscopically, there is hyperplasia and hypertrophy of the muscle fibers.35,82 During early childhood, the tongue remains larger than normal.35. Yet, in older children and adults, the tongue appears to become less protrusive; this is not second- ary to reduction in tongue size, but the result of improved accommodation of the tongue to the oral cavity secondary to repositioning of its base.35, 98
Surgical intervention in order to correct the macroglossia has also been performed.82, 96 In- dications for consideration of a partial glos- sectomy in patients with Beckwith-Wiede- mann syndrome include the following: (1) the unsightly, large protuberant tongue (giving the impression of mental retardation and re- sulting in dribbling); (2) the adverse effect on dentition (with secondary malocclusion and subsequent open bite); and (3) abnormal
speech development (especially with regards to consonant production).82 Removal of about one third of the tongue by resecting a central full-thickness wedge of tissue is a favored surgical technique.82, 6
Cutaneous manifestations of Beckwith- Wiedemann syndrome are abnormalities of the ears and nevus flammeus on the face. Ear anomalies commonly occur; in one series of 22 patients with Beckwith-Wiedemann syn- drome, 75% (15 of 20 individuals) had either ear creases or pits.”% The ear abnormalities ranged from a single crease of the ear lobe to multiple pits on the helix, with creases along the entire ear (“posterior posthelical pits”).35, 98 The creases are typically bilateral, yet not necessarily symmetric; they often ap- pear as slit-like indentations and frequently take the form of an “inverted 4.”35 Excellent figures demonstrating linear creases (fissures) located on the anterior lobule of the external ear and 3-mm semicircular pits on the poste- rior rim of the helix are published in the report of a newborn boy with Beckwith-Wie- demann syndrome who had a congenital gas- tric teratoma.37 Although the creases and pits tend to persist throughout life, they become less prominent with age.98
Facial nevus flammeus is present in be- tween one third35 and two thirds8 of new- borns with Beckwith-Wiedemann syndrome (see Fig. 1). The lesion typically involves the upper eyelids and the center of the forehead. Sometimes, the nevus flammeus also extends
down to involve the nose and upper lip. The vascular lesion becomes less prominent dur- ing the child’s first 12 months and subse- quently continues to fade during the first years of life.35, 98 Photographs of infants with Beckwith-Wiedemann syndrome that illus- trate the facial nevus flammeus are included in references 37, 72, and 82.
Noncutaneous Features
In addition to mucocutaneous features (macroglossia, ear creases and pits, and nevus flammeus), abdominal wall defects, gigan- tism, hypoglycemia, mid-face hypoplasia, and visceromegaly are frequently observed in Beckwith-Wiedemann syndrome.35, 98 Ompha- locele, a herniation of abdominal viscera into the base of the umbilical cord, is the most common umbilical abnormality in newborns with Beckwith-Wiedemann syndrome (excel- lent photographs are published in references 72 and 82). Other clinical findings in Beck- with-Wiedemann syndrome are summarized in Table 1.35, 98
Symptomatic hypoglycemia may develop in up to 50% of infants with Beckwith-Wiede- mann syndrome. A unique combination of hyperinsulinemic hypoglycemia and islet cell hyperplasia has been rarely observed. Also, less commonly, glucagon deficiency with hy- perinsulinism has been reported. Usually, the hypoglycemia is associated with hyperinsu- linism or nesidioblastosis with insulin (beta) cell hyperplasia and a relative decrease of the somatostatin cells.35
The symptoms of neonatal hypoglycemia are nonspecific: apnea, convulsions, cyanosis, lethargy, reluctance to feed, and tremor. Hence, in a hypoglycemic newborn with un- diagnosed Beckwith-Wiedemann syndrome, the hypoglycemia may not be initially sus- pected and the symptoms of low blood sugar not recognized early, resulting in late detec- tion and deleterious consequences (perma- nent brain damage, mental deficiency, or death). Therefore, once the diagnosis of Beck- with-Wiedemann syndrome has been estab- lished, it is important to monitor for hypogly- cemia.35, 98
Neonatal polycythemia, hypocalcemia, and elevated cholesterol or triglycerides are other laboratory abnormalities found in newborns with Beckwith-Wiedemann syndrome.35, 98
Associated Malignancies
Several benign hamartomas and malignant neoplasms have been detected in children
with Beckwith-Wiedemann syndrome (Table 2).32, 34, 37, 72, 82, 98, 117, 118, 131, 133 In 1983, Wiede- mann131 summarized his observations and those previously published with regard to the development of malignancy in patients with this condition. From a total of 388 children with Beckwith-Wiedemann syndrome, he found 29 children with 32 neoplasms (three children had developed second tumors); this calculated to a malignant tumor rate of 7.5%. The majority of the tumors (26 of 32 neo- plasms) were intraabdominal, and Wilms’ tu- mor (14 neoplasms) was the most common malignancy.131
In children with Beckwith-Wiedemann syn- drome, there is an increased risk of malig- nancy associated with the presence of hemi- hypertrophy.117 Hemihypertrophy has been observed in 22% (4 of 18 patients)98 to 27% (8 of 30 patients)82 of children with Beckwith- Wiedemann syndrome. Either partial or com- plete hemihypertrophy was noted in 49 of the 388 patients with Beckwith-Wiedemann syndrome (12.5%) reported by Wiedemann,131 and at least 12 of the 49 children with hemi- hypertrophy developed a malignant tumor. Hence, hemihypertrophy was present in more than 40% of children with Beckwith-Wiede- mann syndrome in whom a malignancy was diagnosed.131
Approximately half of the neoplasms oc- curring in children with Beckwith-Wiede- mann syndrome are Wilms’ tumors.72 Adre- nocortical carcinomas, hepatoblastomas, and pancreatoblastomas are also common in Beck- with-Wiedemann patients who develop ma- lignant tumors.32, 35, 131 All of the tumors in children with Beckwith-Wiedemann syn- drome are diagnosed in early childhood.35 Therefore, recommended management for tu- mor detection should include an extensive abdominal ultrasound at birth and weekly for the first month.72 Subsequently, abdominal ul- trasound should be repeated every 3 months until the age of 5 years and every 6 months from 5 years of age to adolescence.72 Because new tumors in children with Beckwith-Wie- demann syndrome have never been diag- nosed after the age of 10 years,35 it is unlikely that ultrasound examination after the first decade of life will detect a previously asymp- tomatic Beckwith-Wiedemann syndrome- associated malignancy.
BIRT-HOGG-DUBE SYNDROME
The constellation of hereditary multiple fibrofolliculomas with trichodiscomas and
acrochordons, Birt-Hogg-Dube syndrome, was originally presented before the 97th an- nual meeting of the American Dermatological Association in Phoenix, AZ, on March 22, 1977.º The genodermatosis is inherited in an autosomal dominant manner.5 It has subse- quently been named after the three individu- als (who were from the departments of der- matology, pathology, and internal medicine, respectively, at the University of Manitoba, in Winnipeg, Canada) who had studied a large kindred and described these lesions in 15 of 25 adult members.º Six of the family members had hereditary medullary carcinoma of the thyroid; two of these individuals also had numerous small papular skin lesions.9
A related, autosomal dominant condition to Birt-Hogg-Dube syndrome (which some authors consider to be part of the clinicopath- ologic spectrum of Birt-Hogg-Dube syn- drome) had been described 2 years earlier, in 1975, by Hornstein and Knickenberg.60 They had reported their observation of biopsy-con- firmed familial multiple perifollicular fibro- mas in a 47-year-old woman and her 42-year- old brother; in addition, the female patient had three adenomatous polyps in the sigmoid and lower colon (one of which had a begin- ning adenocarcinoma) and a thyroid goiter that had been removed when she was 22 years old. The siblings’ father also had similar skin nodules that had not been evaluated microscopically.60 Prior to Hornstein and Knickenberg’s report, familial occurrence of multiple perifollicular fibromas had only been mentioned by Civatte and LeTreguilly.19
Subsequently, perifollicular fibromas have been described in patients having either (1) fibrofolliculomas and trichodiscomas, (2) tri- chodiscomas and acrochordons, and (3) acro- chordons.º Hence, it is not unreasonable to entertain the possibility that Birt-Hogg-Dube syndrome and “Hornstein-Knickenberg” syn- drome represent variants of the same condi- tion.16
Mucosal and Skin Manifestations
Fibrofolliculomas are 2- to 4-mm, yellow- white, smooth, monomorphous, dome- shaped papules107; they are clinically indistin- guishable from trichodiscomas9, 107 (Fig. 2; Color Fig. 30). Perifollicular fibromas are also papular skin lesions that are flesh-colored and perifollicular in location; some have a central comedo.60, 114 Acrochordons range from small (1 to 2 mm) furrowed papules to larger (1 cm) pedunculated nodules.9
Fibrofolliculomas, perifollicular fibromas, and trichodiscomas are tumors of perifollicu- lar connective tissue. The former term was coined by Birt et al,9 based on the unpub- lished suggestion of Dr. Hermann Pinkus. The histopathology of fibrofolliculomas shows a central, often distorted follicle from which thin, anastomosing bands of follicular epithelium extend into the adjacent mucoid stroma.5, 9, 132
Perifollicular fibromas are characterized microscopically by concentrically arranged young collagen that surrounds a central folli- cle.5, 16, 60, 114 Trichodiscomas are hamartomas derived from the mesodermal component of normal hair discs (Haarscheibe)16; they are lo- cated subepidermally, often bordered by a hair follicle, and appear as a circumscribed area comprised of a sparsely cellular prolifer- ation of fibroblasts and fine fibrillary connec- tive tissue within a myxoid stroma that con- tains telangiectatic vessels.5,9 Microscopically, acrochordons show hyperkeratosis, papillo- matosis, acanthosis, and occasionally horn pseudocysts in the epidermis; in the dermis, the loose, often edematous, stroma typically contains numerous dilated vessels.
A large connective tissue nevus (hamar- toma) has been described in a 49-year-old man with multiple acrochordons and biopsy- confirmed fibrofolliculomas.132
Noncutaneous Features
Intestinal polyposis of the colon has been described in a 47-year-old man with Birt- Hogg-Dube syndrome.105 Sequentially, a total of six polyps were removed. Histopathology showed them to be tubular adenomas (three polyps), tubular adenomas with mild dyspla- sia (two polyps), and a tubular adenoma with marked epithelial dysplasia (one polyp). Be- nign and malignant colon polyps have been described in several patients with multiple perifollicular fibromas.60, 107, 114
Associated Malignancies
A high incidence of medullary carcinoma of the thyroid was observed in the family described by Birt et al.º Thyroid carcinoma has not subsequently been reported in pa- tients with Birt-Hogg-Dube syndrome. Re- cently, Roth et al107 published a report of a 61-year-old white man with Birt-Hogg-Dube syndrome in whom bilateral renal cell carci- noma was diagnosed.
Colon cancer has been reported in two women with multiple perifollicular fibromas. The first individual was the female patient described by Hornstein and Knickenberg60; she not only had two adenomatous polyps, but also a third colon polyp which showed “a beginning adenocarcinoma.” The second patient was a 58-year-old woman with an asymptomatic malignant villous adenoma of the sigmoid colon.114
FAMILIAL ATYPICAL MULTIPLE MOLE MELANOMA SYNDROME
The familial atypical multiple mole mela- noma syndrome is a cancer-associated geno- dermatosis that is characterized by the famil- ial occurrence of malignant melanoma of the skin, multiple atypical moles (“dysplastic nevi”), and a greater than normal number of normal nevi.8,76 It is inherited as an autosomal dominant trait with variable expressivity within families and reduced or nonpene- trance of the cutaneous phenotype.8, 77 This syndrome has also been referred to as: the B- K mole syndrome, the (D-2 familial type of the) dysplastic nevus syndrome, and the large atypical nevus syndrome.8, 78 In addition to increased susceptibility to developing cutane- ous malignant melanomas, there is an in- creased risk for developing primary intraocu- lar melanoma.40, 78, 127 In addition, in some subsets of familial atypical multiple mole melanoma families, there is also an increased
risk for the development of extracutaneous nonmelanoma primary cancers: particularly carcinoma of the pancreas and also other non- colorectal gastrointestinal cancers.8, 40, 76
Skin Manifestations
Greater than normal numbers of normal nevi, multiple atypical moles (“dysplastic nevi”), and cutaneous malignant melanoma are the skin lesions in patients and their rela- tives with familial atypical multiple mole melanoma syndrome. The normal nevi may be junctional (pigmented and flat, demonstra- ting benign-appearing nests of melanocytes located at the junction of the epidermis and the dermis microscopically), intradermal (flesh- colored and raised, demonstrating benign-ap- pearing nests of melanocytes located in the der- mis microscopically), or compound (pigmented and raised, demonstrating benign-appearing nests of melanocytes located both within the dermis and at the junction of the epidermis and the dermis microscopically).
Atypical moles (“dysplastic nevi”) clini- cally appear asymmetric with irregular bor- ders. They often have variation or nonunifor- mity in their color, erythema, and a diameter of greater than 6 mm. Uniform agreement does not currently exist with regard to the nomenclature and histopathologic definition of the clinical lesion referred to as an atypical mole (“dysplastic nevus”); some of the terms used for the pathologic diagnosis include dys-
plastic nevus, nevus with architectural disor- der, and nevus with histologic dysplasia.92, 99 Microscopically, these lesions may have cyto- logic or architectural changes. Limited pag- etoid spread of melanocytes or melanocytes with variable degrees of nuclear atypia may be present. Bridging between nests of mela- nocytes at the tips of epidermal rete ridges and concentric eosinophilic or lamellar fi- broplasia of the papillary dermis around the epidermal rete ridges (subepidermal fibro- plasia) are common architectural features. In addition, a patchy lymphocytic inflammatory infiltrate in the upper dermis or intraepider- mal melanocytes extending singly or in nests beyond the main dermal component (“shouldering” phenomenon) may also be present.
Depending on lesion location, morphology, and histopathology, malignant melanomas have been classified as superficial spreading, nodular, lentigo maligna, and acral lentigi- nous. Clinical features may be characterized by the “ABCDs” for detecting melanomas: asymmetry, border irregularity, color varie- gation, and diameter greater than 6 mm.39 A new, nodular growth and ulceration with bleeding in a preexisting melanocytic lesion can also be clinical features of malignant mel- anoma. The histopathology of melanomas has been recently reviewed.23
Associated Malignancies
Multiple primary cutaneous malignant melanomas have been observed in patients with familial atypical multiple mole mela- noma. Interestingly, some of the individuals with multiple primary cutaneous malignant melanomas in familial atypical multiple mole melanoma kindreds show unusual increased survival. Indeed, one man developed at least 13 histologically verified separate primary cu- taneous malignant melanomas over a period of 19 years; at least two of these lesions were deep nodular melanomas (Clark level IV).76,77
In addition to primary intraocular melano- mas, some familial atypical multiple mole melanoma families show evidence of an in- creased susceptibility to develop excess sys- temic cancers, especially noncolorectal gastro- intestinal malignancies and particularly pancreatic carcinoma.8, 40, 76, 77 Other extracuta- neous cancers observed in familial atypical multiple mole melanoma kindreds are listed in Table 3.8, 77 These internal malignancies may be of late-age onset.40 Therefore, long-
| Site of Cancer | No. of Patients |
|---|---|
| Lung | 3 |
| Breast | 2 |
| Pancreas | 2 |
| Larynx | 1 |
| Prostate | 1 |
| Tonsil | 1 |
| Total | 10+ |
| Site of Cancer | No. of Patients |
|---|---|
| Gastrointestinal | |
| Pancreas | 9 |
| Adenocarcinoma§ | 2 |
| Liver | 2 |
| Nasopharynx | 2 |
| Esophagus | 1 |
| Stomach | 1 |
| Tongue | 1 |
| Total | 18 |
| Breast | |
| Total | 4 |
| Genitourinary | |
| Cervix | 1 |
| Kidney | 1 |
| Prostate | 1 |
| Uterus | 1 |
| Total | 4 |
| "Childhood" cancer | |
| Total | 2 |
| Lung | |
| Total | 2 |
| Otherll | |
| Total | 2 |
| Total | 32 |
*Data derived from four kindred with clinical and pathological verification of the syndrome.”? There were 80 affected or at risk members in these families. A person was considered affected if he or she had cutaneous malignant melanoma or pathologically verified atypical moles or both. A total sample size of 42 af- fected family members was used for the determination of phe- notypic associations (presence of extracutaneous nonmela- noma cancer).
+One patient had both lung and prostate cancer; therefore, a total of nine different individuals with familial atypical multiple mole melanoma syndrome had at least one visceral, noncutaneous malignant melanoma cancer.
There were 10 families in Leiden, The Netherlands, with well- documented syndrome kindreds; the nine families (having a total of 200 cases) with 10 or more high-risk relatives were included in the study.” Three of the nine families had a high frequency of cancer diagnosis as compared with the other six families; the extracutaneous nonmelanoma cancers observed in these families were reported. Three individuals with nonmelanoma primary sys- tem cancers (a man with laryngeal carcinoma from one family and two women with pancreatic carcinoma from another family) were not included in the analysis because there was no evidence of the syndrome in their first-degree relatives. Each of the in- cluded individuals only had a single extracutaneous nonmela- noma cancer.
§Although the primary site of the adenocarcinoma was un- known, it was probably of digestive tract origin.
|[This includes a woman with leukemia and a woman with par- otid carcinoma.
Data from Bergman W, Watson P, deJong J, et al: Systemic cancer and the FAMMM syndrome. Br J Cancer 61:932-936, 1990; and Lynch HT, Fusaro RM, Kimberling WJ, et al: Familial atypical mole-melanoma (FAMMM) syndrome: Segregation analy- sis. J Med Genet 20:342-344, 1983.
term surveillance for the presence of these malignancies should be incorporated into the management of patients with familial atypical multiple mole melanoma syndrome.77” Al- though some studies did not find a significant excess of cancers other than malignant melanomas,46, 122 their “data have methodo- logic selection characteristics that mitigate positive associations.”40
HEREDITARY TYLOSIS
Clarke and McConnell,21 in 1954, originally described a family (Family C) in whom six cases of esophageal carcinoma had occurred in two generations. Unfortunately, the family members with esophageal carcinoma had not been seen, while alive, by the authors; there- fore, Clarke and McConnell had not appreci- ated that the family also had tylosis (keratosis palmaris et plantaris).20, 61 Subsequently (after the discovery of Family S), the presence of tylosis was established in five of the members of Family C who died secondary to esopha- geal carcinoma20; in 1957, Clarke et al20 pub- lished a preliminary letter on “carcinoma of oesophagus associated with tylosis.”
The following year Howel-Evans et al61 re- ported two Liverpool families with tylosis (Families S and C) in which esophageal carci- noma occurred in a total of 18 members. In 17 of these individuals there was unequivocal evidence that the neoplasm was associated with tylosis, and in one individual (from Family C), the presence of tylosis could nei- ther be established nor excluded.54, 61 Follow- up evaluation of Family S in 1959 revealed an additional, previously cancer-free, tylotic member with newly detected squamous cell carcinoma of the esophagus.22
Subsequently the association of autosomal dominantly inherited tylosis and esophageal carcinoma has been confirmed and additional kindreds have been described.54, 79, 112, 123, 124, 134
Mucosal and Skin Manifestations
Tylosis is from the Greek word for woody.112 It is a form of ectodermal anom- aly that is typically characterized by sym- metric, smooth, yellowish thickening of the skin of the palms and soles (keratosis pal- maris et plantaris); rarely, only the soles are involved.61, 112 There can be marked variation in the degree of tylosis among family mem-
bers, and it can be associated with fissuring.54 Usually, there is retention of the normal der- matoglyphic pattern.67 Commonly, although not uniformly,54 hyperhidrosis is also pres- ent.61
Two main clinical types of tylosis occur in families: an early-onset type (appearing between the ages of 3 and 12 months) and a late-onset type (appearing between the ages of 5 and 15 years).112 In Family S, tylosis was late in onset and usually appeared when the individuals were about 14 years of age; in Family C, similar to Family Š, tylosis did not appear until after childhood.61 Tylosis of the late-onset type was also observed in two ad- ditional kindred: Family H (in whom tylosis gradually appeared during childhood, but was definitely not present when the affected individuals were less than 1 year of age) and Family G (in whom the onset of tylosis proba- bly occurred between the ages of 1 and 5 years).54 In contrast, in one family with esoph- ageal carcinoma-associated hereditary tylo- sis, tylosis was present at birth in the affected individuals.134
Microscopically, tylosis demonstrates gen- eral hypertrophy of all epidermal skin layers, the sweat glands, and their ducts.61, 112 Typi- cally, there is marked hyperkeratosis (com- pact orthokeratosis) of the stratum corneum, hypergranulosis, and acanthosis of the under- lying epithelium.112
Hereditary tylosis has also been associated with other mucocutaneous lesions. These in- clude oral leukoplakia (in Family S)123, 124 and the development of squamous cell carcinoma in the tylotic skin located on the right heel, the plantar surface of the right great toe, or the dorsal left middle finger.134 The skin can- cers occurred in a series of three patients from one family with esophageal carcinoma- associated hereditary tylosis; in all cases, the tumor presented as an asymptomatic ulcer.134
The morphologic features of the esophageal squamous epithelium of patients with tylosis have been studied.4 The investigators found abnormalities of differentiation and matura- tion. Specifically, whereas dysplasia was only observed in patients older than 50 years of age, individual cell keratinization and in- flammation were noted to initially appear in a much younger age group (beginning for many patients in their early 20s).4
A preliminary study suggests that human papillomavirus infection does not have a role in the pathogenesis of squamous cell carci- noma in patients with hereditary tylosis.3
Ashworth et al3 detected cells on sections taken from a resected esophageal carcinoma from one patient with tylosis that were indis- tinguishable from koilocytes on the light mi- croscopic and the ultrastructural level. Based on this observation, they evaluated four re- sected esophageal carcinomas from tylosis patients and 10 esophageal biopsies from ty- losis patients without carcinoma with DNA probes to human papillomavirus types 6, 11, 16, 18, 31, 33, and 35, using in situ hybridiza- tion under conditions of high stringency. Hu- man papillomavirus DNA was not detected in either group.3
Associated Malignancies
Malignancy-related hereditary tylosis is classically associated with squamous cell car- cinoma of the esophagus. The calculated probability of death from esophageal carci- noma was 67% by the age of 50 years for the patients with tylosis included in Howel- Evans original series; by 65 years of age, up to 95% of living patients with tylosis would develop carcinoma of the esophagus.61 The median age of onset of carcinoma in this group of patients was 45 years; the youngest patient at the time of diagnosis was 29 years of age.61
Carcinoma-associated hereditary tylosis has also been described in patients without esophageal cancer. In one patient with heredi- tary tylosis, carcinomas of the larynx and stomach were detected.50 At the Spring meet- ing of the French Society of Dermatology in Paris, France, from March 14 to 16, 1985, Dr Chevrant Breton and colleagues reported a family with hereditary palmoplantar kerato- derma in which several women developed breast carcinoma.59
Nonfamilial or acquired tylosis (pal- moplantar keratoderma) has also been associ- ated with neoplasia.1, 67, 89, 94, 101, 110 Pulmonary carcinoma is the most common tumor67, 89, 94, 101, 110; others cancers include esophageal94, 110 and gastric carcinoma.1 In this setting, the appearance of malignancy-associated new- onset acquired keratoderma is more appro- priately considered to be a cutaneous para- neoplastic syndrome than a genodermatosis with malignant potential.
INCONTINENTIA PIGMENTI
Incontinentia pigmenti, also referred to as Bloch-Sulzberger syndrome, is a multisystem
disorder whose gene locus has recently been mapped to the terminal region on the long arm of the X chromosome (Xq28).68, 121 Tradi- tionally, the condition is characterized by an X-linked dominant mode of inheritance, with male hemizygote lethality; thus, it occurs al- most exclusively in female patients. Yet, less commonly, incontinentia pigmenti has also been described in male patients both with and without Klinefelter’s syndrome (47, XXY karyotype).24 Types of mutational events that have been postulated in the latter group of men with incontinentia pigmenti include a half-chromatid mutation, a early postzygotic mutation, and an unstable premutation.121
Mucosal and Skin Manifestations
The clinical morphology and pathologic changes found in the vesicular, verrucous, hyperpigmented, and hypopigmented stages of incontinentia pigmenti are summarized in Table 4 (Fig. 3; Color Fig. 31).24, 27. 28 Although each of the clinical stages usually appears sequentially, lesions of variable morphology may occur concurrently or nonsequentially. Typically, the diagnosis of incontinentia pig- menti is entertained in a female infant who is either born with vesicles or develops blisters shortly after birth. Initial laboratory studies may be normal; yet eosinophilia (ranging from 5% to 65% of leukocytes) often devel- ops within the first 2 weeks of life.24, 28 The pathologic changes observed on a lesional skin biopsy from a vesicular (eosinophilic spongiosis) or a verrucous (eosinophilic dys- keratosis) lesion are helpful in confirming a suspected diagnosis of incontinentia pigmenti (Fig. 4).
Noncutaneous Features
Systemic manifestations of incontinentia pigmenti may involve the bones, breasts, cen- tral nervous system, eyes, hair, nails, or teeth (Table 5).24, 68 Associated abnormalities may be present at birth or detected subsequently. Therefore, in newborns in whom the diagno- sis of incontinentia has been established, ini- tial and follow-up evaluation by appropriate specialists should be performed.
Associated Malignancies
Six children with incontinentia pigmenti who developed malignancy prior to the age
| Stage | Clinical Morphology | Pathologic Changes | |
|---|---|---|---|
| No. | Description | ||
| 1 | Vesicular | Linear vesicles, pustules, and bullae with underlying erythema | Eosinophilic spongiosis, intraepidermal vesicles, and dermal infiltrate |
| 2 | Verrucous | Warty, keratotic papules and plaques* | Eosinophilic dyskeratosis of keratinocytes, hyperkeratosis, acanthosis, and papillomatosis |
| 3 | Hyperpigmented | Macular hyperpigmentation in a swirled pattern* | Dermal melanophages and vacuolar alteration of the epidermal basal layer |
| 4 | Hyperpigmented | Hypopigmented streaks or patches; cutaneous atrophy may be present | Absence of skin appendages, mild epidermal atrophy, and decreased, normal, or small melanocytes |
*Although the hyperkeratotic lesions usually occur in the same location as the vesicles, the subsequent hyperpigmentation often appears in a random distribution that does not necessarily correspond to the site of earlier lesions.
From Cohen PR: Incontinentia pigmenti: Clinicopathologic characteristics and differential diagnosis. Cutis 54:161-166, 1994; with per- mission.
of 3 years have been reported.104 Eight malig- nancies were observed in these children: renal tumors (three patients, Wilms’ tumor in two patients and malignant rhabdoid tumor of the kidney in one patient), leukemia (two pa- tients, acute myelogenous and acute myelo- monocytic), retinoblastoma (two patients), and paratesticular rhabdomyosarcoma (one patient). Five of the children were girls. The sixth patient was a male infant in whom a paratesticular rhabdomyosarcoma was dis- covered at birth and treated by orchiectomy. Subsequently, acute myelogenous leukemia was diagnosed at 2 years of age. He did not survive; an unsuspected Wilms’ tumor in a horseshoe kidney was found at autopsy.
The precise risk of malignancy has not yet been defined for the young child in whom the diagnosis of incontinentia pigmenti has been established.104 Currently, work-up for an early childhood malignancy is not routinely
performed in newborns with incontinentia pigmenti.
SUPERNUMERARY NIPPLES
Supernumerary breast tissue has been clas- sified into eight types (Table 6).64,70 Polythelia refers to supernumerary breast tissue in which only the nipple is present (supernu- merary nipple).70 Although supernumerary nipples are uncommon, they are not rare. Their reported incidence in earlier studies was as low as 0.1% and 0.22% to 0.4%.18, 84, 90 One report cited an incidence of 5%.36 Recent investigations perhaps more accurately esti- mate the incidence of polythelia at 2.5% to 2.7%.44, 88
Supernumerary nipples are considered to be more common in blacks than in Cauca- sians, and a single supernumerary nipple is
more common than bilateral or multiple nipples.66, 70 Some investigators have found supernumerary nipples to occur equally in men and women.66, 70 Yet, other authors have
observed polythelia more frequently in either men70, 126 or women. 48, 62
Polythelia predominantly occurs as a spo- radic event.7º Familial occurrence of supernu-
| Organ System | Frequency of Involvement | Common Manifestations |
|---|---|---|
| Dental | 65%->80% | Anodontia, delayed eruption of teeth, hypodontia, impaction, and malformation of the crowns (accessory cusps and pegged [conical] deformity) |
| Hair | 38%-50% | Thin or sparse hair, and vertex (predominantly) lesions: alopecia and wooly-hair nevus (coarse, lusterless, and wiry patch of hair) |
| Eyes | 35%-40% | Amblyopia, avascularity in the peripheral temporal retina, cataract, cicatricial retinal detachments, fibrovascular proliferation with retinal dysplasia, microphthalmos, optic nerve atrophy, pseudoglioma, retinal pigmentation, and strabismus (squint) |
| Nails | 7%-40% <10%-31% 14% | Onychogryphosis, pitting, ridging, and subungual keratotic tumors Convulsive disorders, mental retardation," microcephaly, motor retardation, nystagmus, and spastic paralysis |
| Central nervous system | ||
| Skeletal and structural Breast | Chondrodystrophy, cleft palate or cleft lip or both, club foot, congenital dislocated hip, contractures, dwarfism (small stature), ear anomalies, extra ribs, hemiatrophy, hemivertebrae, scoliosis, skull deformities, spina bifida, and syndactyly Breast: aplasia and hypoplasia; and nipple: hypoplasia, pigmentation abnormality, and supernumerary |
“In a recent series of 111 patients with incontinentia pigmenti, the incidence of severe mental retardation in familial cases was only 3% as compared with 15% in the sporadic group, and the incidence of breast anomalies was at least 10 times greater than the incidence in the general population.ºn
From Cohen PR: Incontinentia pigmenti: Clinicopathologic characteristics and differential diagnosis. Cutis 54:161-166, 1994; with per- mission.
Table 6. KAJAVA’S CLASSIFICATION OF SUPERNUMERARY BREAST TISSUE
1. Complete supernumerary breast: mammary glandular tissue, nipple, and areola
2. Supernumerary breast tissue and nipple: mammary glandular tissue and nipple (without areola)
3. Supernumerary breast tissue and areola: mammary glandular tissue and areola (without nipple)
4. Supernumerary breast tissue: aberrant mammary glandular tissue only (without nipple and areola)
5. Pseudomamma: nipple, areola, and fat (which has replaced the mammary glandular tissue)
6. Polythelia: nipple only
7. Polythelia areolaris: areola only
8. Polythelia pilosa: patch of hair only
Data from Kajava Y: The proportions of supernumerary nipples in Finnish population. Duodecim 31:143-170, 1915; and Leung AKC: Polythelia. Int J Dermatol 28:429-433, 1989.
merary nipples has been observed, however, not only in siblings but also in sequential generations.25, 62, 69, 120 Visceral malignancy has been reported in two individuals with famil- ial polythelia: renal adenocarcinoma in a 66- year-old black man whose brother also had an accessory nipple and a 42-year-old Cauca- sian woman whose son also had an accessory nipple.43
Skin Manifestations
Supernumerary nipples usually appear as small pigmented or pearl-colored lesions. They are most commonly located below the normal nipple along the mammary ridge (Fig. 5; Color Fig. 32). The morphologic differential diagnosis of polythelia includes acrochor- dons, congenital melanocytic macules, fi- bromas, hidradenitis suppurativa, lipomas, neurofibromas, nevi, pedunculated dermal tumors, and verrucas.
For purposes of epidemiologic studies, Goedert et al43, 44 established the following criteria for lesions to be considered as acces- sory nipples: (1) that the lesion be present in the milk line (which extends superolaterally from the primary nipple to the anterior axil- lary fold and inferomedially to the pubis; (2) that the lesion be present since earliest mem- ory (congenital); (3) that the diameter of the lesion is at least 5 mm; (4) that the pigmenta- tion of the lesion approximates that of the primary nipples (pigmented brown or tan); and (5) that the lesion has a “nipple-like” appearance (centrally elevated, and prefera- bly glandular appearing, with a surrounding pigmented “areola”). These criteria are excel-
lent as clinical guidelines in the screening of large groups of people. Yet, bona fide super- numerary nipples do exist that have not ful- filled all of the criteria of Goedert et al.
Other cutaneous lesions have been de- scribed in persons with supernumerary nip- ples. In some of these individuals, the addi- tional skin manifestations represent the primary lesions of another condition, such as hidrotic ectodermal dysplasia51 and inconti- nentia pigmenti.24, 66 In other patients with polythelia, syndactyly and either aplasia cutis congenita52 or acanthosis nigricans and poly- cystic kidneys11 are present.
Noncutaneous Features
Renal anomalies (Table 7)43, 57, 66, 70, 83, 85, 126 and nonrenal anomalies (Table 8)13, 24, 36, 41, 43, 44, 47, 51, 53, 68-70, 97, 137 have been observed in individ- uals with supernumerary nipples. Whether a significant association between supernumer- ary nipples and renal anomalies exists is con- troversial. 12, 57, 66, 70, 71, 83, 88, 126 The incorrect iden- tification of other lesions as polythelia or the delayed diagnosis of kidney and urogenital tract anomalies may account for the variable frequency of associated renal anomalies in patients with supernumerary nipples.66, 85
| Bladder neck obstruction | Multicystic dysplasia Nephrosclerosis Polycystic kidney disease |
| Duplication of the renal | |
| arteries | |
| Duplication of the urinary | Renal duplication Solitary renal cyst |
| tract | |
| Familial nephritis | Unilateral renal agenesis |
| Hydronephrosis | Ureteral duplication |
| Hypoplastic kidney | Urethral cyst |
| Malignant tumors | Uteropelvic junction |
| Megaloureter | obstruction |
| Membranoproliferative glomerulonephritis | Vesicoureteral reflux |
Associated Malignancies
Goedert et al42, 43 described two men with accessory nipples and clear cell carcinoma of the kidney in 1981; one of the men also had a prior seminoma during childhood. They also reported their observation of supernumerary nipples in 6 of 32 patients with renal adeno- carcinoma; two of the patients had familial polythelia.43 Four of the six patients had addi- tional renal or urogenital congenital anoma- lies. 43
In a subsequent study published in 1984, Goedert et al4 reported an association be- tween polythelia and testicular cancer: 11% (8 of 73 patients) of the men with testicular can- cer that they retrospectively evaluated had an accessory nipple. Polythelia was independent of tumor laterality and tumor histologic type.44 Seven of the eight patients also had
either an associated urinary or skeletal abnor- mality.44
Prompted by earlier studies by Goedert et al,43, 44 Mehes et al86 evaluated patients with urologic malignancies for supernumerary nipples. In all types of urologic tumors exam- ined, a significantly higher frequency of su- pernumerary nipples was found. Supernu- merary nipples were found in 32 of 203 patients: 11 patients with carcinoma of the urinary bladder, nine men with prostatic car- cinoma, eight patients with renal adenocarci- noma, and four men with testicular cancer.86
A single case of Wilms’ tumor involving the left kidney was described by Meggyessy and Mehes83 in a 3-year-old girl with left- sided polythelia. Supernumerary nipples in four other patients with visceral malignancies have been observed by one of the authors (PRC) either during dermatology clinic or while rounding on the dermatology consulta- tion service at the University of Texas M. D. Anderson Cancer Center: (1) bilateral poly- thelia in a Caucausian man in whom em- bryonal cell carcinoma of the left testes was diagnosed at age 22 years26; (2) right-sided polythelia in a 35-year-old Caucausian woman with metastatic renal cell carcinoma involving the left kidney and lungs that was initially diagnosed at age 32 years; (3) right- sided polythelia in a Hispanic man with neu- rofibromatosis type 1 in whom rhabdomyo- sarcoma of the prostate was diagnosed at age 18 months and radiation-induced malignant fibrous histiocytoma was subsequently diag-
| Cardiovascular disease | Genetic syndromes Aplasia cutis congenita Ectodermal dysplasia (Hay-Wells syndrome) Fleischer's syndrome |
|---|---|
| Cardiac conduction disturbances | |
| Congenital heart defects | |
| Hypertension | |
| CNS disease | Incontinentia pigmenti |
| Epilepsy | Neurofibromatosis type I |
| Intracranial aneurysm | Ruvalcaba-Myhre syndrome |
| Neurosis | Simpson-Galabi-Behmel syndrome |
| Chromosome trisomy | Turner's syndrome |
| Chromosome 8 trisomy | Genitourinary disorders |
| Partial chromosome 3p trisomy | Hypospadias |
| Cutaneous disorders | Gonadal hypoplasia |
| Acanthosis nigricans | Varicoceles |
| Ear abnormalities | Malignancies |
| Gastrointestinal disease | Skeletal disease |
| Peptic ulcers | Arthrogryposis multiplex congenita |
| Pyloric stenosis | Bifid condyle of the mandible, clinodactyly, and polydactyly Coronal suture synostosis Syndactyly Vertebral malformations |
| Supernumerary nipples (polythelia) | Ectopic breast tissue of the axillae |
| Local tumors | Axillary lymph node |
| Benign | Papillary carcinoma129 |
| Epidermoid cyst14 | Axillary soft tissue |
| Malignant | Carcinoma2, 31 |
| Paget's disease"1 | Cystosarcoma phylloides109, 115 |
| Visceral malignancies | Fibroadenoma31 |
| Hodgkin's lymphoma (PO) | Supernumerary breast of the vulva |
| Kidney cancers | Adenocarcinoma45, 47, 56 Fibroadenoma38, 55, 113 Intraductal papilloma102 |
| Adenocarcinoma42, 43. 86 (PO) | |
| Wilms' tumor83 | |
| Malignant fibrous histiocytoma (PO) Prostate cancer | |
| Adenocarcinoma86 | |
| Rhabdomyosarcoma (PO) | |
| Testicular cancer06 | |
| Choriocarcinoma44 | |
| Embryonal cell26, 44 Mixed cell44 | |
| Seminoma42-44 | |
| Teratocarcinoma44 | |
| Urinary bladder86 |
PO = personal observation.
| Genodermatosis | Tumor* |
|---|---|
| Beckwith-Wiedemann syndrome+32. 34. 37. 72. 82. 98, 117, 118. 131. 133 | Adrenocortical carcinomas Hepatoblastomas Pancreatoblastomas Wilms' tumor |
| Birt-Hogg-Dube syndrome9, 107 | Medullary carcinoma of the thyroid Renal cell carcinoma |
| Familial atypical multiple mole melanoma syndrome+8, 40, 76-78, 127 | Intraocular malignant melanoma Noncolorectal gastrointestinal cancers Pancreatic carcinoma |
| Hereditary tylosis+20, 22, 50, 54, 59, 61 Hornstein-Knickenberg syndrome (multiple perifollicular fibromas)60, 114 | Esophageal squamous cell carcinoma Colon carcinoma |
| Incontinentia pigmenti104 Supernumerary nipple+26, 42-44, 83, 86 | Kidney (malignant rhabdoid and Wilms' tumors) Leukemia (acute myelogenous and myelomonocytic) Retinoblastoma Rhabdomyosarcoma (paratesticular) |
| Kidney (renal cell carcinoma and Wilms' tumor) Prostate carcinoma Testicular cancer Urinary bladder carcinoma |
*Tumors for each genodermatosis are listed alphabetically and not necessarily in order of incidence. +Other malignancies, less frequently, have also been observed in patients with this genodermatosis.
| Condition | Tumor* |
|---|---|
| Autosomal dominant ichthyosis vulgaris74 Congenital ichthyosis73. 108. 128 | Testicular cancer Medulloblastoma Ovarian endodermal sinus tumor Thyroid carcinoma |
| Dermatofibroma103 Down syndrome (Trisomy 21)87, 91, 106 | Malignant fibrous histiocytoma (of lung) Leukemia (acute lymphocytic and nonlymphocytic) Melanoma (acral lentiginous) |
| Epidermal nevus syndrome+58, 03, 116, 136 | Benign: chondroma, endometrioma, glioma, hemangioma (leptomeningeal), hepatic adenoma, lymphangioma (gastrointestinal), meningioma, odontoma, pituitary tumor Malignant: ameloblastoma (mandible), astrocytoma, breast adenocarcinoma, esophageal carcinoma, gastric carcinoma, giant cell tumor (mandible), salivary gland adenocarcinoma, squamous cell carcinoma (metastatic), urinary bladder (transitional cell carcinoma and rhabdomyosarcoma), Wilms' tumor |
| Epidermolysis bullosa17, 95, 119. 135 | Extramammary Paget's disease Melanoma Osteosarcoma Squamous cell carcinoma (cutaneous and metastatic) Urinary bladder (squamous cell carcinoma) |
| Epidermolytic hyperkeratosis33 | Basal cell carcinoma Breast infiltrating ductal carcinoma Squamous cell carcinoma (cutaneous and metastatic to lymph nodes) |
| Goltz syndrome (focal dermal hypoplasia)20, 63 Hereditary epidermolytic palmoplantar keratoderma10, 125 | Giant cell tumor of bone Osteochondroma |
| Breast adenocarcinoma Melanoma Ovarian adenocarcinoma | |
| Noonan syndrome65,80,100 | Acute lymphoblastic leukemia Ganglioneuroma Malignant schwannoma Pheochromocytoma |
| Palmar keratoses30 | Urinary bladder cancer (carcinoma in situ, dysplasia, squamous cell carcinoma, and transitional cell carcinoma) |
| Papillon-Lefevre syndrome49 | Melanoma |
| Recessive X-linked icthyosis74, 75, 111 | Testicular cancer |
*Tumors for each genodermatosis are listed alphabetically and not necessarily in order of incidence.
tThe following benign and malignant cutaneous tumors have been reported to occur within the skin lesions of epidermal nevi: apocrine cystadenoma, basal cell carcinoma, infundibuloma, keratoacanthoma, sebaceous epithelioma, solid hidradenoma, squamous cell carci- noma, syringocystadenoma papilliferum, and syringoma.
nosed at age 20 years; and (4) an accessory nipple in a 33-year-old Caucausian woman with Hodgkin’s disease.
Table 9 summarizes the benign and malig- nant tumors that have been described in per- sons with supernumerary breast tissue.2, 14, 26, 31, 38, 42-45, 47, 55, 56, 81, 86, 102, 109, 113, 115, 129 In particular, supernumerary nipples have been primarily associated with genitourinary malignancies: specifically, cancer of the kidney, prostate, testes, and urinary bladder. Similar to the earlier onset of malignancy observed in other syndromes characterized by hereditary neo- plasms, the onset of renal cancer was at a younger age in patients with supernumerary nipples compared with those without poly- thelia.43
CONCLUSION
The most frequently associated malignan- cies that have been observed in patients with Beckwith-Wiedemann syndrome, Birt-Hogg- Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, Hornstein-Knickenberg syndrome, inconti- nentia pigmenti, and supernumerary nipples are summarized in Table 10 .* There are also several other conditions that have the follow- ing characteristics: (1) dermatologic manifes- tations; (2) familial occurrence or inherited gene defect; and (3) associated tumors in re- ported cases (Table 11).+ Additional observa- tion and documentation are needed in order to determine which of these conditions are also bona fide genodermatoses with malig- nant potential.
References
1. Akritidis NK, Kistis KG: Hyperkeratosis of the soles. [photoclinic] Consultant 33:122, 1993
2. Andreasen AT: Medullary carcinoma in an axillary breast. Br J Surg 35:322-323, 1948
3. Ashworth MT, McDicken IW, Southern SA, et al: Human papillomavirus in squamous cell carcinoma of the oesophagus associated with tylosis. J Clin Pathol 46:573-575, 1993
4. Ashworth MT, Nash JRG, Ellis A, et al: Abnormali- ties of differentiation and maturation in the oesoph- ageal squamous epithelium of patients with tylosis:
*References 8, 9, 20, 22, 26, 32, 34, 37, 40, 42-44, 50, 54, 59-61, 72, 76-78, 82, 83, 86, 98, 104, 107, 114, 117, 118, 127, 131, 133.
+References 10, 17, 29, 30, 33, 49, 58, 63, 65, 73-75, 80, 87, 91, 93, 95, 100, 103, 106, 108, 111, 116, 119, 125, 128, 135, 136
Morphological features. Histopathology 19:303- 310, 1991
5. Bayrou O, Blanc F, Moulonguet L, et al: Birt-Hogg- Dube syndrome: Fibrofolliculomas, trichodiscomas and acrochordons. Ann Dermatol Venereol (Paris) 117:37-41, 1990
6. Beckwith JB: Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig-cell hyperplasia-An- other syndrome? Presented at the Annual Meeting of Western Society for Pediatric Research, Los Angeles, CA, November 11, 1963
7. Beckwith JB, Wang C, Donnell GN, et al: Hyperplas- tic fetal visceromegaly, with macroglossia, ompha- locele, cytomegaly of the adrenal cortex, postnatal somatic gigantism, and other abnormalities: A newly recognized syndrome. Abstract read by title, at the Annual Meeting of American Pediatric Soci- ety, Seattle, WA, June 16-18, 1964
8. Bergman W, Watson P, deJong J, et al: Systemic cancer and the FAMMM syndrome. Br J Cancer 61:932-936, 1990
9. Birt AR, Hogg GR, Dube WJ: Hereditary multiple fibrofolliculomas with trichodiscomas and acrochor- dons. Arch Dermatol 113:1674-1677, 1977
10. Blanchet-Bardon C, Nazzaro V, Chevrant-Breton J, et al: Hereditary epidermolytic palmoplantar kera- toderma associated with breast and ovarian cancer in a large kindred. Br J Dermatol 117:363-370, 1987
11. Bonnekoh B, Wevers A, Spangenberger H, et al: Keratin pattern of acanthosis nigricans in syn- dromelike association with polythelia, polycystic kidneys, and syndactyly. Arch Dermatol 129:1177- 1182, 1993
12. Bortz J, Parker S, Ray TL: Lack of associated anoma- lies in familial polythelia [letter]. Am J Dis Child 143:883, 1989
13. Brightmore T: Bilateral double nipples. Br J Surg 59:55-57, 1972
14. Brightmore TGJ: Cystic lesion of a dorsal supernu- merary breast in a male. Proc R Soc Med 64:662- 663, 1971
15. Brown KW, Gardner A, Williams JC, et al: Paternal origin of 11p15 duplications in the Beckwith-Wiede- mann syndrome: A new case and review of the literature. Cancer Genet Cytogenet 58:66-70, 1992
16. Burgdorf WHC, Koester G: Multiple cutaneous tu- mors: What do they mean? J Cutan Pathol 19:449- 457, 1992
17. Chorny JA, Shroyer KR, Golitz LE: Malignant mela- noma and a squamous cell carcinoma in recessive dystrophic epidermolysis bullosa, Arch Dermatol 129:1212, 1993
18. Chung CS, Myrianthopoulos NC: Factors affecting risks of congenital malformations. I. Epidemiologic analysis. Birth Defects 11:1-22, 1975
19. Civatte J, LeTreguilly J-P: Multiple perifollicular fi- bromas of the skin of the face. Bull Soc Franc Der- matol Syphil 78:100-103, 1971
20. Clarke CA, Howel-Evans AW, McConnell RB: Car- cinoma of oesophagus associated with tylosis [let- ter]. Br Med J 1:945, 1957
21. Clarke CA, McConnell RB: Six cases of carcinoma of the oesophagus occurring in one family. Br Med J 2:1137-1138, 1954
22. Clarke CA, McConnell RB, Howel-Evans W, et al: Carcinoma of oesophagus in association with tylosis [letter]. Br Med J 2:1100, 1959
23. Clark WH Jr, Elder DE, Guerry D IV: Dysplastic nevi and malignant melanoma. In Farmer ER, Hood
AF (eds): Pathology of the Skin. Norwalk, CT, Ap- pleton & Lange, 1990, pp 684-756
24. Cohen PR: Incontinentia pigmenti: Clinicopatho- logic characteristics and differential diagnosis. Cutis 54:161-166, 1994
25. Cohen PR: The significance of familial polythelia. The reply. J Am Acad Dermatol, in press
26. Cohen PR: Polythelia and testicular cancer: Case report of a man with embryonal cell carcinoma of the left testes and bilateral supernumerary nipples. Cancer Bulletin, in press
27. Cohen PR, Beltrani VP, Zalar G: Picture of the month. Am J Dis Child 143:255-256, 1989
28. Cohen PR, Garcia J: Pathological case of the month: Incontinentia pigmenti. Arch Pediatr Adolesc Med 148:531-532, 1994
29. Cox NH, Paterson WD: Osteochondroma of hu- merus in focal dermal hypoplasia (Goltz) syndrome. Clin Exp Dermatol 16:283-284, 1991
30. Cuzick J, Babiker A, DeStavola BL, et al: Palmar keratoses in family members of individuals with bladder cancer. J Clin Epidemiol 43:1421-1428, 1990
31. de Cholnoky T: Accessory breast tissue in the axilla. NY State J Med 51:2245-2248, 1951
32. Drut R, Jones MC: Congenital pancreatoblastoma in Beckwith-Wiedemann syndrome: An emerging association. Pediatr Pathol 8:331-339, 1988
33. Edwards JM, Cooper MACS, Bannerjee S: Congeni- tal epidermolytic hyperkeratosis associated with multiple malignancies [letter]. Br J Dermatol 120:141-144, 1989
34. Emery LG, Shields M, Shah N, et al: Neuroblastoma associated with Beckwith-Wiedemann syndrome. Cancer 52:176-179, 1983
35. Engstrom W, Lindham S, Schofield P: Wiedemann- Beckwith syndrome. Eur J Pediatr 147:450-457, 1988
36. Evans W: Polythelia in cardio-arterial disease. Br Heart J 21:130-136, 1959
37. Falik-Borenstein TC, Korenberg JR, Davos I, et al: Congenital gastric teratoma in Wiedemann-Beck- with syndrome. Am J Med Genet 38:52-57, 1991
38. Friedel R: Ein fibroadenom einer nebenbrustdruse im rechten labium maius. Virchow Arch Path Anat 286:62-69, 1932
39. Friedman RJ, Rigel DS, Silverman MK, et al: Malig- nant melanoma in the 1990’s: The continued impor- tance of early detection and the role of physician examination and self-examination of the skin. CA 41:201-226, 1991
40. Fusaro RM, Lynch HT: Conceptual differences on the occurrence of internal malignancies in the FAMMM syndrome [letter]. J Am Acad Dermatol 30:672-674, 1994
41. Garganta CL, Bodurtha JN: Report of another family with Simpson-Golabi-Behmel syndrome and a re- view of the literature. Am J Med Genet 44:129-135, 1992
42. Goedert JJ, McKeen EA: Accessory nipples (AN) and renal cell carcinoma (RCC) [Abstract C-519]. Proceedings of the Seventeenth Annual Meeting of the American Society of Clinical Oncology, Wash- ington, DC, April 30 to May 2, 1981
43. Goedert JJ, McKeen EA, Fraumeni JF Jr: Polymastia and renal adenocarcinoma. Ann Intern Med 95:182- 184, 1981
44. Goedert JJ, McKeen EA, Javadpour N, et al: Poly- thelia and testicular cancer. Ann Intern Med 101:646-647, 1984
45. Greene HJ: Adenocarcinoma of supernumerary breasts of the labia majora in a case of epidermoid
carcinoma of the vulva. Am J Obstet Gynecol 31:660-663, 1936
46. Greene MH, Tucker MA, Clark WH Jr, et al: Heredi- tary melanoma and the dysplastic nevus syndrome: The risk of cancers other than melanoma. J Am Acad Dermatol 16:792-797, 1987
47. Guerry RL, Pratt-Thomas HR: Carcinoma of super- numerary breast of vulva with bilateral mammary cancer. Cancer 38:2570-2574, 1976
48. Guest EM: Polythelia [letter]. Br Med J 2:85, 1923
49. Hacham-Zadeh S, Goldberg L: Malignant melanoma and Papillon-Lefevre syndrome. Arch Dermatol 118:2, 1982
50. Haines D: Primary carcinoma duplex associated with tylosis. J R Nav Med Serv 53:75-78, 1967
51. Halal F, Setton N, Wang N-S: A distinct type of hidrotic ectodermal dysplasia. Am J Med Genet 38:552-556, 1991
52. Halper S, Rubenstein D: Aplasia cutis congenita associated with syndactyly and supernumerary nip- ples: Report of a second family with similar clinical findings. Pediatr Dermatol 8:32-34, 1991
53. Harper R: Supernumerary nipples and neurosis. Lancet 1:899-903, 1948
54. Harper PS, Harper RMJ, Howel-Evans AW: Carci- noma of the oesophagus with tylosis. Q J Med 39:317-333, 1970
55. Hassim AM: Bilateral fibroadenoma in supernumer- ary breasts of the vulva. J Obstet Gynecol 76:275- 277, 1969
56. Hendrix RC, Behrman SJ: Adenocarcinoma arising in a supernumerary mammary gland in the vulva. Obstet Gynecol 8:238-241, 1956
57. Hersh JH, Bloom AS, Cromer AO, et al: Does a supernumerary nipple/renal field defect exist? Am J Dis Child 141:989-991, 1987
58. Hodge JA, Ray MC, Flynn KJ: The epidermal nevus syndrome. Int J Dermatol 30:91-98, 1991
59. Hogan DJ, Zeide DA: French society of dermatol- ogy: Spring meeting, Paris, France, March 14-16, 1985 [meeting report]. J Am Acad Dermatol 15:1309-1313, 1986
60. Hornstein OP, Knickenberg M: Perifollicular fi- bromatosis cutis with polyps of the colon-A cuta- neo-intestinal syndrome sui generis. Arch Dermatol Res 253:161-175, 1975
61. Howel-Evans W, McConnell RB, Clarke CA, et al: Carcinoma of the oesophagus with keratosis pal- maris et plantaris (tylosis): A study of two families. Q J Med 27:413-429, 1958
62. Iwai T: A statistical study on the polymastia of the Japanese. Lancet 2:753-759, 1907
63. Joannides T, Pringle JAS, Shaw DG, et al: Giant cell tumour of bone in focal dermal hypoplasia. Br J Radiol 56:684-685, 1983
64. Kajava Y: The proportions of supernumerary nip- ples in Finnish population. Duodecim 31:143-170, 1915
65. Kaplan MS, Opitz JM, Gosset FR: Noonan syn- drome: A case with elevated serum alkaline phos- phatase levels and malignant schwannoma of the left forearm. Am J Dis Child 116:359-366, 1968
66. Kenney RD, Flippo JL, Balck EB: Supernumerary nipples and renal anomalies in neonates. Am J Dis Child 141:987-988, 1987
67. Khanna SK, Agnone FA, Leibowitz AI, et al: Nonfa- milial diffuse palmoplantar keratoderma associated with bronchial carcinoma. J Am Acad Dermatol 28:295-297, 1993
68. Landy SJ, Donnai D: Incontinentia pigmenti (Bloch- Sulzberger syndrome). J Med Genet 30:53-59, 1993
69. Leung AKC: Familial supernumerary nipples. Am J Med Genet 31:631-635, 1988
70. Leung AKC: Polythelia. Int J Dermatol 28:429-433, 1989
71. Leung AKC, Robson WLM: Renal anomalies in fa- milial polythelia [letter]. Am J Dis Child 144:619- 620, 1990
72. Lodeiro JG, Byers JW III, Chuipek S, et al: Prenatal diagnosis and perinatal management of the Beck- with-Wiedemann syndrome: A case and review. Am J Perinatol 6:446-449, 1989
73. Lopez M, Papaldo P, Sciarretta F, et al: Congenital ichthyosis and endodermal sinus tumor of the ovary in a ten year old child. Med Pediatr Oncol 11:238- 241, 1983
74. Lykkesfeldt G, Bennett P, Lykkesfeldt AE, et al: Testis cancer: Ichthyosis constitutes a significant risk factor. Cancer 67:730-734, 1991
75. Lykkesfeldt G, Hoyer H, Lykkesfeldt AE, et al: Ste- roid sulphatase deficiency associated with testes cancer. Lancet 2:1456, 1983
76. Lynch HT, Fusaro RM: Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome. Pancrease 6:127-131, 1991
77. Lynch HT, Fusaro RM, Kimberling WJ, et al: Famil- ial atypical multiple mole-melanoma (FAMMM) syndrome: Segregation analysis. J Med Genet 20:342-344, 1983
78. Lynch HT, Fusaro RM, Pester J, et al: Tumour spec- trum in the FAMMM syndrome. Br J Cancer 44:553- 560, 1981
79. Marger RS, Marger D: Carcinoma of the esophagus and tylosis: A lethal genetic combination. Cancer 72:17-19, 1993
80. Marghoob AA, Orlow SJ, Kopf AW: Syndromes as- sociated with melanocytic nevi. J Am Acad Derma- tol 29:373-388, 1993
81. Martin VG, Pellettiere EV, Gress D, et al: Paget’s disease in an adolescent arising in a supernumerary nipple. J Cutan Pathol 21:283-286, 1994
82. McManamny DS, Barnett JS: Macroglossia as a pre- sentation of the Beckwith-Wiedemann syndrome. Plastic Reconstruct Surg 75:170-176, 1985
83. Meggyessy V, Mehes K: Association of supernumer- ary nipples with renal anomalies. J Pediatr 111:412- 413, 1987
84. Mehes K: Association of supernumerary nipples with other anomalies. J Pediatr 95:274-275, 1979
85. Mehes K: Association of supernumerary nipples with other anomalies [letter]. J Pediatr 102:161, 1983
86. Mehes K, Szule E, Torzsok F, et al: Supernumerary nipples and urologic malignancies. Cancer Genet Cytogenet 24:185-188, 1987
87. Miller RW: Neoplasia and Down’s syndrome. Ann NY Acad Sci 171:637-644, 1970
88. Mimouni F, Merlob P, Reisner SH: Occurrence of supernumerary nipples in newborns. Am J Dis Child 137:952-953, 1983
89. Murata Y, Kumano K, Tani M, et al: Acquired dif- fuse keratoderma of the palms and soles with bron- chial carcinoma: Report of a case and review of the literature [letter]. Arch Dermatol 124:497-498, 1988
90. Myrianthopoulos NC, Chung CS: Congenital mal- formations in singletons: Epidemiologic survey: Re- port from the Collaborative Perinatal Project. Birth Defects 10:1-58, 1974
91. Nakano J, Muto M, Arikawa K, et al: Acral lentigi-
nous melanoma associated with Down’s syndrome. J Dermatol (Tokyo) 20:59-60, 1993
92. NIH Consensus Development Panel on Early Mela- noma: Diagnosis and treatment of early melanoma. JAMA 268:1314-1319, 1992
93. Paller AS: Epidermal nevus syndrome, Neurol Clin 5:451-457, 1987
94. Parnell DD, Johnson SAM: Tylosis palmaris et plan- taris: Its occurrence with internal malignancy. Arch Dermatol 100:7-9, 1969
95. Parker SC, Schofield OMV, Black MM, et al: Non- lethal junctional epidermolysis bullosa complicated by squamous cell carcinoma. In Priestley GC, Tid- man MJ, Weiss JB, et al (eds): Epidermolysis Bullosa: A Comprehensive Review of Classification, Man- agement and Laboratory Studies. Crowthorne, Berk- shire, United Kingdom: Dystrophie Epidermolysis Bullosa Research Association, 1990, pp 103-106
96. Patterson GT, Ramasastry SS, Davis JU: Macro- glossia and ankyloglossia in Beckwith-Wiedemann syndrome. Oral Surg Oral Med Oral Pathol 65:29- 31, 1988
97. Pellegrini JR, Wagner RF Jr: Polythelia and associ- ated conditions. Am Fam Phys 28:129-132, 1983
98. Pettenati MJ, Haines JL, Higgins RR, et al: Wiede- mann-Beckwith syndrome: Presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 74:143-154, 1986
99. Piepkorn MW, Barnhill RL, Cannon-Albright LA, et al: A multiobserver, population-based analysis of histologic dysplasia in melanocytic nevi. J Am Acad Dermatol 30:707-714, 1994
100. Piombo M, Rosanda C, Pasino M, et al: Acute lymphoblastic leukemia in Noonan syndrome: Re- port of two cases. Med Pediatr Oncol 21:454-455, 1993
101. Powell F, Mackey JP: Bronchial carcinoma and hy- perkeratosis palmaris et plantaris. Postgrad Med J 57:57-59, 1981
102. Rickert RR: Intraductal papilloma arising in super- numerary vulvar breast tissue. Obstet Gynecol 55(suppl):845-875, 1980
103. Roberts JT, Byrne ER, Rosenthal D: Familial variant of dermatofibroma with malignancy in the proband. Arch Dermatol 117:12-15, 1981
104. Roberts WM, Jenkins JJ, Moorhead EL II, et al: In- continentia pigmenti, a chromosomal instability syndrome, is associated with childhood malignancy. Cancer 62:2370-2372, 1988
105. Rongioletti F, Hazini R, Gianotti G, et al: Fibrofolli- culomas, tricodiscomas and acrochordons (Birt- Hogg-Dube) associated with intestinal polyposis. Clin Exp Dermatol 14:72-74, 1989
106. Rosner F, Lee SL: Down’s syndrome and acute leu- kemia: Myeloblastic or lymphocytic? Am J Med 53:203-218, 1972
107. Roth JS, Rabinowitz AD, Benson M, et al: Bilateral renal cell carcinoma in the Birt-Hogg-Dube syn- drome. J Am Acad Dermatol 29:1055-1056, 1993
108. Ruzicka T, Goertz G, Anton-Lamprecht I: Syndrome of ichthyosis congenita, neurosensory deafness, oli- gophrenia, dental aplasia, brachydactyly, clinodac- tyly, accessory cervical ribs and carcinoma of the thyroid. Dermatologica 162:124-136, 1981
109. Saleh HA, Klein LH: Cystosarcoma phylloides aris- ing synchronously in right breast and bilateral axil- lary ectopic breast tissue. Arch Pathol Lab Med 114:624-626, 1990
110. Schwindt WD, Bernhardt LC, Johnson SAM: Tylosis and intrathoracic neoplasms. Chest 57:590-591, 1970
111. Shapiro LJ: Steroid sulfatase deficiency and the ge- netics of the short arm of the human X chromosome. In Harris H, Hirschhorn K (eds): Advances in Hu- man Genetics. New York, Plenum Press, 1985, pp 331-381
112. Shine 1, Allison PR: Carcinoma of the oesophagus with tylosis (keratosis palmaris et plantaris). Lancet 1:951-953, 1966
113. Siegler AM, Gordon R: Fibroadenoma in a supernu- merary breast of the vulva. Am J Obstet Gynecol 62:1219-1224, 1951
114. Simon M Jr, Hornstein OP, Haneke E: Perifollicular fibromatoses. A cutaneous paraneoplastic disease? Hautarzt 33:481-483, 1982
115. Singh J, Singh B, Chander J: Extramammary cysto- sarcoma phylloides with bilateral breast involve- ment. Aust NZ J Surg 50:56-58, 1980
116. Solomon LM, Esterly NB: Epidermal and other con- genital organoid nevi. Curr Prob Pediatr 6:1-56, 1975
117. Sotelo-Avila C, Gonzalez-Crussi F, Fowler JW: Com- plete and incomplete forms of Beckwith-Wiede- mann syndrome: Their oncogenic potential. J Pedi- atr 96:47-50, 1980
118. Sotelo-Avila C, Gooch WM 3rd: Neoplasms associ- ated with the Beckwith-Wiedemann syndrome. Per- spect Pediatr Pathol 3:255-272, 1976
119. Tidman MJ: Skin malignancy in epidermolysis bul- losa. In Priestley GC, Tidman MJ, Weiss JB, et al (eds): Epidermolysis Bullosa: A Comprehensive Re- view of Classification, Management and Laboratory Studies. Crowthorne, Berkshire, United Kingdom: Dystrophic Epidermolysis Bullosa Research Associ- ation, 1990, pp 156-160
120. Toumbis-Ioannou E, Cohen PR: Familial polythelia. J Am Acad Dermatol 30:667-668, 1994
121. Traupe H, Vehring K-H: Unstable pre-mutation may explain mosaix disease expression of inconti- nentia pigmenti in males. Am J Med Genet 49:397- 398, 1994
122. Tucker MA, Fraser MC, Goldstein AM, et al: Risk of melanoma and other cancers in melanoma-prone families. J Invest Dermatol 100:350S-355S, 1993
123. Tyldesley WR: Oral leukoplakia associated with ty- losis and oesophageal carcinoma. J Oral Pathol 3:62- 70, 1974
124. Tyldesley WR, Hughes RO: Tylosis, leukoplakia, and oesophageal carcinoma [letter]. Br Med J 4:427, 1973
125. Urmacher C, Shiu MH: Malignant melanoma in as- sociation with keratosis palmaris et plantaris (epi- dermolytic hyperkeratosis variant). Am J Dermato- pathol 7:187-190, 1985
126. Varsano IB, Jaber L, Garty B-Z, et al: Urinary tract abnormalities in children with supernumerary nip- ples. Pediatrics 73:103-105, 1984
127. Vink J, Crijns MB, Mooy CM, et al: Ocular mela- noma in families with dysplastic nevus syndrome. J Am Acad Dermatol 23:858-862, 1990
128. Walach N: Congenital ichthyosis and medulloblas- toma. Dermatologica 154:49-52, 1977
129. Walker AN, Fectiner RE: Papillary carcinoma aris- ing from ectopic breast tissue in an axillary lymph node. Diag Gynecol Obstet 4:141-145, 1982
130. Wiedemann HR: Complex malformatif familial avec hernie ombilicale et macroglossie. Un syndrome no- veau? J Genet Hum 13:223-232, 1964
131. Wiedemann HR: Tumours and hemihypertrophy associated with Wiedemann-Beckwith syndrome [letter]. Eur J Pediatr 141:129, 1983
132. Weintraub R, Pinkus H: Multiple fibrofolliculomas (Birt-Hogg-Dube) associated with a large connective tissue nevus. J Cutan Pathol 4:289-299, 1977
133. Wojciechowski AH, Pritchard J: Beckwith-Wiede- mann (exomphalos-macroglossia-gigantism-EMG) syndrome and malignant lymphoma. Eur J Pediatr 137:317-321, 1981
134. Yesudian P, Premalatha S, Thambia AS: Genetic tylosis with malignancy: A study of a south Indian pedigree. Br J Dermatol 102:597-600, 1980
135. Yoshioka K, Kono T, Kitajima J, et al: Squamous cell carcinoma developing in epidermolysis bullosa dystrophica. Int J Dermatol 30:718-721, 1991
136. Young AE, Ackroyd J, Baskerville P: Combined vas- cular malformations. In Mulliken JB, Young AE (eds): Vascular Birthmarks: Hemangiomas and Mal- formations. Philadelphia, WB Saunders, 1988, pp 246-274
137. Zohar Y, Laurian N: Bifid condyle of the mandible with associated polythelia and manual anomalies. J Laryngol Otol 101:1315-1319, 1987
Address reprint requests to Philip R. Cohen, MD Department of Dermatology University of Texas-Houston Medical School 6431 Fannin, Suite 1.186 Houston, Texas 77030