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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.
REFERENCES
1. Ross CM. Generalized folded skin with an underlyinglipomatous nevus. Arch DermatoI1969;100:320-3.
2. Niikawa N, Ishikiriyama S, Shikirnani T. The "MichelinTire Baby" syndrome: an autosomal dominant trait. Am JMed Genet 1985;22:637-8.
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
mosome 11 in babies with Michelin tire syndrome. ArchDermatoI1980;116:622.
7. Wallach D, Sorin M, Saurat JH. Naevus rnusculaire generalise avecaspect cliniquede "bebe Michelin." Arch Dermatol Venereal (Paris) 1980;107:923-7.
8. Burgdorf WN, Doran CK, Worret WI. Folded skin withscarring: "Michelin" tire "baby" syndrome? J AM ACADDERMATOL 1982;7:9Q..3.
9. DeProst Y, Geoffroy G, Rault G, et al. Syndrome de Laronavec aspect clinique de "bebe Michelin." Ann DermatolVenereol 1984;111:751-2.
10. Patrizi A, Neri I, Varotti C. Un autre cas de naevus musculaire generalise avec aspect clinique de "bebe Michelin"associea une mastocytose cutanee. Ann Dermatol Venereol1989;116:551-4.
11. Aldridge M, Kunkel L, Bruns G, et al. A strategy to revealhigh frequency RFLPs along the human X chromosome.Am J Hum Genet 1984;36:546-64.
12. Kidd KK, BowcockAM, Schmidtke J, et al. Report of theDNA committee and catalogs of cloned and mapped genesand DNA polymorphisms, Cytogenet Cell Genet(HGMlO) 1989;51:622-947.
13. Zvu1unov A, Rotem A, Merlob P, et al. Congenital smoothmuscle hamartoma: prevalence, clinical findings, and follow-up in 15 patients. Am J Dis Child 1990;144:782-4.
14. Johnson MD, Jacobs AH. Congenital smooth muscle hamartoma: a report of six casesand a reviewof the literature.Arch Dermatol1989;125:820-2.
15. Lever WF, Schaumburg-Lever G. Histopathology of theskin. 7th ed. Philadelphia: J B Lippincott, 1990:728, 774.
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.
20. Watt JL, Ward K, Couzin DA, et al. A paracentric inversion of 7q illustrating a possibleinterchromosomal effect. JMoo Genet 1986;23:341-4.
21. Lamberti L, Massa ER. Paracentric inversion in a femalewith multiple miscarriages (7inv)(q2.13;q3.13). HumGenet 1987;75:391.
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