Multiple Lentigines Syndrome Case Report and Review of the Literature

DAVID A. VORON, M.D.’ HAYES H. HATFIELD, M.D. RONALD K. KALKHOFF, M.D. Milwaukee, Wisconsin

The multiple lentigines syndrome is reviewed and a new case is presented. The major features of this syndrome are lentigtnes and other cutaneous abnormalities, cardiac defects, neurologic defects, cephalofacial dysmorphism, shortness of stature, skeletal anoma!ies, genitourinary abnormalities, and a family history consistent with an autosomal dominant mode of inheritance. the multiple lentlgines syndrome manifests markedly variable expressivity; no single finding is pathognomonic and few patients have all major features. We propose specific criteria for diagnosis. The multiple lentigines syndrome is a complex dysmorphogenetic disorder transmitted as an autosomal dominant trait with variable penetrance and expressivity. Synonyms for this condition include Leopard syndrome [l-7], progressive cardiomyopathic lentiginosis [ 81, cardiocutaneous syndrome [ 9- 111, and lentiginosis profusa syndrome [ 7,12,13]. In recent years this multifaceted syndrome has attracted the interest of dermatologists [ 5-7,12-221, pediatricians [4,8,23-301, cardiologists [31-351, endocrinologists [36], orthopedists [37] and radiologists [ 381. Precise definition of the multiple lentigines syndrome is difficult because of the absence of any pathognomonic morphologic or biochemical markers. Several recent reports of “new findings” in isolated patients or families add to the problem of determining criteria for diagnosis. We review previously reported cases in an attempt to define this syndrome as precisely as possible. In addition, we present a detailed endocrinologic investigation of a new patient with the multiple lentigines syndrome. CASE REPORT

From the Dermatology and Endocrine-Metabolic Sections of the Department of Medicine, The Medical College of Wisconsin, Milwaukee, Wisconsin. Requests for reprints should be addressed to Dr. Hayes H. Hatfield, EndocrineMetabolic Section, Milwaukee County General Hospital, 8700 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. Manuscript accepted July 25, 1975. Present address: Suite 205, 612 West Duatte Road, Arcadia, California 91006. l

A 16 year old white boy presented with a complaint of short stature. He was the product of a full-term, uncomplicated pregnancy. His birth weight was 3.09 kg and length, 45.7 cm. He reached developmental milestones slightly late, crawling at 12 months and walking at 24 months. He has remained below the 10th percentile in both height and weight. His intelligence seems to be normal as he is a B-C student in the appropriate grade in school. At the age of 14 the patient fractured his left clavicle. This has been very slow to heal. Although there is exuberant callus formation, there still is not a solid union. The patient fractured this bone twice in the past and it seemed to heal normally. He was completely asymptomatic from a car-

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ET AL.

vicular line. There were no heaves or thrills. There was a grade 2/6 systolic ejection murmur at the pulmoniC area. The genitalia were prepubertal, without axillary, pubic or facial hair growth. The skin was of velvety smooth texture, covered with myriads of light to dark brown macules in all areas, and hyperelastic (Figure 2). There was a 3 cm by 3 cm nodule palpable at the fracture site in the clavicle. There was an asymmetric rib cage with marked predominance of the left anterior hemithorax. This has increased in prominence over the past six months. Certain joints, especially those of the fingers and wrists w&e hypermobile (Figure 3). The knees were unstable with a positive drawer sign. Other joints, such as those of the hips and vertebral column, were not hypermobile. The hemoglobin level, hematocrit value, white blood cell count and differential count were normal. Also normal were serum electrolytes, total protein and albumin, calcium, phosphorus, bilirubin, blood urea nitrogen, creatinine, fasting glucose, serum glutamic oxaloacetic transaminase @GOT), uric acid and urinalysis. Alkaline phosphatase level was 23 KAU (N = 4 to 17). Chest, skull roentgenograms and intravenous pyelogram were normal. An electrocardiogram showed left axis deviation. A pure tone au-

Figure 1. Numerous lentigines are present on chest, arms and face. Note mandibular prognathism and epicanthal folds. diorespiratory standpoint. He had not yet entered puberty. The only significant finding in his past medical history was the fact that he had had a bilateral inguinal herniorrhaphy at five weeks of age. The patient’s father, age 54, is 185 cm tall and has advanced coronary vascular disease. His mother, age 45, is 170 cm tall and has many brown macules on her trunk, although they are not as numerous as the patient’s. The patient has two brothers, one aged 16 who is 188 cm tall, and another aged 18 who is over 180 cm tall. There is no family history of delayed puberty or other similar problems. On physical examination the patient (Figure 1) was frail and slender. His face had a triangular appearance with prominence of the chin. His height was 156 cm; pubis to floor measurement, 75.5 cm; pubis to vertex, 80.5 cm; arm span, 179.4 cm; weight, 38.5 kg; blood pressure, 90/55 mm Hg; pulse rate, 80/min and regular. Abnormal physicat findings were confined to the heart, genitalia, skin and skeleton. The cardiac examination revealed the point of maximal impulse to be in the fifth intercostal space in the mid-cla-

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Figure 2.

60

Hyperelastic skin of the forearm.

MULTIPLE LENTIGINES SYNDROME-VORON

diogram was normal. Bone age was 11 years, 6 months at a chronologic age of 14 years, 6 months. A subsequent bone age of 13 years, 3 months corresponded to a chronologic age of 15 years, 6 months. Endocrine evaluation (Table I) was consisten! with a prepubertal state. Growth hormone levels were determined using a modification of the method of Catt [39]. Because of the question of connective tissue disturbances a mucopolysaccharide screening test [40] was performed at Milwaukee Childrens’ Hospital. Total hydroxyproline determination and qualitative tests for homogentisic acid, cystine and homocystine were performed by Bioscience Laboratories. These tests were nondiagnostic. A skin biopsy specimen (Figure 4) was diagnostic of a lentigo. The patient was seen in consultation by the dermatology service, and the diagnosis of multiple lentigines syndrome was made. Because of delayed puberty the administration of intramuscular testosterone cypionate was begun, 50 mg monthly for two months, and 100 mg monthly for four months [41]. There was a marked increase in penile size, pubic hair growth and some increase in muscle bulk. (Figure 5). The patient did manifest a growth spurt that continued after the

TABLE

-

I

Endocrine

_--___

Evaluations

-_-

Serum protern bound iodine (pg/lOO ml) Serum follrcle stimulating hormone ~mlUimi~ Serum luteinrzing hormone (mllJ/ml) Serum testosterone f&g/100 ml) 24 hr urinary 17-ketogenic steroids lmg/24 hr) 24 hr urinary 17-ketosteroids (mg/24

ET AL.

6.6

(N =,4-8)

9

1N = 2-50)

6

(N = 5-100)

0.086

(N = 0.2-l

7.3

(N = 5-17)

3.9

(N = 8-22)

.I

1

hr)

Intravenous arginine infusion test* Plasma growth hormone (ng/ml) 0 min. 15 min. 30 min. 45 mtn. 60 min. 90 mm.

6.3 6.3 15.9 33.1 33.8 15.0

* 1 g/min from 0 to 30 minutes as a 5 per cent solutron.

administration of testosterone was discontinued. No other secondary sex changes developed until his last visit one year after he received his last injection of testosterone. At that time he had deepening of his voice and gynecomastia, which we interpreted as early signs of puberty. CLINICAL FEATURES OF THE MULilPLE LENTIGINES SYNDROME

Figure 3.

Hypermobite joints of the wrist and hand.

The clinical features of our patient and those in 79 previously reported cases of the multiple lentigines syndrome are summarized in Table II. Forty-seven patients were male and 30 female; sex was not specified in three cases. Median age at the time of diagnosis was 14 years. Lentignes. The names multiple lentigines syndrome, progressive cardiomyopathic lentiginosis and lentiginosis profusa syndrome all suggest that lentigines are an essential feature of this syndrome. However, Gorlin [ 11, one of the first to carefully delineate this condition, now believes that many of these patients do not have lentigines [3]. He and his associates have described several patients without lentigines as having the multiple lentigines syndrome [i31. Watson [23] and Korexinidis and his co-workers [42] have also described patients with features of the multiple lentigines syndrome, but without lentigines. Some of these patients had relatives with well expressed multiple lentigines syndrome, but others did not. Because of the striking appearance of multiple lentigines, it Is possible that they have been overemphasized as a feature of this syndrome. Nevertheless, until more bona fide cases of “multiple lentigines syndrome sine lentigines” are identified, we believe that multiple lentigines should be present in the patient or in an immediate relative with other characteristics of the syndrome before a diagnosis

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Figure 4. Biopsy specimen of a typical lentigo on patient’s back reveals elongated rete ridges. Basal layer contains numerous, well-melanized melanocytes. Hematoxylin and eosin stain; magnification X 60, reduced by 2 per cent.

of this disorder can be considered. Patients with several features of the multiple lentigines syndrome, but who lack lentigines and a positive family history, may have Noonan’s syndrome, which is characterized. by many of the same anomalies, with the notable exception of lentigines [43]. Lentigines are brown macules, usually 2 to 8 mm in diameter, but sometimes larger. In the multiple lentigines syndrome, they are usually most heavily concentrated on the upper part of the trunk and neck, but they are also often present on the face, scalp, limbs, palms, soles and genitalia. The mucous membranes are invariably spared. Lentigines are present at birth or appear during childhood, and they become more numerous and darker with age. They should be distinguished from freckles (ephelides), which appear later in life and are induced by exposure to sunlight. Freckles are also generally lighter in color than lentigines. Junctional nevi may be difficult to distinguish clinically from lentigines, but the former rarely appear in the abundant numbers characteristic of multiple lentigines. Biopsy of a lentigo (Figure 4) reveals an increased number of melanocytes per unit skin area and prominent rete ridges. Other Cutaneaus Abnormalities. In addition to lentigines, a variety of unusual skin findings were noted in 20 patients. Axillary “freckling,” previously thought to be pathognomonic of von Recklinghausen’s neurofibromatosis [44], was observed in three patients. Fifteen patients had cafe au lait spots. These light brown patches are also found in neurofi450

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bromatosis and Albright’s syndrome, and are occasionally seen in normal persons. Careful histologic examination of the cafe au lait spots and axillary freckling in neurofibromatosis has revealed increased numbers of active melanocytes with characteristic giant pigment granules [45]. Comparable investigations have not yet been undertaken in patients with the multiple lentigines syndrome. Localized hypopigmentation Was noted in two cases. In one patient, hypopigmented macules appeared where lentigines previously existed [ 12,131. Interestingly, other pigmented tesions, such as nevocellular nevi and malignant melanomas also occasionally undergo, depigmentation. The significance of this process is unknown. Dermatoglyphic abnormalities were reported in five patients. Interdigital webs were observed in a mother and daughter with the multiple lentigines syndrome. In both cases, hyperextensibility of the thumb and index finger was an associated feature. Onychodystrophy in the form of koilonychia and longitudinal ridging was identified in one patient. Multiple granular cell myoblastomas have been reported in one patient with the multiple lentigines syndrome. This tumor is believed to arise from Schwann cells, which, like melanocytes, are derived from the neural crest. Selmanowltz and his associates [ 12,131 believe that this common origin suggests a possible relationship between the lentigines and granular celi tumors in this patient.

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ET AL.

Wt. kgs

Wt kgs.

75

75

D. S. fl2//3/58 70_ 65 60. 55. 50_ 45_ 40_

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Age - Years Figure 5. Growth record of our patient showing initiation and termination of testo&erone treatment.

Our patient’s skin was clinically hyperelastic, but biopsy revealed normal collagen and elastic tissue. Cardiac Abnormalities. Pulmonic stenosis of the valvular type was the most common structural defect. Several investigators believe that cardiomyopathy is an important feature of the multiple lentigines syndrome [ 8,341. Seventeen patients had documented cardiomyopathy, and this was predominantly obstructive in type. Several other types of structural defects were found, including one case of, left atrial myxoma. Electrocardiograms generally reflected the underlying structural anomalies. Left axis deviation, however, was seen in almost one third of the cases in which electrocardiographic information was given. The majority of patients were not symptomatic from a cardiac standpoint. One patient with severe cardiomyopathy died during cardiac surgery [8], and

another with severe pulmonary stenosis died shortly after cardiac surgery [ 231. Sudden death occurred in a 14 year old boy \ivith severe cardiomyopathy [8]. Genitourinary Abnormalities. The predominance of males with genitourinary abnormalities was striking. Since most anomalies involved visible genitalia, male predominance may simply be a reflection of this fact. Cryptorchid testes, the most frequent anomaly, was reported in 12 patients. This was most often bilateral. Several isolated genitourinary anomalies were reported (Table II). Hormonal therapy to bring the testes into the scrotum was attempted in three cases [ 1,3,28]; it was successful in only one [ 31. Endocrine Findings. Growth hormone levels were determined in five patients. Two patients had normal basal determinations [8]. One patient had a normal provocative test using tolbutamide as the stimulus [8], and two patients, including our own, had normal

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TABLE

II

Features

ET AL.

in 80 Patients with Multiple

Lentigines

Syndrome

Feature

No. of Patients

Lentigines

74

Other cutaneous abnormalities Axillary “freckling” Cafe au lait spots Localized hypopigmentation Dermatoglyphic abnormalities Interdigital webs Onychodystrophy Multiple granular cell myoblastomas Hyperelasticity Cardiac abnormalities: structural Pulmonary valve stenosis alone Valvular lnfundibular Type not determined Murmur compatible with but not diagnostic Aortic valve stenosis (all infundibular) Aortic and pulmonic stenosis (all infundibular) Other structural defect Obstructive cardiomyopathy, type not mentioned Cardiomyopathy and mitral insufficiency Complete heart block and cardiomyopathy Left atria1 myxoma Murmur present but not characterized Cardiac abnormality: electrocardiographic Left axis deviation

22

References

[ 1,3-5.7-9,1122,24-38,47,49,*1

Right bundle branch block Electrocardiogram, other Abnormal S waves (S,,,,,

3 15 3 5 3 1 1 1

Paroxysmal atrial tachycardia Sudden death Death at cardiac surgery Genitourinary Male

[12,131 [12,131 *

49 32 14 4 6 8 4 3 10 4

[1,3,4.16.241 i3.24.25.381 i8.281 [5.11,331 [8.12.421

39 15

[1,9,12,13,16,21, 28.33.42,“)

8 16

[3,4,9,27.311 L3.301 [7,28,30,371 [81 [Ill [311 [41’ [311 [221 [381

10 8 1 1 1 2

I

i8.23.31 I41 [311 [81 L8.231

21 18

[1,3,7,8,10,16,18,20, 23,28,29.36,40,“1

3 12

L8.33.371 4 8

Unilateral Bilateral Delayed puberty Hypospadius Miscellaneous abnormalities Absent right ovary and cystic hyperplastic left ovary Small penis attached to anterior abdominal wall Absent left kidney and ureter, right hydroureter Delayed menstruation Double right ureter

6 2 5

[ 1,23,401 [3,7,8,16,20,28,301 [3,8,29,36,42,*1 LT.81 (81 181 L3.361 1371 [331

Continued

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[1,4,7,8,23,27,381 [3,23,28,301

[I71 [311 [351 [4.10.371

Female Cryptorchidism

March 1976

[4,8,9,22,23.27.491 [9,12,13,491 [12,13,19,20,25,261 [12,13,221

or S, ,_s)

Right ventricular hypertrophy Left ventricular hypertropy Left and right ventricular hypertrophy Right axis deviation and paroxysmal atrial tachycardia Premature ventricular contractions Complete heart block Low voltage Abnormality, type not mentioned Cardiac symptoms Dyspnea on exertion Maternal congestive heart failure

452

[12,13,22,*1

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MULTIPLE LENTIGINES SYNDROME-VGRON

TABLE

II (Cont’d)

Features .I_-

in 80 Patients

Mental retardation

Abnormal

Lentigines

Syndrome References

No. of Patients

Feature

Endocrine (work-up reported) Normal growth hormone Gonadotropins Normal Low Normal PBI or T, Borderline abnormal 113’ uptake Urinary 17-ketosteroids Normal Low High Urinary 17.hydroxysteroids Normal High Normal plasma cortisol Normal catecholamine, vanillylmandelic Neurologic defects Sensorineural deafness

Oculomotor

with Multiple

[3,8,12,13,21,491

13 5

[8,21,*1

5

[8,21 .*I r3.361 [3,8,21,28,31,36,37,*1

8 2

acid

7 1 1

[12,21,28,491

7 1

[3,12,21,28,36,*1

3

[21,30,311

18 23 16

defects

11

electroencephalogram

Mandibular prognathism Broad nasal root Dysmorphic skull Low-set ears Dental abnormalities High palatal arch Ptosis of upper lids Epicanthal folds Lateral canthi lower than medial canthi Cleft palate Shortness of stature Less than 3rd percentile

[491

;81

El [211

50

(mild)

Seizures Hyposmia Slowed peripheral nerve conduction Cephalofacial dysmorphism Ocular hypertelorism

ET AL.

2 1 1

[1,12,13,18,21,23,25, 26,28,30,361 [1,3,4,8,16,21,22,23, 27,28,34,36,491 [9,12,13,18,20, 27,47,491 [7,8,15;16,21, 28,34,491 L8.161 [361 [211

30 20

[1,3,4,8,12,13,18,22, 27.29,37,491 ~1,4,20,35,47,48,*1 [4,21,22,27,351 [12,13,20,27,491 [18,37.*1 [22,28,481 [20,21,481 L20.281

[22.“1 [281 [211 25 16

[1,3,7,8,9,16,18. 28,31,371

Skeletal anomalies Pectus carinatum or excavatum Retarded bone age Kyphoscoliosis Winging of scapulas Hypermobile joints Cubitus valgus Rib anomalies Hypoplastic fifth digit Syndactyly Cervical spine fusion Spina bifida occulta Madelung’s deformity of the wrist Delayed healing of fracture Severe scoliosis with posterior spinal fusion Famrly history consistent with autosomal dominant mode of inheritance

5

~1,3,4,8,21.271 r29.321 f4.8.271

8 4 5

~18,21,22,24,38,47,*1 [15,21,28,34,37, 'I [15,22,23,34,491

4

[3,18,30,*1

3 3 1 1 1 1 4 1 1 1

I11,13,*1 [4,15,24,341

7 2

Between 3rd and 25th percentile “Short” Birth weight under 25th percentile

26

53

[31 [I91 [261 [381 [21,491 Lg.341 * [371 [1,3-6,8-15,23,25,26, 30,31,34,38.47,48,491

*Present case reoort.

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provocative

[211.

tests

using

arginine

ET AL.

as the stimulus

Gonadotropins were measured in six patients. Our patient had follicle stimulating hormone (FSH) and Iuteinizing hormone (LH) values in the low normal range. One patient was especially interesting in that he presented with low FSH and LH levels which did not rise appropriately when stimulated with clomiphene [3,36]. This patient also had hyposmia, fitting the description of Kallman’s syndrome. Thyroid studies were normal in eight cases; however, one patient, who was known to have been hypothyroid since age three, was taking thyroid replacement [37]. Two other patients were noted to be “hypothyroid” clinically but had borderline 113’ uptake values [49]. Basal adrenal testing was carried out in nine patients. Results were normal in all but one. This patient had elevated values for 17-hydroxy and 17-ketosteroids. However, no details were given [8]. One patient had a Metopironem provocative test that was normal [21]. Only two patients had sufficient data available to make a definite endocrine diagnosis. One, as mentioned, was found to be hypothyroid at age three. The other patient fits the pattern of hypogonadotropic hypogonadism [3,36]. Although our patient was hypogonadal and had low normal serum FSH and LH [3,36], it is difficult to differentiate delayed puberty from hypogonadotropic hypogonadism in a 16 year old patient. Indeed, from our most recent examination, it would appear that our patient may well be entering puberty at this time. Although few detailed endocrine evaluations have been made on patients with this syndrome, it would appear that endocrine deficiency states are not a prominent feature, with the possible exception of delayed puberty. It will be important in the future to study and closely follow these patients to see if a significant number of them do have true hypogonadism. In view of the theoretic possibility of circulating melanin metabolites in this syndrome, three patients had catecholamine or catecholamine metabolite determinations [21,31]. These determinations were normal. Neurologic Defects. Several investigators have attempted to attribute the sensorineural hearing loss found in many patients with multiple lentigines syndrome to a primary abnormality in neural crest development [ 8,12,13,2 11. Melanocytes participate in the formation of the inner ear, and the association of hearing defects and pigmentary abnormalities is seen in Waardenburg’s syndrome and the Vogt-Koyanagi-Harada syndrome, as well as in the multiple lentigines syndrome. Hereditary deafness in Dalma454

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tian dogs [46] may represent a partial canine analogue of the multiple lentigines syndrome in human subjects. Among the patients who manifested oculomotor defects were eight members of one family who had a combination of multiple lentigines and nystagmus

[471. Swanson and his associates [36] described a patient with the multiple lentigines syndrome and hyposmia. This patient also had hypogonadotropism; these investigators theorized that both defects might be attributable to a central developmental abnormality, possibly in the hypothalamic region. Cephalofacial Dysmorphism. The most common feature was ocular hypertelorism. Other features, as listed in Table II, are similar to those found in a variety of genetic syndromes. Short Stature. Birth weights were normal in six of the 11 cases reported, suggesting that the growth lag may begin after birth and then continue until growth stops. Growth retardation is not related to other coexisting abnormalities, as there was no predominance of severe systemic disease in patients with retarded growth. Endocrine studies, as detailed previously, do not support an endocrine cause for short stature, although delayed or absent puberty may be contributory in some cases. It is most likely that shortness of stature represents a defect in skeletal growth center response to physiologic levels of various growth factors and is a manifestation of a mesodermal disorder in this syndrome. Skeletal Anomalies. Fourteen different skeletal anomalies were observed in a total of 26 patients. Most defects were relatively minor. Chest deformity, either pectus carinatum or excavatum, was the most frequently observed abnormality. One patient underwent posterior spinal fusion to prevent progression of severe scoliosis [37]. Family History Consistent with Autosomal Dominant Mode of Inheritance. The family histories of 53 patients were consistent with an autosomal dominant pattern of inheritance. Other patients presumably represent spontaneous mutations or reflect variable penetrance in cases in which a complete family history could not be obtained. Several reports of male-to-male transmissions rule out X-linked inheritance. In families with the syndrome, the affected parent was usually the mother, possibly suggesting more severe hypogonadism in males. The reason for the preponderance of males in our collected cases is unclear. COMMENTS Determination of the true incidence of individual features in the multiple lentigines syndrome is difficult 60

MULTIPLE LENTIGINES SYNDROME-VORON

because in many reports the clinical descriptions are incomplete. In particular, normal findings are often not mentioned, and it is impossible to know whether a specific defect was looked for. Thus, one cannot always accurately compute the incidence of a specific abnormality by using the figures listed in Table II. This is especially true when considering a subtle defect easily overlooked by most investigators, e.g., hyposmia or dermatoglyphic abnormalities. Anomalies recorded in only one or a few patients cannot, of course, be unconditionally accepted as features of the multiple lentigines syndrome, since they may merely represent chance occurrences. In 1969 Gorlin and his colleagues [I] used the mnemonic acronym Leopard to classify the features of the multiple lentigines syndrome as follows: L = conduction delentigines, E = electrocardiographic fects, 0 = ocular hypertelorism, P = pulmonary stenosis, A = abnormalities of genitalia, R = retardation of growth and D = deafness. Although this classification has the advantage of being easily remembered, we believe that the features of this syndrome can best be grouped into the nine categories listed in Table II. The markedly variable expressivity of this syndrome makes establishment of diagnostic criteria difficult. Nevertheless, based on our analysis of the data we have collected, we propose the following minimum criteria for diagnosis: (1) If the patient has multiple lentigines, features in at least two other categories in Table II must be present. (2) If lentigines are absent, a diagnosis of multiple lentigines syndrome may be made if the patient has features in at least three other categories listed in Table II, and has an immediate relative with multiple lentigines syndrome as defined in (1). Of the 80 cases we selected for inclusion in our review, 74 met criteria (1) and six met criteria (2). Cases previously reported as

ET AL.

examples of the multiple lentigines syndrome, but not meeting these criteria, were excluded [3,42]. As more patients with the multiple lentigines syndrome are identified, a clearer picture of the clinical spectrum of this entity should emerge. It is essential that the presence or absence of all pertinent features be documented in individual case reports. Theories regarding the pathogenesis of the multiple lentigines syndrome are entirely speculative. Several investigators have suggested the possibility of a mutation in the embryonic neural crest to explain the presence of cutaneous and neurologic defects [8,12,13,21]. Polani and Moynahan [8] also attribute the cardiac abnormalities in these patients to vasoactive substances produced by abnormal neural crest cells in the heart. Since melanocytes also contribute to the formation of the genitourinary system, these investigators believe that here, too, abnormal neural crest cells are responsible for the ultimate pathology. The skeletal anomalies in these patients cannot be directly attributed to neural crest mutations, since bone is of mesodermal origin. Nordlund and his coworkers [21], however, suggest that in the multiple lentigines syndrome, gene products from a mutant neuroectodermal cell population interact with cells of mesodermal origin to produce the observed abnormalities in mesodermal tissues. Of course, considerable data must be accumulated before these intriguing hypotheses of pathogenesis can be accepted. Most patients with the multiple lentigines syndrome are able to lead normal lives. Heart disease, especially obstructive cardiomyopathy, causes the greatest morbidity, and has been responsible for the few deaths reported. Cardiac pathology in the multiple lentigines syndrome is often progressive and patients should be reevaluated at frequent intervals.

REFERENCES

2. 3.

4.

5. 6. 7.

6. 9.

Gorlin RJ, Anderson RD, Blaw M: Multiple lentigines syndrome. Am J Dis Child 117: 652. 1969. Gorlin RJ, Sedan0 H: Leopard syndrome. Mod Med 37: 178, 1969. Gorlin RJ, Anderson RC, Moller JH: The leopard (multiple lentigines) syndrome revisited. Laryngoscope 81: 1674, 1971. Sommer A, Contras SB, Craenen JM, Hosier DM: A family study of the leopard syndrome. Am J Dis Child 121: 520, 1971. Lynch PJ: Leopard syndrome. Arch Dermatol 101: 119. 1970. Deschamps JP, Didier F: Leopard syndrome. Bull Sot Fr Dermatol Syphiligr 79: 185, 1972. Laughier P, Reiffers J, Ferrier PE, Haenggeli C: Leopard syndrome (lentiginosis profusa). Bull Sot Fr Dermatol Syphiligr 79: 540, 1972. Polani PE. Moynahan EJ: Progressive cardiomyopathic lentiginosis. Q J Med 41: 205, 1972. Walther RJ, Polansky BJ, Grots IA: Electrocardiographic

10. 11. 12.

13. 14.

15.

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abnormalities in a family with generalized lentigo. N Engl J Med 275: 1220, 1966. Walther RJ: Cardiocutaneous syndrome. N Engl J Med 278: 1127, 1968. Kraunz RF, Blackman JR: Cardiocutaneous syndrome continued. N Engl J Med 279: 325, 1968. Selmanowitz VJ, Orentreich N, Felsenstein JM: Lentiginosis profusa syndrome (multiple lentigines syndrome). Arch Dermatol 104: 393, 197 1. Seimanowitz VJ: Lentiginosis profusa syndrome. Acta Derm Venereol (Stockholm) 5 1: 388, 197 1, Moynahan EJ: Multiple symmetrical moles with psychic and somatic infantilism and genital hypoplasia: first male case of a new syndrome. Proc Roy Sot Med 55: 959, 1962. Moynahan EJ, Polani PE: Progressive profusa lentiginosis, progressive cardiomyopathy, short stature with delayed puberty, mental retardation, or psychic infantilism, and other developmental abnormalities: a new familial syndrome. 13th Congressus Internationalis Dermatologial

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16.

17.

16.

19.

20. 21.

22. 23. 24. 25.

26.

27.

26.

29. 30. 31.

32.

456

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Multiple lentigines syndrome. Case report and review of the literature.

The multiple lentigines syndrome is reviewed and a new case is presented. The major features of this syndrome are lentigines and other cutaneous abnor...
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