Inherited Macrocephaly–Hamartoma Syndromes

John H. DiLiberti*Department of Pediatrics, University of Illinois College of Medicine at Peoria, Children’s Hospital of Illinois at OSFSaint Francis Medical Center, Peoria, Illinois

Recent discoveries in the molecular biologyof the phosphatase and tensin homolog(PTEN) locus in the q22-23 region of chro-mosome 10 prove and/or suggest that sev-eral syndromes previously considered to beclinically and genetically distinct entitiesshould actually be unified into a single en-tity. This conclusion is most secure for theCowden and ‘‘Bannayan-Zonana’’ pheno-types, but almost certainly should also in-clude the ‘‘Riley-Ruvalcaba’’ and Lhermitte-Duclos phenotypes as well benign familialmacrocephaly and external hydrocephalus.The clinical and molecular data supportingthis unification are presented along with aproposal for new nomenclature—the PTENMATCHS (macrocephaly, autosomal domi-nant, thyroid disease, cancer, hamartomata,skin abnormalities) syndrome—based onthe observed clinical abnormalities. Am. J.Med. Genet. 79:284–290, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: macrocephaly; autosomaldominant; PTEN; hamar-toma; MATCHS; Ruvalcaba-Myhre-Smith syndrome;Bannayan-Riley-Ruvalcabasyndrome; Lhermitte-Duclossyndrome; Cowden disease;carnitine; lipid myopathy

INTRODUCTION

Macrocephaly occurs in a large number of syn-dromes. The most recent edition of Recognizable Pat-terns of Human Malformation tabulates 39 syndromeswith macrocephaly as one of the clinical findings, while

a query of the London Dysmorphology Database using‘‘macrocephaly’’ as the search term identified 208[Jones, 1997; Winter and Baraitser, 1996]. It should benoted that among the half dozen or so terms used todescribe a large head/brain, ‘‘macrocephaly’’ has appar-ently supplanted its closest rival ‘‘megalencephaly’’ inprevalence of usage. This may be a consequence of com-pactness—megalencephaly does have an extra syl-lable—but since we generally know that a head is largebefore we know whether the underlying brain is large,macrocephaly may, in fact, be semantically more rep-resentative of our usual state of clinical knowledge.

Discussion and review of several hundred conditionsassociated with enlarged heads/brains is clearly be-yond the scope of this article. In keeping with thetheme of the assigned title for the 1997 Gorlin lecturesand with some interesting recent advances in molecu-lar knowledge, I limit the present discussion to a smallgroup of conditions, at least some of which are appar-ently related by clinical and molecular considerations.The ‘‘cardinal’’ findings in each generally include mac-rocephaly and the development of benign and/or malig-nant tumors. A wide range of names has been coinedfor what may turn out to be variable subsets of a singlegenetic entity. For present purposes I will usually use‘‘macrocephaly–hamartoma phenotype’’ for clarity andgenerality. Cohen and I have previously commented onthis issue, but as the clinical–molecular correlation hasevolved subsequently, I withhold further comment un-til recently reported data are presented below [Cohen,1990; DiLiberti, 1990]. Instead I begin with a discus-sion of the concept of ‘‘macrocephaly’’ and comment onsome of the difficulties that arise from its use.

MACROCEPHALY

In a sample of recently published articles, use of theterm macrocephaly generally appears to imply that themeasured (occipito-frontal) head circumference (OFC)exceeds the population mean by at least two standarddeviations [DiLiberti et al., 1983; Miles et al., 1984;Starink et al., 1986]. Although the cutoff at thisparticular point on the distribution curve has beencustomarily used for a variety of other classifica-tion purposes (IQ and mental retardation, etc.) I havebeen unable to find any information to the effectthat a 2.0 standard deviation cutoff has any greaterutility than 1.5, 3.0, or even 3.14159. The present ten-dency seems to be to use ‘‘macrocephaly’’ as a diagnosis

*Correspondence to: John H. DiLiberti, M.D., Ph.D., Depart-ment of Pediatrics, University of Illinois College of Medicine atPeoria, Children’s Hospital of Illinois, 530 N.E. Glen Oak Avenue,Peoria, IL 61637. E-mail: JHD@UIC.edu

Received 18 November 1997; Accepted 2 December 1997

American Journal of Medical Genetics 79:284–290 (1998)

© 1998 Wiley-Liss, Inc.

rather than a useful tool to sort out clinical informa-tion.

An additional problem with this diagnostic constructis the selection of the appropriate reference group.Variations in OFC by age and sex are well established,and certainly familiar to all who use OFC measure-ments clinically. However, OFC is correlated with atleast three other potentially confounding variables—parental head circumference, height, and ethnicity[Bale et al., 1991; Fraser et al., 1988; Weaver andChristian, 1980]. Adjustment of measured OFC valuesfor these covariates does not seem to have entered intocommon use. How does one decide whether a tall WestIndian Child, whose parents both have generous OFCs,is macrocephalic? A similar problem arises when evalu-ating the child with a body size below the 10th centile,for example, who has an OFC at the 90th. Does the useof a cutoff two standard deviations above the (predomi-nantly white) U.S. population mean, in these cases,add much to clinical understanding?

Although laboratory methods are expected to be de-scribed in any scientific paper, with rare exception theanthropometric methods are rarely mentioned. Thesemeasures are apparently presumed to be correct/true.Yet considerable information has been published re-garding the importance of adherence to standardizedmethods and the variability that results from the use ofdifferent types of tools [Roche et al., 1986, 1987]. Itwould seem reasonable for scientific journals to requirethe same degree of rigor for anthropometric measure-ments as for laboratory measurements.

Anthropometric measurements do not appear tohave been subjected to rigorous quality assessment toany great extent, particularly in typical clinical set-tings. Of particular concern is the lack of data regard-ing reproducibility of measurements by a single ob-server or several observers. A single report concludedthat, for term infants, head circumference was one ofthe most reliable anthropometric measures, but intra-and interobserver variations were still typically on theorder of 20% of reported population standard devia-tions [Johnson et al., 1997]. One unpublished study hasexamined inter- and intraobserver variability for theOFC of adults and found a high degree of reproducibil-ity for both circumstances (Pober, personal communi-cation). These studies suggest that similar resultsmight be found for OFC measurements done on chil-dren, but this conjecture remains unproved. It isknown that the choice of measurement instrumentdoes influence the accuracy of the measurement [Rocheet al., 1987].

Two commonly used references for childhood OFCmeasurements are the National Center for Health Sta-tistics (NCHS) data based on the Fels LongitudinalStudy, and the Nellhaus data [Hamill et al., 1977,1979; Nellhaus, 1968]. The former is apparently basedon a study population that was 98.5% of European an-cestry, but on families with a wide range of socioeco-nomic status. The latter study oversampled childrenfrom families of low socioeconomic status and includeda range of ethnic groups. While these charts may beuseful for the anthropometric assessment of children inroutine child health settings, it is by no means clear

that they are appropriate for syndromic classification.For example, Fraser et al. [1988] demonstrated thatWest Indian children have substantially larger OFCsthan standard data suggest. Bale et al. [1991] sug-gested that OFC and height may be correlated in atleast some genetic disorders and in a small, highly se-lected population. If ethnicity and height are truly im-portant covariates for OFC, then perhaps the mea-sured OFC must be adjusted for these covariates beforeany classification of macrocephaly may be made.

I conclude this section with one final point. Appar-ently, it is commonly thought that children with themacrocephaly–hamartoma phenotype experience rapidprenatal somatic growth and subsequently ‘‘postnatalgrowth deceleration’’ [Miles et al., 1984]. In an unpub-lished paper I demonstrate that the apparent earlymacrosomia and subsequent growth deceleration maybe explained by macrocephaly alone (DiLiberti, submit-ted for publication). Total body length and mass arehigh initially because of the additional contributionfrom head size. The body, exclusive of the head, wasprobably never growing at an accelerated rate, so thatas the child grows, the head contributes proportionate-ly less to total body length and mass and the growthtrajectory crosses centile lines on the charts. This willoccur even if the head and body maintain constantgrowth patterns. A recent report on fetal ultrasonogra-phy implicitly supports this argument by demonstrat-ing that the cheek-to-cheek diameter explained ‘‘moreof the variance in birth weight than other parameters’’[Abramowicz et al., 1997]. Except for the macro-cephaly, this group of disorders should probably not beclassified among the overgrowth syndromes.

THE EVOLUTION OF A SYNDROME

Although much of the commonly used nomenclaturefor the macrocephaly–hamartoma phenotype refer-ences publications from the 1960s–1980s era, the be-ginning of this story apparently leads to a time overfour decades earlier.

Lhermitte-Duclos Syndrome and CowdenDisease—The Multiple Hamartoma Syndrome

In 1920, Lhermitte and Duclos, writing in a Frenchcancer journal, described an uncommon condition thatlater came to bear their names, but has also been calleddysplastic gangliocytoma. The most salient aspects ap-parently include macrocephaly, a slowly progressivecerebellar ataxia syndrome, generally appearing inadulthood, increased intracranial pressure, hamarto-matous changes in the cerebellum in which normalcells are replaced by hypertrophic ganglion cells, en-larged hands and feet; hyperkeratotic papules, and li-pomata [Lhermitte and Duclos, 1920]. These cases andsubsequently reported ones appeared to be predomi-nantly sporadic, but the number of reported cases re-mains small. Mental retardation is also common [Mil-bouw et al., 1988].

A 1963 paper by Lloyd and Dennis described a con-dition consisting of oral papillomatosis, craniofacialanomalies, thyroid adenomata, cystic adenoma andcarcinoma of the breast, bone cysts, frequent respira-

Macrocephaly–Hamartoma Syndromes 285

tory infections, and borderline intelligence. They pro-posed the term Cowden disease from the surname ofthe propositus [Lloyd and Dennis, 1963]. Although noother affected relatives were identified explicitly, sev-eral had what in retrospect appear to be strongly sug-gestive clinical findings.

The Lloyd-Dennis observations appear to have laindormant until 1972, when a multicenter report byWeary, Gorlin and others, in describing five new cases,expanded the description of this disorder and in theprocess renamed it the multiple hamartoma syndrome[Weary et al., 1972]. Although these authors focused onthe dermatologic description (for a publication in thedermatologic literature), they did explicate the risks forthyroid, breast, and gastrointestinal tumors—both be-nign and malignant. These observations were laterconfirmed and expanded in a pair of papers by Starink[Starink, 1984; Starink et al., 1986]. These reportsadded macrocephaly to the list of prevalent clinicalfindings, emphasized the ‘‘adenoid facies’’ first noted byLloyd and Dennis, and apparently confirmed an in-creased risk of malignancies at a variety of sites, andautosomal dominant inheritance.

A 1990 report by Padberg et al. and the subsequentobservations of Eng et al. provided strong clinical evi-dence that Lhermitte-Duclos ‘‘disease’’ and Cowden‘‘disease’’ were a ‘‘single phakomatosis’’ [Eng et al.,1994; Padberg et al., 1991]. The Padberg article de-scribed two families of three generations of individualswith Cowden disease and an individual concordant forCowden and Lhermitte-Duclos. Eng described a sibshipin which three individuals in successive generationswere concordant for the two conditions.

Bannayan, Riley, Zonana, Ruvalcaba, andRelated Observations

In 1960 Riley and Smith described a family with anapparently dominantly inherited condition comprisedof macrocephaly, multiple hemangiomata, and pseudo-papilledema. A woman and four of her seven offspringwere affected, although the two youngest children hadno evidence of hemangiomata. Microscopic examina-tion of a tissue samples obtained at biopsy in severalrelatives was ‘‘interpreted as a hemangioma’’ [Rileyand Smith, 1960]. They suggested, apparently cor-rectly, that there had been no prior descriptions of in-dividuals with these three clinical findings.

Bannayan subsequently described a three-and-a-halfyear old child with ‘‘Lipomatosis, Angiomatosis, andMacrencephalia’’ who died of complications followingthe attempted surgical removal of extensive lipoma-tous masses from the chest wall; abdominal wall, axil-lary, and extensive intrathoracic lesions were presentas well [Bannayan, 1971]. At necropsy similar tumorswere identified throughout the abdominal cavity, alongwith subserosal sessile and pedunculated masses alongthe entire length of the intestinal tract. The entire spi-nal canal was lined with lipomatous tissue 0.5 cm indepth. A vascular malformation extended from the su-perior mediastinum and occupied the entire left side ofthe neck as far as C1, damaging the clavicle and ver-tebrae. The parents had neither macrocephaly nor anyclinical signs of soft tissue tumors.

Stephan et al. reported on 10 unrelated patients withmacrocephaly and limb asymmetry along with one ormore patterns of angiomatosis: Sturge-Weber, cutismarmorata telangiectatica congenita, and Klippel-Trenaunay-Weber [Stephan et al., 1975]. No other rela-tives had macrocephaly, and the only observed vascu-lar anomaly was in the great-grandmother of one child.Subsequent reports by Moore et al. [1996] and Clayton-Smith et al. [1997] appear to be similar, if not identical.There was no evidence supporting Mendelian inheri-tance.

Zonana et al. [1976] described a family in which aman and his two sons had macrocephaly, multiple vis-ceral lipomas, lymphangiomata, and hemangiomata asan apparent autosomal dominant trait. They differen-tiated their family from the one previously reported byRiley and Smith, but suggested the phenotype was sub-stantially the same as that described by Bannayan.

When Ruvalcaba, Myhre, and Smith published their1980 report of two unrelated men with macrocephaly,hamartomata, and penile macules they initially sug-gested a variety of Sotos syndrome as a likely diagno-sis. Subsequent reports by DiLiberti et al. demon-strated that these men, along with another family, hadwhat appeared at that time to be a previously unre-ported condition, with an unusual lipid myopathy pres-ent along with the other abnormalities [DiLiberti et al.,1983; 1984]. This myopathy, and the presence of juve-nile intestinal polyps, clearly differentiated these indi-viduals from the Sotos syndrome; their separation fromthe ‘‘Bannayan–Zonana’’ syndrome was less definite. Itis of interest that unspecified thyroid disease and earlyonset bilateral breast cancer were also reported inthese papers.

A 1986 report by Okumura et al. describes a five-year-old girl with a phenotype virtually identical to theone reported by Bannayan 15 years earlier [Okumuraet al., 1986]. The lipomatosis was extremely aggres-sive, involving the pleural and abdominal cavities, theformer covered with thick sheets of tumor. Skeletalchanges secondary to tumor growth were also ob-served. This child, as in the Bannayan report, died ofsurgical complications of lipoma removal. Neither themother nor the father had any signs of soft tissue tu-mors or macrocephaly.

Somewhat later, DiLiberti demonstrated that theanomalies in muscle biopsy histochemistry seen in theoriginal ‘‘Ruvalcaba-Myhre-Smith’’ syndrome patientswere also evident in children and adults with macro-cephaly and hamartoma alone, and in individuals withfamilial macrocephaly [DiLiberti, 1992]. Because of thepossibility of an abnormality in muscle carnitine me-tabolism, seven of these children were treated with oralL-carnitine in a dose of 150 mg/kg/day. A clinically andstatistically significant improvement in gross motorquotient was observed following a six-month treatmentwith each child serving as her/his own control [DiLi-berti, 1993]. Subsequently Powell et al. confirmed themuscle biopsy observations in a group of 27 macroce-phalic children with heterogeneous phenotypes rang-ing from benign familial macrocephaly to the ‘‘Ruval-caba-Myhre-Smith syndrome.’’ They also treated their

286 DiLiberti

patients with L-carnitine and reported ‘‘subjective im-provement’’ in 17 [Powell et al., 1993].

CLINICAL SYNTHESIS

I have argued previously that similarities in clinicalphenotypes by themselves do not inform our decisionsto separate or unify the macrocephaly–hamartomasyndromes in any conclusive fashion [DiLiberti, 1990].Examples of phenocopies abound, making this sort ofconjecture risky. However, since my interchange withCohen on this issue both my own work, and that ofPowell et al. on muscle histochemistry and metabolism,provide much stronger evidence in favor of some sort of‘‘grand unification,’’ such as I have proposed more re-cently [DiLiberti, 1991; 1992; 1993; Powell et al., 1993].Additional clinical support for this point of view comesfrom a family reported by Gorlin et al. in which whatthe authors consider to be the ‘‘Ruvalcaba-Myhre,’’ ‘‘Ri-ley-Smith,’’ and ‘‘ Bannayan-Zonana’’ phenotypes arevariously expressed [Gorlin et al., 1992]. Based onthese published reports and personal observations cov-ering dozens of affected individuals I conclude (andagree with Cohen) that the macrocephaly–hamartomaphenotypes described by Zonana and Ruvalcaba, and inother similar patients, represent substantially thesame phenotype, comprised of macrocephaly, hamarto-mata, lipid myopathy, male preponderance, penilemacules, ocular anomalies, and autosomal dominantinheritance. Zonana first suggested that the family hereported had the same condition as the child describedby Bannayan—leading to the eponym now sometimesused. Careful review of that report, and of the subse-quent, nearly identical, report by Okumura et al., leadsme to doubt he reported the same condition as Zonanafor several reasons. First, Bannayan and Okumuraeach reported apparently isolated cases. Both sets ofparents were examined and neither had any evidentmanifestations, including macrocephaly. Each childwas a girl and succumbed to complications of their con-dition. Macrodactyly and a soft tissue tumor werenoted at birth in the Okumura report. Second, al-though the lipomatosis was histologically benign, itwas an incredibly invasive process, covering the entirespinal canal to a depth of 0.5 cm in Bannayan’s report.In both girls thick sheets of lipomatous tissue coverednearly the entire parietal pleura. In addition, an exten-sive vascular malformation invaded cervical vertebraeand eroded a clavicle. Lesions of this extent and behav-ior do not appear to have been observed in any otherreported individuals. These two cases appear to differclinically from the other macrocephaly–hamartomaphenotypes; the absence of parental involvement ineach case suggests the possibility of a genocopy (possi-bly autosomal recessive). Arguing from a statisticalperspective, what is the likelihood that two childrenwith the condition we are considering in this articlewould each be both sporadic cases and female when theprior probabilities of these events are quite low? Theresulting joint probability should be very small. Cou-pling this exceedingly low probability with a phenotypethat, in my opinion, differs quite markedly from theones described by Zonana and Ruvalcaba argues

against including the Bannayan and Okumura cases inthe spectrum of the macrocephaly–hamartoma pheno-type presently under consideration. Although the re-port by Riley and Smith was arguably the first well-characterized example of this phenotype, the apprecia-tion of this apparent priority came slowly. Inclusion ofpseudopapilledema as a clinical characteristic of thisdisorder seems reasonable, however, keeping in mindthe relative scarcity of clinical reports as well as thepresence of associated hamartomata in only one [Dviret al., 1988; Hoover et al., 1986; Riley and Smith, 1960].

The patients reported by Stephan et al. and thosedescribed more recently by Toriello et al. and Clayton-Smith et al. all seem to differ substantially from themacrocephaly–hamartoma phenotype we are consider-ing, for much the same reasons as stated previously.All were sporadic, and the clinical phenotypes appearto relate to underlying vascular malformations ratherthan to ‘‘overgrowth’’ per se.

Having now excluded several conditions from furtherdiscussion, I add several that had until recently notbeen considered as part of this phenotypic spectrum.The child development and neurology literature appar-ently first proposed the existence of ‘‘benign familialmacrocephaly’’ (BFM) comprised of autosomal domi-nant macrocephaly, extreme male preponderance, andhypotonia in infancy with generally normal subsequentdevelopment [Asch and Myers, 1976]. Curiously, whenthis same group of children reached neurosurgicalevaluation, they were considered to have either ‘‘ar-rested’’ or ‘‘external’’ hydrocephalus, especially the lat-ter, subsequent to modern neurodiagnostic imagingmodalities [Alvarez et al., 1986]. Relatively large fron-tal collections of subarachnoid fluid were noted on com-puted tomography/magnetic resonance imaging lead-ing to the construction of an hydraulic pathophysiologicmodel. Similar, if not identical, neuroimaging findingswere noted in BFM. The identity of BFM with arrested/external hydrocephalus seems reasonably certain atpresent [Alvarez et al. 1986]. The relevance of this syn-thesis became apparent when DiLiberti [1992] andsubsequently Powell et al. [1993] demonstrated thatthe muscle histopathology was apparently identical inindividuals with the macrocephaly–hamartoma andthe BFM phenotypes. Powell went on to show that theyshared another characteristic—skeletal muscle carni-tine deficiency.

Prior to molecular investigations then, classificationof an autosomal dominant macrocephaly +/− hamarto-ma phenotype would appear to be justified based onclinical, histochemical, and genealogical data. Malesapparently come to medical attention far more fre-quently than females, perhaps due to a higher likeli-hood of hypotonia in infancy and early childhood. It isunknown whether the prevalences of macrocephalyand hamartomata are actually higher among malescarrying this gene or whether males only come to medi-cal attention more frequently. Ocular anomalies suchas prominent Schwalbe’s lines, prominent cornealnerves, and pseudopapilledema are observed occasion-ally. Penile macules appear to be reasonably commonamong males, although they may be more evident inmidchildhood than at other times, and their prevalence

Macrocephaly–Hamartoma Syndromes 287

in comparison with the general population is uncer-tain. The clinical phenotype associated with the spec-trum of cases reported by Riley, Zonana, Ruvalcaba,and others probably represents only a small fraction ofthe total prevalence, the bulk falling into the BFM phe-notype.

Both Gorlin and I have long had suspicions thatCowden disease and the autosomal dominant macro-cephaly–hamartoma phenotypes might be allelic [Gor-lin, personal communication]. My research for thismanuscript leads me to conclude that he was undoubt-edly the first to ponder this possibility based on hisearlier work on the Cowden syndrome [Weary et al.,1972]. Recent discoveries in molecular genetics haveelucidated some of the questions raised by historic at-tempts to classify these conditions.

MOLECULAR ADVANCES

Understanding of the molecular biology of this groupof disorders has progressed rapidly recently. In May of1996 Nelen et al. localized the gene for Cowden diseaseto the q22-23 region of chromosome 10 [Nelen et al.,1996]. Ten months later, in March of 1997, Liaw et al.correlated mutations in the PTEN (phosphatase andtensin homolog deleted on chromosome ten) gene at10q23 with the Cowden disease phenotype [Liaw et al.,1997]. That same month Li et al. reported that PTENmutations were observed with high frequency in brain,breast, and prostate cancer [Li et al., 1997]. One monthlater Steck et al. reported ‘‘a candidate tumor suppres-sor gene, MMACl, at chromosome band 10q23.3 that ismutated in multiple advanced cancers’’ [Steck et al.,1997]. PTEN and MMCA1 were subsequently shown tobe the same gene. In August of 1997 Marsh et al. pro-vided convincing evidence that what they call the ‘‘Ban-nayan-Zonana’’ syndrome was due to mutations ofPTEN. The following month Arch et al. reported asingle child with the ‘‘Bannayan-Riley-Ruvalcaba’’ syn-drome with an interstitial deletion at 10q23.2-q24.1.Absence of the PTEN gene was confirmed using fluo-rescent in situ hybridization [Marsh et al., 1997; Archet al., 1997]. Kong et al. subsequently reported thatloss of heterozygosity at the PTEN locus was stronglyassociated with endometrial carcinoma [Kong et al.,1997].

To some extent a hazy but consistent picture is be-ginning to emerge from these data. PTEN appears tohave both a protein phosphatase kinase domain and aregion of extensive homology to tensin. The homologywith protein phosphatase kinase strongly suggeststhat PTEN should function as a tumor suppressor,with loss of heterozygosity leading to faulty regulationof cell growth. The prevalence of hamartomatous and ofmalignant tumors in both the multiple hamartoma andmacrocephaly–hamartoma phenotypes, along withovergrowth of at least one organ—the central nervoussystem—would appear to fit these postulated gene ac-tivities. Possible explanations for the commonly ob-served autoimmune thyroiditis and lipid myopathy(with probable carnitine deficiency) are less evidentfrom the known molecular data, but presumably willbecome clear as the gene function is further delineated.

Mutation analysis of the PTEN locus has been un-dertaken in 13 families and 11 isolated individualswith the Cowden phenotype; mutations were detectedin 13. Mutations were detected in both families withthe macrocephaly–hamartoma phenotype. Several ofthe mutations were detected in more than one family orindividual, but at the present time the correlation be-tween clinical phenotype and specific mutations mustbe viewed as very preliminary (Table I). Of particularinterest is the identification of an Arg233Stop muta-tion in one family with the Cowden phenotype of mac-rocephaly, goiter, and trichilemmoma, while a familyconsidered to have the ‘‘Bannayan-Zonana’’ phenotypewith macrocephaly, lipomata, penile macules, andHashimoto’s thyroiditis was found to have the identicalmutation [Liaw et al., 1997; Marsh et al., 1997].

In addition to these studies of gene function, exten-sive clinical-molecular correlations remain to be eluci-dated. Do all of the macrocephaly–hamartoma pheno-types map to PTEN, and how consistently do the mu-tations and clinical phenotypes correlate? A perhapslarger question is the hypothesis of an ‘‘expanded phe-notype.’’ Muscle histopathologic findings appear to beconsistent across a broad range of phenotypes. Lipidmyopathy has generally been thought to be relativelyrare per se, but the presence of intracellular lipid, largetype 1 muscle fibers, and small type 2 fibers is mostunusual. In a retrospective analysis of muscle biopsyresults in a large neuropathology laboratory the onlytwo children with unexplained lipid myopathy weretracked and both found to belong to familial macro-cephaly kindreds (DiLiberti, personal observation).

ANOTHER LOOK AT NAMING ANDNOMENCLATURE

As noted above, Cohen and I have previously dis-cussed this issue from opposing perspectives—he favor-ing eponymic nomenclature, while I continue to sup-port descriptive terminology. Science in general, andmedicine in particular, have often attempted to honordiscoverers through the use of eponyms. As most his-torians of science tell us, discovery is rarely a totallyindividual process. The individual(s) who receive(s)

TABLE I. Correlation Between Mutation Analysis andPrinciple Clinical Findings Among Cowden Disease (CD) and

Hamartoma Autosomal Dominant Macrocephaly(HAM) Syndrome*

Phenotype MutationIncreased

OFC Thyroid Skin CNS

CD1 FrSh N1192 ? + − −CD1 ‘‘N262 + − + +CD1 ‘‘N183 + + + +CD1 His123Arg + + + +CD1 Cys124Arg + + + −CD1 Arg130Stop + + + +CD1,2 Glu157Stop + − + +CD2 Gly129Glu ? + + +CD2 Arg233Stop + + + −HAM3 Arg233Stop + + − −HAM3 Ser170Arg + − − −

*References: 1. Nelen et al. [1997], 2. Liaw et al. [1997], 3. Marsh et al.[1997].

288 DiLiberti

credit for discovery may in fact be deserving but sub-sequent scholarship not infrequently identifies an an-tecedent discovery that for any one of a number of rea-sons failed to achieve notice. The disorder currentlyunder discussion provides a seminal example. At vari-ous times over the past few decades, cases of what wenow fairly confidently consider to be the same conditionhave been variously categorized using perhaps a dozenor more eponymic terms, e.g., Ruvalcaba-Myhre-Smith.Who deserves the most credit? Probably Lhermitte, be-cause he was the first author on the earliest known (sofar) paper probably describing (part of) this condition;Lloyd, Bannayan, Zonana, and Ruvalcaba because theywere credited with the initial description other parts;Nelen for being the first author of the first paper ap-parently identifying the genetic locus; and Gorlin, be-cause he was (as far as I know) the only person involvedwith the clinical and molecular description of this con-dition, as well as participating in the description ofboth the Cowden disease phenotype and the phenotypefirst reported by Riley, Zonana, and Ruvalcaba. Basedon historical considerations then the eponymic nomen-clature ought to be the ‘‘Lhermitte-Duclos-Riley-Smith-Lloyd-Dennis-(Bannayan ?)-Zonana-(Ruvalcaba-Myhre)-Nelen-Marsh-Gorlin syndrome,’’ perhaps withthe parenthesized authors removed because Bannayanprobably characterized an entirely different disorderand Ruvalcaba at first proposed his patients had a So-tos variant, although one of his coauthors, DavidSmith, apparently disagreed (Cohen, personal commu-nication). Even with the exclusions most would findthis rather unwieldy—not only is it a bit on the longside, but it fails to describe anything about the condi-tion. Nor does it seem that naming it after a patient,Rachel Cowden, as Lloyd and Dennis did in their 1963paper, is any more appropriate. Indeed, Weary, Gorlin,et al. argued previously: ‘‘Because the eponymCowden’s disease is of no significance as far as classi-fication of this disorder is concerned, [emphasis added]we propose an alternative title, the multiple hamarto-ma syndrome (MHS).’’ I likewise suggest that an acro-nym makes the most sense for compactness and utility.Based on the most prevalent aspects of individuals de-scribed to this point (and knowing full well the prob-lems of ascertainment and publication bias), I offer thefollowing nomenclature for consideration: MATCHS,for macrocephaly (and myopathy), autosomal domi-nant, thyroid disease, cancer, hamartomata, and skinabnormalities.

Reasonably compact and descriptive/mnemonic, thisterm could prove useful, knowing of course that mo-lecular biology and epidemiology may totally changeour current perceptions of this disorder in the future.Since a gene locus has now been identified, includingPTEN in whatever terminology comes into wide accep-tance would seem to be logical. PTEN - MATCHSwould appear to serve a useful function, for at least thetime being, by including both the currently acceptednomenclature for the gene locus and an acronym thatcovers the present level of understanding regarding therange of the clinical phenotype. The latter may changeas we develop further understanding of mutation–phenotype correlations. Both Zonana and Ruvalcaba

support acronymic nomenclature that includes the cur-rent gene name, PTEN (Zonana, personal communica-tion; Ruvalcaba, personal communication).

UNFINISHED BUSINESS

The recent rapid progress in understanding thisgroup of disorders still leaves many questions unan-swered. One of the most interesting is the relationshipof PTEN - MATCHS to the Sotos syndrome (SS). Al-though attempts have been made to maintain SS as adistinct entity, not infrequently misclassification hasoccurred. These misclassifications have generally re-sulted from what might be considered liberal use of theSS diagnosis, with subsequent reclassification to whatI propose should now be called PTEN - MATCHS[Halal, 1982; Powell et al., 1993; Ruvalcaba et al.,1980]. My earlier comments regarding the contributionof large head size to the appearance of macrosomia/overgrowth in young children may explain part of theconfusion. Misclassification may also occur becausethere is so much overlap, either between two similardisorders or between two similar sets of diagnostic cri-teria that in fact, are actually being used to separatevariability among individuals with a single disorder. Atleast a subset of patients considered to have SS shouldbe studied for PTEN mutations to see if this over-growth disorder may also be explained, at least in part,by these mutations. Similarly, BFM must be studiedsystematically to confirm or refute the apparentlystrong histochemical and metabolic data suggestingidentity with PTEN - MATCHS.

REFERENCES

Abramowicz JS, Robischon K, Cox C (1997): Incorporating cheek-to-cheekdiameter, biparietal diameter and abdominal circumference improvesweight estimation in the macrosomic fetus. Ultrasound Obstet Gynecol9:409–413.

Alvarez LA, Maytal J, Shinmar S (1986): Idiopathic external hydrocepha-lus: Natural history and relationship to benign familial hydrocephalus.Pediatrics 77:901–907.

Arch EM, Goodman BK, Van Wesep RA, Liaw D, Clarke K, Parsons R,McKusick VA, Geraghty MT (1997): Deletion of PTEN in a patient withthe Bannayan-Riley-Ruvalcaba syndrome suggests allelism withCowden disease. Am J Med Genet 71:489–493.

Asch AJ, Meyers GJ (1976): Benign familial macrocephaly. Pediatrics 57:535–539.

Bale SJ, Amos CI, Parry DM, Bale AE (1991): Relationship between headcircumference and height in normal adults and in the nevoid basal cellcarcinoma syndrome and neurofibromatosis type I. Am J Med Genet40:206–210.

Bannayan GA (1971): Lipomatosis, angiomatosis, and macroncephalia: Apreviously undescribed congenital syndrome. Arch Pathol 92:1–5.

Clayton-Smith J, Kerr B, Brunner H, Tranebjaerg L, Magee A, HennekamRC, Mueller RF, Brueton L, Super M, Steen-Johnsen J, Donnai D(1997): Macrocephaly with cutis marmorata, haemangioma and syn-dactyly—a distinctive overgrowth syndrome. Clin Dysmorphol 6:291–302.

Cohen MM (1990): Bannayan-Riley-Ruvalcaba syndrome: Renaming threeformerly recognized syndromes as one etiologic entity. Am J Med Genet35:291.

DiLiberti JH, Weleber RG, Budden SS (1983): Ruvalcaba-Myhre-Smithsyndrome: A case with probable autosomal dominant inheritance andadditional manifestations. Am J Med Genet 15:491–495.

DiLiberti JH, D’Agostino AN, Ruvalcaba RH, Schimschock JR (1984): Anew lipid storage myopathy observed in individuals with the Ruval-caba-Myhre-Smith syndrome. Am J Med Genet 18:163–167.

Macrocephaly–Hamartoma Syndromes 289

DiLiberti JH (1990): Comments on Dr. Cohen’s letter. Am J Med Genet35:292.

DiLiberti JH (1991): Prevalence of lipid storage myopathy in the macro-cephaly syndromes: Clinical correlations and outcome of carnitinetherapy. Pediatr Res 29:68A.

DiLiberti JH (1992): Correlation of skeletal muscle biopsy with phenotypein the familial macrocephaly syndromes. J Med Genet 29:46–49.

DiLiberti JH (1993): Familial macrocephaly: synthesis and semantics. ProcGreenwood Genet Center 12:69–70.

Dvir M, Beer S, Aladjem M (1988): Heredofamilial syndrome of mesoder-mal hamartomas, macrocephaly, and pseudopapilledema. Pediatrics81:287–290.

Eng C, Murday V, Seal S, Mohammed S, Hodgson SV, Chaudary MA,Fentiman IS, Ponder BA, Eeles RA (1994): Cowden syndrome andLhermitte-Duclos disease in a family: a single genetic syndrome withpleiotropy? J Med Genet 31:458–461.

Fraser FC, Smith R, Esseltine D, Arbour L (1988): Head circumference isbigger in West Indian blacks than Montreal whites. Am J Hum Genet43:A49.

Gorlin RJ, Cohen MM, Condon LM, Burke BA (1992): Bannayan-Riley-Ruvalcaba syndrome. Am J Med Gen 44:307–314.

Halal F (1982): Male to male transmission of cerebral gigantism. Am J MedGenet 12:411–419.

Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF (1977): Growthcurves for children birth–18 years, United States. Vital Health Stat11(165): I-IV. Department of Health, Education and Welfare Publica-tion No. (PHS) 78-1650. Government Printing Office.

Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM (1979):Physical growth: National Center for Health Statistics percentiles. AmJ Clin Nutr 32:607–629.

Hoover DL, Giangiacomo J, Burns F (1986): Pseudopapilledema and mac-rocephaly in a child. Ophthalmic Paediatr Genet 7:181–185.

Johnson TS, Engstrom JL, Gelhar DK (1997): Intra- and interexaminerreliability of anthropometric measurement of term infants. PediatrGastroenterol Nutr 24:497–505.

Jones KL (1997): ‘‘Smith’s Recognizable Patterns of Human Malforma-tion.’’ 5th Ed. Philadelphia: W.B. Saunders.

Kong D, Suzuki A, Zou TT, Sakurada A, Kemp LW, Wakatsuki S, Yo-koyama T, Yamakawa H, Furukawa T, Sato M, Ohuchi N, Sato S, YinJ, Wang S, Abraham JM, Souza RF, Smolinski KN, Meltzer SJ, HoriiA (1997): PTEN1 is frequently mutated in primary endometrial carci-nomas. Nat Genet 17:143–144.

Lhermitte J, Duclos P (1920): Sur un ganglioneurome diffus du cortex ducervelet. Bull Assoc Fr Etude Cancer 9:99–107.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SJ (1997): PTEN, aputative protein tyrosine phosphatase gene mutated in human brain,breast, and prostate cancer. Science 275:1943–1947.

Liaw D, Marsh D, Li J, Dahia PLM, Wang SI, Zheng Z (1997): Germlinemutations of the PTEN gene in Cowden disease, an inherited breastand thyroid cancer syndrome. Nat Genet 16:64–67.

Lloyd KM, Dennis M (1963): Cowden’s disease: A possible new symptomcomplex with multiple system involvement. Ann Intern Med 58:136–142.

Marsh DJ, Dahia PLM, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C(1997): Germline mutations in PTEN are present in Bannayan-Zonanasyndrome. Nat Genet 16:333–334.

Milbouw G, Born JD, Martin D, Collignon J, Hans P, Reznik M, Bonnal J(1988): Clinical and radiological aspects of dysplastic gangliocytoma(Lhermitte-Duclos disease): A report of two cases with review of theliterature. Neurosurgery 22:124–128.

Miles JH, Zonana J, Macfarlane J, Aleck KA, Bawle E (1984): Macro-

cephaly with hemangiomas: Bannayan-Zonana syndrome. Am J MedGenet 19:225–234.

Moore CA, Toriello HV, Abuelo DN, Bull MJ, Curry CJ, Hall BD, HigginsJV, Stevens CA, Twersky S, Wedsberg R, Dobyns WB (1997): Macro-cephaly-cutis marmorata telangiestatica congenita: A distinct disorderwith developmental delay and connective tissue abnormalities. Am JMed Genet 70:67–73.

Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR,Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, HodgsenS, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM,Ponder BA, Ropers HH, Kremer H, Longy M, Eng C (1996): Localiza-tion of the gene for Cowden disease to chromosome 10q22-23. NatGenet 13:114–116.

Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H,Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, PadbergGW, Kremer H (1997): Germline mutations in the PTEN/MMAC1 genein patients with Cowden disease. Hum Mol Genet 6:1383–1387.

Nellbaus G (1968): Head circumference from birth to eighteen years: Prac-tical composite international and interracial graphs. Pediatrics 41:106–114.

Okumura K, Sasaki Y, Ohyama M, Nishi T (1986): Bannayan syndrome—generalized lipomatosis associated with megalencephaly and macro-dactyly. Acta Pathol Jpn 36:269–277.

Padberg GW, Schot JDL, Vielvoye GJ, Bots GTAM, de Beer FC (1991):Lhermitte-Duclos Disease and Cowden Disease: A single phakomato-sis. Ann Neurol 29:517–523.

Powell BR, Budden SS, Buist NRM (1993): Dominantly inherited mega-lencephaly, muscle weakness, and myoliposis: A carnitine-deficientmyopathy within the spectrum of the Ruvalcaba-Myhre-Smith syn-drome. J Pediatr 123:70–75.

Riley HD, Smith WR (1960): Macrocephaly, pseudopapilledema and mul-tiple hemangiomata: A previously undescribed heredofamilial syn-drome. Pediatrics 26:293–300.

Roche AF, Mukherjee D, Guo S (1986): Head circumference growth pat-terns: birth to 18 years. Hum Biol 58:693–906.

Roche AF, Mukherjee D, Guo S, Moore WM (1987): Head circumferencereference data: birth to 18 years. Pediatrics 79:706–712.

Ruvalcaba RHA, Myhre S, Smith DW (1980): Sotos syndrome with intes-tinal polyposis and pigmentary changes of the genitalia. Clin Genet18:413–416.

Starink M (1984): Cowden’s disease: Analysis of 14 new cases. J Am AcadDermatol 11:1127–1141.

Starink T, van der Veen JP, Arwert F, de Waal LP, de Lange GG, Gille JJ,Eriksson AW (1986): The Cowden syndrome: A clinical and geneticstudy in 21 patients. Clin Genet 29:222–233.

Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, LangfordLA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B,Teng DH, Tavtigian SV (1997): Identification of a candidate tumoursuppressor gene, MMAC1, at chromosome 10q23.3 that is mutated inmultiple advanced cancers. Nat Genet 15:356–362.

Stephan MJ, Hall BD, Smith DW, Cohen MM (1975): Macrocephaly inassociation with unusual cutaneous angiomatosis. J Pediatr 87:353–359.

Weary PE, Gorlin RJ, Gentry WC, Comer JE, Greer KE (1972): Multiplehamartoma syndrome (Cowden’s disease) Arch Dermatol 106:62–66.

Weaver DD, Christian JC (1980): Familial variation of head size and ad-justment for parental head circumference. J Pediatr 96:990–994.

Winter RM, Baraitser M (1996): ‘‘London Dysmorphology Database.’’ Ox-ford: Oxford University Press.

Zonana J, Rimoin DL, Davis DC (1976): Macrocephaly with multiple lipo-mas and hemangiomas. J Pediatr 89:600–603.

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