Variability in the Michelin tire syndrome

A child with multiple anomalies, smooth muscle hamartoma, andfamilial paracentric inversion ofchromosome 7q

Rhonda E. Schnur, MD,a,b,c* Arlene J. Herzberg, MD,d Nancy Spinner, Phl),"Jeffrey A. Kant, MD, PhD/ Mark Magnusson, MD, PhD,c Donna McDonald-McGinn, MS,bKimberly Rehberg, MS,b Paul J. Honig, MD,a.c and Elaine H Zackai, MDb, c

Philadelphia, Pennsylvania

We describe a 2~-year-old boy who has hirsutism and ringed creases of the extremities as­sociated with an underlying smooth muscle hamartoma. Cutaneous findings in this child re­semble those in other reports ofthe"Michelin tire syndrome." Histologic examination showednumerous well-demarcated fascicles of smooth muscle cells randomly distributed at all levelsof the reticular dermis with haphazard orientation. These cells were immunoreactive withdesmin, which confirmed their smooth muscle nature. In addition to the skin changes, thischild has multiple unusual phenotypic anomalies, some of which have not previously been as­sociated with the Michelin tire syndrome. These include distinctive facial dysmorphia, sub­mucous cleft palate, lateral clefting of the mouth, genital, and dental anomalies. He also de­veloped seizures at age 2~ years and has moderate developmental delay. The patient and hismother have apparently identical paracentric inversions of the long arm of chromosome 7(46,XY,inv(7)(q22q31.3) with no detectable loss or gain of either chromosomal material orDNA markers from the cystic fibrosis (CFTR) region. The relevance, if any, of the karyo­typic abnormality to the phenotype in this child is discussed. (J AM ACAD DERMATOL1993;28:364-70. )

Symmetric ringed creases around the extremitiesare a relatively rare and dramatic clinical feature ofan underlying hamartomatous malformation. Suchringed creases were initially referred to by Ross 1 in1969 as the Michelin tire syndrome. Ringed creasesof the extremities may be inherited in an autosomaldominant fashion.v 3They may be an isolated abnor­mality.v" or they may be associated with additionalphenotypic abnormalities.Vc!"

We have identified a boy with the cutaneous ap­pearance of the Michelin tire syndrome who hasmultiple anomalies not previously reported with this

From the Divisions of Dermatology,' Genetics," Pediatrics," andPathology," Children's Hospital of Philadelphia lind the University ofPennsylvania School of Medicine, and the Divisions of Dermatopa­thology" and Pathology," University of Pennsylvania School of Med­icine.

Reprint requests: Rhonda E. Schnur, MD, Genetics/Dermatology,Children's Hospital of Philadelphia, Rm. 5086, Wood Bldg., 34th St.and Civic Center Blvd., Philadelphia, PA 19104.

*Supported by National Institutes ofHealth Physician Scientist AwardNo. EYOO298-03, The Dermatology Foundation, and a BasilO'Connor Starter Scholar Award from the March of Dimes.

Copyright @) 1993 by the American Academy of Dermatology.

0190-9622/93 $1.00 + .1016/4/40017

364

entity. In addition, he has an unusual, but seeminglybalanced, karyotypic abnormality that he inheritedfrom his mother, who does not have the ringedcreases. We also initiated a study to determinewhether a submicroscopic alteration of this patient'sDNA, such as a deletion, duplication, or uniparen­tal disomy, is the underlying cause of this phenotypicpresentation.

CASE REPORT

Clinical evaluation

The patient was the 8 pound, 2 ounce product of a termgestation born to a 38-year-old father and a 30-year-oldgravida 7, para 4, spontaneous abortions 2 mother whohad preeclampsia. There was no parental consanguinity.The babyhad an increased number of deep skin creases,excessive hair, and a dark complexion (Fig. 1, A and B).Additional anomalies noted at birth included bilateralcalcaneovalgus deformity, inguinal hernias, a submucouscleft palate, coxa valga deformity of the hips, clefting ofthe lateral corners of the mouth, and a shawl scrotum withan absent foreskin. At age 22 months he underwent sur­gical repair of his submucous cleft and macrostomia andhad a frenulectomy. He had frequent episodes of otitismedia and upper respiratory tract infections throughout

Journal of the American Academy of DermatologyVolume 28, Number 2, Part 2 Variability in the Michelin tire syndrome 365

Fig. 1. A, Note distinctive facial appearance of propositus, prominent eyelashes, lateral andmidline clefting of lip, abnormal dentition, pectus excavatum, and ringed creases on arms.B, Detail of ringed creases on patient's legs.Note also thevalgusdeformities, overlapping toes,and generalized hirsutism.

infancy. When we examined him at age 30 months, weobserved multiple circumferential creases around all fourextremities; these creases were deeper and more numer­ous in more distal regions. The skin was not lax; rather,it felt thick and fibrotic. The patient was hirsute. He alsohad bilateral symmetric, firm, ~5 to 7 mm nodules on themedial aspect of the arches on his feet and small, softer,and more superficial nodules at the bases of the great toes.His parents noted a marked diminution in the depth andnumber of his skin creases and a decrease in the amountof his body hair since birth.

The remainder of the physical examination revealed adysmorphic boy who was 88 cm tall (25th percentile forhis age) with a head circumference of 47.75 em (lOthpercentile). The child had extremely long lashes, thickeyebrows, hypertelorism, bilateral epicanthal folds, andan antimongoloid slant to the eyes. The nasal bridge washigh and wide, and the nasal alae were asymmetric, withwidening on the left. There was a midline notching of theupper lip, and he had remnants of lateral clefts at the cor­ners of the mouth bilaterally. The palate was high andarched. The oral cavity was also distinctly unusual. Therewere multiple oral frenula, the lateral maxillary incisorswere absent, and the mandibular central incisors werepegged. The patient had extensive carious decay that re­quired extraction of several teeth. The ears were low set

and posteriorly rotated with overfolded thick helices. Theneck was shorter and wider than normal with an excessnumber of skin folds. He had a mild pectus excavatum,and the nipples were narrowly spaced. The phallus wassmall, and he had a shawl scrotum. Both testes were de­scended. Both feet featured overlappingof the second overthe first toes. He had valgus deformities of both the kneesand the ankles and generalized laxity of the joints. Thedermatoglyphic pattern revealed seven fingertips withwhorls. Although his development was delayed, he wasalert, oriented to his parents, and was able to follow sim­ple commands and say several simple words. He had alsojust recently started to walk; a wide-based gait wasobserved. Results of a radiographic skeletal survey did notreveal any underlying osteochondrodystrophy.

A short time after our initial examination, the patientdeveloped generalized and focal seizures that were con­trolled with phenobarbital. Cerebrospinal fluid, serumelectrolytes, and results of a magnetic resonance imagingscan of the brain were normal at that time.

Family history: The mother had a small, painless nod­ule on the inner aspect of her left heel that had beenpresent as long as she could remember; she also had small,irregularly spaced teeth. The patient's four older siblingswere in good health, except for some speech delays. Onematernal cousin also has small testicles. Multiple mater-

366 Schnur et at.Journal of the American Academy of Dermatology

February 1993

Fig. 2. Low-power (A)and high-power (B)viewsof a 4 mm punch biopsyspecimen from thecenter of a leg crease. Mu ltiple, well-demarcated profiles of smooth muscle are randomlydistributed at all levels of the reticular dermis. Epidermis and subcutaneous adipose tissuewere unremarkable.

nal relatives have carious dentition. However, no one inthe family has ringed creases of the extremities, a facialappearance similar to that of our patient, developmentaldelay, or seizures.

Histopathologic evaluation

Histopathologic examination of a 4 mm punch biopsyspecimen from one of the left calf creases revealednumerous, well-demarcated groups, fascicles, and bun­dles of smooth muscle cells that ranged in size from 0.02to 0.2 mm in cross-sectional diameter (Fig. 2, A and B).These were randomly distributed at all levels of the retic­ular dermis with haphazard orientation. Portions of th reenormal hair follicles were observed. One larger smoothmuscle bundle in the deep reticular dermis projected fas­cicles to the follicular protuberance (hair bulge), the at­tachment of the arrector pili, before resuming a circuitous

route through the mid-reticular dermis. The epidermisand subcutaneous adipose tissue were unremarkable.

The bundlesof cellswere immunoreactive with desmin,which confirmed their smooth muscle nature.

Chromosome analysis

The patient's karyotype from peripheral blood was in­terpreted as 46,XY,inv(7)(q22q31.3) (Fig. 3). Themother appeared to have the identical paracentric inver­sion of chromosome 7, and there was no apparent lossorgain of chromosomal material in either the mother orchild. The patient's father had a normal 46,XY karyo­type.

Cytogenetic and DNA analysis

DNA was extracted from white cells of peripheralblood obtained from the patient and his parents, using

Journal of the American Academy of DermatologyVolume 28, Number 2, Part 2 Variability in the Michelin tire syndrome 367

----.In••rt

mother

31.231.1

22

31.3

proband

22 ;;31.131.2 ..--...

31.3 inv.rt

7 inv(7)

Fig. 3. Partial karyotypes demonstrate chromosome 7 pairs from the propositus and hismother. In each case the normal chromosome is on the left and the inverted 7 is on the right;arrows indicate region of inversion.

standard procedures. 11 Epstein-Barr virus-transformedlymphoblastoid lines were also established. PolymorphicDNA probes (pmetH, pXV-2C, pKM19, pJ3.II, andpJUR-beta-1 from the TCR f:3 locus) from the regionaround the cystic fibrosis (CFTR) gene (which lies closeto or within the region of the inversion) were used toscreen for allelic losses, duplications, and uniparental di­somy by Southern blotting. References for all of theseprobes may be found in Human Gene Mapping 10.12 Toverify paternity in our patient, we used the highlypolymorphic probe pYNH24, which hybridizes to a vari­able number of tandem repeat sequences on chromosome2. One allele was derived from each parent.

For the probes around the CFTR locus, the child washeterozygous for probes pmetH, pKM19, and pJ3.lI,thus excluding deletions of their respective loci. FormetH, the child had alleles that were inherited from eachparent, which clearly excluded maternal heterodisomy atthis locus. For pKMl9 and pJ3.lI, maternal heterodis­omy could not be ruled in or out, because the mother wasalso heterozygous at these loci. The child had only one ofthe two possibleallelic fragmen ts ofboth pXV-2C and theTCR (3 probes; he was thus probably homozygous for

these restriction fragment length polymorphisms, al­though by visual inspection of the autoradiogram, wecould not fully exclude the possibility that the patient ishemizygous (i.e., deleted for one copy) for pXV-2C.

DISCUSSION

Other case reports of patients with the Michelintire syndrome are summarized in Table I. At leastthree demonstrated underlying smooth muscle ha­marromasv 7,10 and had increased smooth musclebundles within the dermis. Lack of connection to thehair follicles was reported in two of these cases.I: 10and elastic fiber abnormalities were noted in one.?

The diffuse nature and distinct clinical appear­ance of the smooth muscle hamartomas in theMichelin tire syndrome contrasts greatly with moretypical, localized, congenital smooth muscle hamar­tomas. The latter appear as patch, plaque, or papu­lar forms. Localized smooth muscle hamartoma isalso much more frequent, with an estimated inci­dence of 1 in 2600 live births in a recent Israelistudy.P Both entities histologically share the hyper-

368 Schnur et al.

Table I. Michelin tire syndrome: Review of reported cases

Journal of the American Academy of DermatologyFebruary 1993

Wallach et al.,? 1980 Smooth musclehamartoma

Burgdorf et al} 1982 One section withnevus lipomatosis

Kunze and Riehm' 1982Family A Not reported

Family B Not reported

Unrelated Not reported

DeProst et al.,9 1984 Nevus lipomatosis(smooth musclenormal)

Niikawa et at? 1985Family A Not reported

Family B Not reported

Glover et aL,4 1989 Smooth musclehamartoma

Patrizi et aL,10 1989 Smooth musclehamartoma

Present report Smooth musclehamartoma

Report/Reference No.

ROSS,11969Gardner et al.,5,6 1979, 1980

Histologic features

Nevus lipomatosisNevus lipomatosis

Karyotype

46,XX46,XX,del(11)

(q2lq23)

46,XY

46,XX

46,XY (Fatherand son)

46,XY,46,XX(Father andtwo daughters)

Not reported

Not reported

Not reported

Not reported

Nat reported

"Normal"

46,XY,inv(7)(q22q31.3)

Other findings

Left hemihypertrophyMicrocephaly, obesity,

low-set ears, abnormalhelices, esotropia,rocker-bottom feet,metatarsus abductus

Lax joints, seizures at age 2years, mentally retarded

Stellate scarring, no otherproblems

Median cleft palate,neuroblastoma, epicanthalfolds, hypertelorism

Median cleft palate,micrognathia, malformedears, ureterocoeles

Obesity, slight motorretardation, recurrentfebrile convulsions

Laron syndrome, facialdysmorphia, obesity,consanguinity

Three generations, isolatedproblem

Two brothers, isolatedproblem

No other abnormalities

Cutaneous mastocytosis,normal development,normal skeletal radiographs

Submucous cleft palate,lateral clefting of themouth, facial dysmorphia,developmental delay,seizures, coxa valgadeformity, genu valgus,overlapping of toes, pectusexcavatum, dentalanomalies, small phallus,shawl scrotum

plasia of well-demarcated, smooth muscle bundleswithin the dermis and their haphazard orientation,with or without connections to the hair follicles.13, 14Although the epidermis is unremarkable in mostsmooth muscle hamartomas, some show acanthosis,papillomatosis, and keratinocyte hyperpigmenta­tion.!"

Smooth muscle hamartoma is also histologicallydifferent from piloleiomyoma. Piloleiomyomas have

ill-defined, interlacing bundles of smooth muscle in­terspersed with collagen.P whereas the smoothmuscle hamartoma shows well-defined, distinctsmooth muscle bundles that usually occupy a smallerarea of the biopsy specimen. Becker's nevialso showsmooth muscle hyperplasia but have associated epi­dermal acanthosis, papillomatosis, and hyperpig­mentation with the distinctive finding of increasednumbers of melanocytes.

Journal of the American Academy of DermatologyVolume 28, Number 2, Part 2

In none of the other reports of the Michelin tiresyndrome, summarized in Table I, are additionalphenotypic abnormalities as extensive as those ob­served in this child . Dominant patterns of inherit­ance were reported in two families by Kunze andRiehm- and in a third family by Niikawa et al.2 Al­though neither of our patient's parents appeared tohave the ringed creases , the patient's mother dis­played a similar nodule on the foot and also had un­usual dentition. Although these subtle signs areprobably coincidental, they might reflect variableexpression of a "dominant" gene for the Michelintire syndrome. Unfortunately, histologic examina­tion of the foot nodules in both the patient and hismother was not performed.

Our patient shares some of the other previouslyreported anomalies in addition to the ringed skincreases , including the median clefting of his palate,epicanthal folds, hypertelorism, malformed ears,and developmental delay. Seizures have been notedin only two other reports.b 7 and joint laxity wasfound in one other patient." Features that differen­tiate our patient from all other patients describedinclude the lateral clefting of the mouth and oralfrenula, abnormal dentition, pectus excavatum, theantimongoloid position of the eyes, shawl scrotum,small phallus, and joint anomalies.

Only one previous case was associated with anytype of cytogenetic abnormality (46,XX,del(ll)(q21q23).5,6 This child also had microcephaly,obesity, low-set ears with an abnormal trihelicalstructure, esotropia, rocker-bottom feet, metatarsusabductus, and severe mental retardation in additionto the ringed creases. Histologically, this child didnot have an underlying smooth muscle hamartoma;instead, there was an increase in the adipose tissuewithin the deep dermis but without lobules of fat inthe papillary dermis.

Our patient also has an abnormal, but quite dis­tinct, karyotype: an apparently balanced paracentricinversion of7q, which appears identical to that seenin the patient's mother. Thus it seems doubtful thatthis chromosomal rearrangement is causally relatedto the Michelin tire phenotype. However, we cannotexclude the possibility that an additional, submicro­scopic deletion or duplication of chromosomal ma­terial has occurred. This would then implicate thearea at or between the two breakpoint regions as acandidate locus for a "Michelin tire gene," in addi­tion to other genes that contribute to the abnormalphenotype observed in our patient.

Variability in the Michelin tire syndrome 369

An alternative possibility to an actual loss or gainof chromosomal material is uniparental disomy forall or part of chromosome 7; that is, both copies ofthe chromosome derive from thesame parent. Hall16

has recently reviewed this phenomenon. For someregions of the genome, a contribution of geneticmaterial from both parents is required for a normalphenotype because of "imprinting" differences be­tween the sexes, probably caused by methylationdifferences of DNA in the male and female germlines. In the special case of uniparental isodisomy(identical chromosomehomologues probablycausedby a meiosis II nondisjunctional event), phenotypicchanges may result from homozygosity for recessivegenes.

Because the CFTR locus lies close to the break­points of the inversion in this family, we studiedpolymorphic probes around CFTR to search for de­letions, duplications, or uniparental disomy that wasnot detectable at the cytogenetic level. Although wecould not conclusively exclude these possibilities atevery locus tested because of limitations in the "in­formativeness" of these probes in the parents, wedetected no definite loss Or gain of DNA at any ofthe loci. A deletion and maternal heterodisomy wereruled out at the metH locus, and deletions were ex­cluded at the loci detected by pKM19 and pB.ll.However, partial uniparental disomy or other DNArearrangements are still theoretically possible over amuch wider region than we tested.

Paracentric inversions are often familial, appar­ently balanced, and benign. J7Through meiotic mis­pairing, they may be associated with recognizablyunbalanced karyotypes, phenotypic abnormalities,and a higher incidence of spontaneous abortions orstillbirths in the offspring of a parent with such atranslocation. In several other familial paracentricinversions, similar to the situation in the family de­scribed herein, no differences were detectable cyto­genetically between a clinically normal parent and aphenotypically abnormal child, although the possi­bility of a submicroscopic difference between the in­versions could not be excluded. Familial paracentricinversions that specifically involve the long arm ofchromosome 7 are relatively frequent, 17,21 and sev­eralhave been associated with additional aneuploidyof the sex chromosomes. Other associated anoma­liesl8 included one unbalanced karyotype in a childof a carrier, acute leukemia (one individuaI), unde­scended testis (one individual), translocation in ad­dition to the inversion (one individual), subfertility

370 Schnur et al.

(one individual), and intrauterine death (one indi­vidual). Although several of the breakpoints of theother reported familial paracentric inversions ofchromosome 7q were similar, none of the associatedabnormalities was reminiscent of those in our pa­tient.

The child we have described has a seemingly bal­anced karyotypic abnormality, a paracentric inver­sion of 7, that may be coincidental to his distinctivephenotype, Alternatively, it may be the region withinwhich reside the causative genes. We suggest that allcases of the Michelin tire syndrome be investigatedfor both their underlying histology and for any cy­togenetic abnormalities.

The authors are grateful for the expert technical assis­tance of Penelope A. Wick and Theresa Mazzotta. Aftersubmission of this paper, we learned that the maternalgrandfather, whom we have not examined clinically, alsocarries the chromosome 7q inversion. His karyotypingwas performed by Dr. Robin Dawn Clark at Lorna LindaUniversity, California.

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3. Kunze J, Riehm H. A new genetic disorder: autosomaldominant multiple benign ring-shaped skin creases. Em JPediatr 1982;138:301-13.

4. Glover MT, Malone M, Atherton DJ. Michelin-tire babysyndrome resulting from diffuse smooth muscle hamar­toma. Pediatr Dermato1 1989;6:329-31.

5. Gardner EW, Miller HM, Lowney ED. Folded skin asso­ciated with underlying nevus lipomatous. Arch Dermatol1979;115:978-9.

6. Gardner EW, Miller HM, Lowney ED. Deletion of chro-

Journal of the American Academy of DermatologyFebruary 1993

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16. Hall J. Genomic imprinting and its clinical implications. NEngl J Med 1991;326:827-9.

17. Madan K, Seabright M, Lindenbaum RF, et al. Paracen­tric inversions in man. J Med Genet 1984;21:407-12.

18. Schmid M, HaafT, Zorn M. Paracentric inversions in hu­man chromosome 7. Hum Genet 1986;74:197-9.

19. Martin RH. Sperm chromosome analysis in a man het­erozygous for a paracentric inversion of chromosome7(q11q22). Hum Genet 1986;73:97-100.

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