572Med Genet 1997;34:582-586

Syndrome of the month

Multiple lentigines syndrome (LEOPARDsyndrome or progressive cardiomyopathiclentiginosis)

Brian D Coppin, I Karen Temple

The multiple lentigines syndrome is an auto-somal dominant condition which has manysimilarities to Noonan syndrome,' except inthe most striking feature from which its name isderived. The less neutral but very apt mne-monic, LEOPARD syndrome, was first used byGorlin et al' to whom the major debt in thedefinition of this syndrome lies,3 that is,Lentigines, ECG abnormalities, Ocularhypertelorism/Obstructive cardiomyopathy,Pulmonary valve stenosis, Abnormalities ofgenitalia in males, Retardation of growth, andDeafness. Not previously included in the mne-monic is cardiomyopathy which is an impor-tant feature because it is associated withsignificant mortality.( Med Genet 1997;34:582-586)

Keywords: cardiomyopathy; deafness; lentigines; pul-monary stenosis

The first documented case was probably thatdescribed in 1936 by Zeisler and Becker,4 whopresented a 24 year old woman with lentigino-sis and pectus carinatum to the American Der-matology Association. Photographs show hy-pertelorism and ptosis. In 1966 Walther et ardescribed a family with ECG abnormalities,systolic murmurs, and lentiginosis. In 1968Matthews6 described lentigo with electrocar-diographic changes. In 1972, after the 1969publication of Gorlin et a!' established the con-dition as a distinct entity, Polani andMoynahan79 re-reported a sibship previouslyreported by themselves in an article involvingeight patients in a total of six families. In 1975,Voron et al'° presented a new case and reviewedthe subject, pointing out the highly variablemanifestations and suggesting criteria for thediagnosis. Many others have contributed to themore than 80 cases reported to date.""-'5

Clinical presentationLENTIGINES AND OTHER PIGMENTARY CHANGES

Classically, thousands of lentigines appear inchildhood and increase in number untilpuberty.7 They are flat, dark brown to black incolour, and 1 to 2 millimetres in size, althoughthey can be larger and are then described ascafe noir patches (fig 1).2 These may be

Figure 1 Typical multiple lentigines in an adult with cafenoir patches.

congenital.5 They are present on the palms,soles, face, scalp, and external genitalia,'6 butless so in these areas than the rest of the body.The irides may be involved but not the fundi.7The mucosae are spared. The colour and den-sity of the lentigines are not related to sunexposure, which differentiates them fromfreckles. Some patients lack lentigines'7 18 andthis makes the diagnosis difficult in the absenceof deafness or a family history of lentigines.Additional cases presented by Gorlin et al'8 in1971 included a mother and son who bothlacked lentigines but whose other featuresincluded sensorineural deafness, ocular hyper-telorism, pulmonary stenosis, and (in the son)undescended testes. They also presented acousin of a previously reported family who haddysplastic pulmonary valve stenosis and thetypical ECG changes, but in contrast to theproband lacked lentigines.'8

Wessex ClinicalGenetics Service,Princess AnneHospital, CoxfordRoad, SouthamptonS016 SYA, UKB D CoppinI K Temple

Correspondence to:Dr Temple.

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Multiple lentigines syndrome

On histological examination of the lentiginesthere is pigment accumulation in the dermis aswell as the deeper layers of epidermis. There isan increase in melanocytic density owing tocorrugation of the dermoepidermal junction.There are no naevus cells and the rete ridgesare prominent.'0 11' 9 20

Cafe au lait patches as well as axillary freck-ling have been described.'02' Localised hypo-pigmentation (in one case in places where pre-vious lentigines existed) is also a knownfeature.22 23

CARDIOVASCULAR ABNORMALITIES

The frontal plane QRS axis is rotated anti-clockwise so as to be superiorly orientated andgenerally lies between -60° and -120°. Thisfeature is not present in all cases and converselymay be the only cardiovascular feature, and is a

useful diagnostic clue.5 10 24Valvular pulmonary stenosis is the common-

est anomaly, occurring in 40% of reportedcases.25 It is usually mild. It occurs either as

typical valvular pulmonary stenosis"' or more

commonly as a dysplastic pulmonary valve.213In a dysplastic pulmonary valve, three leafletsare present with no fusion of commissures, butthe leaflets are poorly mobile owing to dysplas-tic myxomatous deposits.'3 No ejection click ispresent in this instance. Infundibular and sup-ravalvular pulmonary stenosis have also beendescribed.25

Hypertrophic obstructive cardiomyopathy(HOCM) is a major concern in these patientsand echocardiography to exclude this shouldbe offered to all patients regardless of symp-toms. It may be progressive and commonlyinvolves the intraventricular septum." In 30%,right ventricular outflow tract obstruction isalso present. Muscular subaortic stenosis mayor may not be part of HOCM.'0 Heart block,bundle branch block, hemiblock, atrial septaldefect, arrhythmias, and endocardial fibroelas-tosis have all been described in multiplelentigines syndrome.7 10-12 24 26

DYSMORPHIC FEATURESThe principal facial features include ocularhypertelorism, broad, flat nose, low set, poste-riorly rotated ears, and ptoSiS.21025 Thesepatients often have a short neck which may bewebbed. Pectus excavatum and carinatum are

common and 10% of patients have a

scoliosis. lo 27 A prognathic mandible ischaracteristic.2 Joint hypermobility is an occa-

sional feature, as is winging of the scapulae.These patients are usually growth retarded,their adult height being below the 25th centile,despite having normal or above average birthweights.'0 25 28

UROGENITAL ABNORMALITIESA few isolated renal anomalies have beendescribed.'o 29 Genital hypoplasia in males,including a small penis and small, often unde-scended testicles, are the commonestassociation."' Hypospadias, delayed puberty,absence or hypoplasia of an ovary, and latemenarche are also listed.7 lo 18 In the reportedpedigrees, the affected parent is more often the

mother, suggesting that the affected malepopulation may have diminished fertility. Manyaffected fathers have however been reported,thus ruling out an imprinted gene.

DEAFNESSThis is the rarest of the mnemonic features,

2 10 22 25 30occurring in 15-25% of reported cases.Deafness is sensorineural in nature, may beunilateral, but can be profound. Most caseshave deafness diagnosed in childhood, but someare reported to have developed this in adult life.

OTHER FEATURESMild learning difficulty occurred in 23 of the80 cases reviewed by Voron et al.'0 Oculomotordefects were present in 16/80 and EEG abnor-malities in 11/80 patients in this series.

GeneticsThis condition is clearly autosomal dominantin its inheritance. Penetrance is high but maybe incomplete. One of the additional cases pre-sented by Gorlin et al"' in 1971 was the cousinof the proband in an earlier report. His mother(aunt and sister to affected members) was ofnormal stature and cardiovascular status. Noother features are mentioned in the report.

Expressivity is highly variable. Many of thefamilies reported are discordant, particularlyfor the cardiac manifestations.

Case reports (table 1)Case 1 presented with HOCM following thediscovery of a murmur in infancy. Long termpropranolol was prescribed and apart from thedevelopment of mild right ventricular outflowtract obstruction he has remained haemody-namically stable. The pulmonary valve wasnormal on echocardiography. At the age of 2years he developed dark lentigines diffuselyover his whole body, including his scalp, palms,and soles. Relative sparing of his back wasnoted. There was no involvement of fundi ormucous membranes. The anterior fontanelleclosed late (at 2 years of age). He had severeunilateral right nerve deafness with normalhearing on the left. When last reviewed at 9years, he was noted to have mandibularprognathism, mild ptosis, posteriorly rotatedears, anteverted nares, mild joint hypermobil-ity, winged scapulae, and hypertelorism withboth the inner and outer canthal distancesbeing on the 90th centile. He also had pectusexcavatum (fig 2A).

His parents had a previous child who died atbirth. The cause of death was thought to havebeen cardiac in origin but necropsy was notperformed and there was no further infor-mation. There was no family history of lentigi-nes but his father's height was on the 3rd cen-tile and he had downward slanting, wide seteyes with mild ptosis. He had a triangular faceand a small jaw and he too had a sternaldepression. He had a normal echocardiogram.

FAMILY KCase 2 was noted to be dysmorphic in infancy.He had a large anterior fontanelle, hyperte-

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Coppin, Temple

Table I Case report features

Case 1 Case 2 Case 3 Case 4 Case S

Lentigines + + + + +OFC, centile 85-95 90 > 90 Large 50-75Hypertelorism, 90 > 95 > 95 + +

centilePtosis + - - +Posteriorly rotated ++ + + + ++

earsSuperior ECG axis + (-90°) + (-130°) + (-105°) + (-70°) + (-55°)OtherECG - + + + -

anomaliesCardiac symptoms + - - + -

Hypertrophy - septal + + + + -

Right ventricle + - - + -

Left ventricle + - - + -

RVOT obstruction + - - +LVOT obstruction + - + +Pulmonary stenosisGenitourinary Normal Normal Normal * Normal

featuresBirth weight (g) 3900 2980 3440 4000 ?Latest height, centile 25-50 < 5 5-10 < 5 < 5Deafness Left sided Mild, - Unilateral, At 59

only conduction congenital yearsSternal + + + -?

abnormalities

+ = feature present, - = feature absent, ? = feature not ascertained, * = unilateral undescendedtestis, OFC = occipitofrontal circumference, RVOT = right ventricular outflow tract, LVOT = leftventricular outflow tract.

c.t.-..:

r* a

Figure 2 (A) The face of case 1 aged 9 years showing hypertelorism and lentigines. (B)Case 2 in infancy showing the typicalfacies. Lentigines became manifest later. (C, D) Case3 in adulthood. Note the hypertelorisni, multiple lentigines, and low set, posteriorly rotatedears.

lorism, posteriorly rotated ears, and a low pos-terior hairline (fig 2B). In addition he haddivarication of the rectus abdominus, anumbilical hernia, an ejection systolic murmur,bilateral simian creases, short fingers, and limi-tation of thumb extension. At birth a 1 cm cafeau lait patch was present on the knee but therewere no lentigines. His length was 51 cm (onthe 50th centile). He had mild feedingproblems. At 9 months of age he was shown tohave a floppy mitral valve and thickening of theinterventricular septum with bulging into theleft ventricular outflow tract on echocardiogra-phy. His development was delayed; he sat at 1year, walked at 2 years, and had speech delay.Unilateral conduction deafness was diagnosed.By 2 years, over 10 lentigines were present

on the trunk but also on the face and hands,including the volar surfaces. At the time ofwriting he attended a school for children withmoderate learning difficulties. His height at 2years was below the 3rd centile and remainedbelow the 3rd centile at 6 years.

Case 3, the father of case 2, was reported tohave had a few lentigines at birth with manymore appearing later. On examination as anadult, he had hypertelorism, ptosis, posteriorlyrotated ears, and a low hairline. In addition tothe ECG findings he had mild interventricularseptal hypertrophy and a floppy mitral valve(fig 2C, D).Case 4, the brother of case 3, was one of the

original cases reported by Moynahan andPolani7 in 1972.

Case 5, the mother of case 3, had multiplelentigines as well as two cafR au lait patches.The lentigines developed when she was 4 yearsold. She had hypertelorism, posteriorly rotatedears, anteverted nares, and short palpebral fis-sures. She had no documented cardiac prob-lems when she was investigated aged 41 years.A systolic mitral murmur was noted in old age.She was treated for hypothyroidism from theage of 41 years and she developed cataractsaged 66 years. Aged 59 years she had a 50-70dB hearing loss recorded in both ears.

DiagnosisDiagnostic criteria were proposed by Voron etallo in 1976, which included lentigines plus twoother recognised features or a first degree rela-tive with lentigines plus three other features inthe patient. This still seems reasonable pendingclarification of the genetic defect.

Differential diagnosis (table 2)NOONAN SYNDROMEThe presence of lentigines and deafness inLEOPARD syndrome are the only distinguish-ing features between this and Noonansyndrome.' The cardiovascular, growth, anddysmorphic findings are identical.' Cases oflentiginosis sine lentigines are well described infamilies with LEOPARD syndrome'7 and suchpatients would be indistinguishable from Noo-nan syndrome in the absence of a familyhistory. It is speculative that the two conditionsmay be allelic.'

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Multiple lentigines syndrome

Table 2 Differential diagnosis

Leopard Noonzan NFI IJ NAME

Skin lentigines/freckling + (93%) - + + +Mucosal lentigines - - - + +Hypertelorism + + - - -Deafness + (15-25%) - - - tMale genital abnormalities + (38%) + - - tHOCM + + - - -Pulmonary valve stenosis + (40%) + - - tCardiac tumour * - - - +GIT polyposis - - - + -Cafe au lait patches + (19%) + + + +Growth retardation + + +

+ = a well described association, - = not a recognised association, * one reported case, t not apreviously reported feature but present in the family discussed under 'Differential diagnosis'.

NEUROFIBROMATOSIS TYPE 1 (NF1)LEOPARD syndrome has features in commonwith NFl.3 However, the skin findings differand the number of true cafe au lait patches donot usually fulfil the diagnostic criteria forNFl. In 1996, Wu et afP2 reported a de novomissense mutation in exon 18 of the NF1 genein a woman with possible LEOPARD syn-drome. She had multiple lentigines, mild men-tal retardation, and both valvular and subaorticstenosis. In the review of 80 cases by Voron etall' valvular aortic stenosis was not described,hence this is atypical. In addition, the patientwas not deaf. She lacked neurofibromas andLisch nodules and therefore features were alsonot typical of NFl. This finding is yet to berepeated in a patient with classical LEOPARDsyndrome. In cases 1 to 5, mutations werelooked for in 6.6 kb of the NF1 cDNA but werenot found (Dr Lois Mulligan, CRC, HumanCancer Research Genetics Group, Cambridge,personal communication, 1993).Watson syndrome (cafe au lait spots, atypical

pulmonary valve stenosis, and learningdifficulties)26 has phenotypic features commonto both NFl and LEOPARD syndrome.Mutations in the NF1 gene have been shown inpatients with this condition.33

PEUTZ-JEGHER SYNDROME (Pj)It is easy to confuse these two conditionsbecause gastrointestinal symptoms are notalways present, particularly in childhood, andthe lentigines may appear similar. However, inPeutz-Jegher syndrome the lentigines are also

eNFigure 3 Patient with NAME syndrome. The lentiginesare very similar to those in multiple lent'gines syndrome,but the distribution differs as buccal mucosa is involved.

present on mucosal surfaces. Patients with PJsyndrome, however, lack the coarse facialappearance and characteristic ECG seen inpatients with LEOPARD syndrome.

NAME SYNDROME (NAEVI, ATRIAL MYXOMA,MYXOID NEUROFIBROMATA AND

EPIPHILIDES/ENDOCRINE NEOPLASIA)Multiple dark macules occur in this conditionwith a similar appearance to freckles (fig 3).Mucosal involvement and the lack of dysmor-phic features characteristic of LEOPARD syn-drome help the clinician to differentiate thesediagnoses; 60% of patients manifest subcuta-neous myxomas, most commonly on theeyelids, pinnae, and nipples. Half of patientsdevelop intracardiac myxomas, usually biatrial,but some are intraventricular. Endocrine neo-plasia occurs in 15-30%.'35The authors were recently consulted by a

family with NAME syndrome who were misas-signed as LEOPARD syndrome until routinecardiac follow up showed an atrial myxoma.Several features of LEOPARD syndrome werenoticed in those who had lentigines; theseincluded sensorineural deafness, valvular pul-monary stenosis, innocent heart murmurs,winged scapulae, glandular hypospadias, cafeau lait patches, moderate learning difficulties,hypermobile joints, kyphoscoliosis, pectus ex-cavatum, and prognathism.

We would like to thank Dr L Mulligan for molecular investiga-tion of patients with LEOPARD syndrome and Dr A P Salmonfor discussions regarding the cardiac features.

1 Blienden LC, Schneeweiss A, Shem-Tov A, Feigel A, Neu-feld HN. Unifying link between Noonan's and Leopardsyndromes? Pediatr Cardiol 1983;4: 168-9.

2 Gorlin RJ, Anderson RC, Blaw M. Multiple lentigines syn-drome. Amz 7 Dis Child 1969;1 17:652-62.

3 Gorlin JR, Anderson RC, Moller JH. The Leopard (multiplelentigines) syndrome revisited. Birth Defects 1971 ;VII: 110-15.

4 Zeisler EP, Becker WS. Generalised lentigo. Arch DermiiatolSyph 1936;32:109-25.

5 Walther RJ, Polansky BJ, Grots IA. Electrocardiographicabnormalities in a family with generalised lentigo. N Engl ]Med 1966;275:1220-5.

6 Matthews NL. Lentigo and electrocardiographic changes. NEngli3Med 1968;278:780.

7 Polani PE, Moynahan EJ. Progressive cardiomyopathic len-tiginosis. Q] Med 1972;162:205-21.

8 Moynahan EJ. Multiple symmetrical moles with psychic andsomatic infantilism and genital hypoplasia. Proc R Soc Med1962;55:959-60.

9 Moynahan EJ. Progressive cardiomyopathic lentiginosis.Proc R Soc Med 1970;63:448-51.

10 Voron DA, Hatfield HH, Kalkhoff MD. Multiple lentiginessyndrome. Case report and review of the literature. Am ]Med 1976;60:447-56.

11 Sutton MJ, Tajik AJ, Giulliani ER, Gordon H, Daniel WP.Hypertrophic obstructive cardiomyopathy and lentiginosis:a little known neuroectodermal syndrome. Anm 7 Cardiol1981;47:214-17.

12 Seunez H, Mane-Garzon F, Kolski R. Cardio-cutaneoussyndrome (the LEOPARD syndrome). Review of theliterature and a new family. Clin Genet 1976;9:266-76.

13 Rodrigo M, Cheng C, Tai Y, O'Donnell D. 'Leopard'syndrome. Anaesthesia 1990;45:30-3.

14 Alday LE, Moreyra E. Secondary hypertrophic cardiomyo-pathy in infancy and childhood. Anm Heart]r 1984;108:996-9.

15 Garty B, Waisman Y, Weitz R. Gerstmann tetrad in Leopardsyndrome. Pediatr Neurol 1989;5:391-2.

16 Weiss LW, Zelickson AS. Giant melanosomes in multiplelentigines syndrome. Arch Dermatol 1977; 113:491-4.

17 Koroxenidis GT, Webb NC, Moschos CB, Lehan PH. Con-genital heart disease, deaf-mutism and associated somaticmalformations occurring in several members of one family.Am ] Med 1966;40:149-55.

18 Gorlin RJ, Anderson RC, Moller JH. The leopard (multiplelentigines) syndrome revisited. Laryngoscope 1971 ;81:1664.

19 Lucky PA, Nordlund JJ. The biology of the pigmentary sys-tem and its disorders. Dermlatol Clin 1985;3:197-216.

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20 Fryer PR, Pope FM. Accumulation of membrane boundmelanosomes occurs in Langerhans cells of patients withthe Leopard syndrome. Clin Exp Dermatol 1972;17:13-15.

21 Crow FW. Axillary freckling as a diagnostic aid inneurofibromatosis. Ann Intern Med 1964;61:1142.

22 Selmanowitz VJ, Oretreich N, Felsenstein JM. Lentiginosisprofusa syndrome (multiple lentigines syndrome). ArchDermatol 1971;104:393.

23 Selmanowitz VJ. Lentiginosis profusa syndrome. ActaDermatol Venereol 197 1;58:388.

24 Somerville J, Bonham-Carter RE. The heart in lentiginosis.Br HeartJf 1972;34:58-66.

25 Gorlin JR, Cohen MM, Levin LS. Syndromes of the head andneck. New York: Oxford University Press, 1990:461-4.

26 Watson GH. Pulmonary stenosis, Cafe-au-lait spots anddull intelligence. Arch Dis Child 1967;42:303-7.

27 David LM. Multiple lentigines syndrome. Arch Dermatol1973;108:590.

28 Salti R, Galluzzi F, Albanese A, Morandi A. La sindromeLEOPARD: un caso con deficit di ormone della crescita.Riv Ital Pediatr 1991;17:342-4.

29 Swanson SL, Santen RJ, Smith DW. Multiple lentiginessyndrome. New findings of hypogonadotropism, hyposmiaand unilateral renal agenesis. JPediatr 1971;78:1037.

30 Capute AJ. Congenital deafness with multiple lentigines inmother and daughter. In: Bergsma D, ed. The clinical deline-ation of birth defects. Part II. Malformation syndromes. Vol V.New York. The National Foundation-March of Dimes,1969:236.

31 Ahlbom BE, Dahl N, Zetterqvist P, Anneren G. Noonansyndrome with cafe-au-lait spots and multiple lentiginessyndrome are not linked to the NFI locus. Clin Genet1995;48:85-9.

32 Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman J,Fryns J. Neurofibromatosis type 1 gene mutation in a

patient with features of LEOPARD syndrome. Hum Mutat1996;8:51-6.

33 Tassabehji M, Strachan T, Sharland M, et al. Tandem dupli-cation within an NFl exon in a family with features ofWatson syndrome and Noonan syndrome.AmJ7Hum Genet1993;53:90-5.

34 Allanson JE, Upadhyahya M, Watson GH, et al. Watsonsyndrome: is it a subtype of type 1 neurofibromatosis? JMed Genet 1991;28:752-6.

35 Koopman RJ, Happle R. Autosomal dominant transmissionof the NAME syndrome. Hum Genet 199 1;80:300-4.

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