American Journal of Medical Genetics 43669-677 (1992)

Variability Versus Heterogeneity in Syndromal Hypothalamic Hamartoblastoma and Related Disorders: Review and Delineation of the Cerebro-AcroVisceral Early Lethality (CAVE) Multiplex Syndrome Alain Verloes, Yves Gillerot, Jean-Paul Langhendries, Jean-Pierre F’ryns, and Lucien Koulischer Centre for Human Genetics, L i 2 e University (A.V.,L.K.),Centre for Human Genetics, Institute for Morphologic Pathology, Loverval (Y.G.),Neonatal Intensive Care Unit, Clinique St Vincent, Rocourt (J.P.L.),and Centre for Human Genetics, Leuven University, Belgium (J.P.F.) We report on a case of neonatal hypothalamic hamartoblastoma with holoprosencephaly, Hirschsprung disease, and tetramelic postaxial polydactyly. Twenty-seven previous cases of congenital hypothalamic embryonic tumours with associated congenital defects are reviewed. A classification in isolated, associated, and syndromal forms is proposed. The difficulties encountered in differential diagnosis between the syndromal form (mainly represented by the Pallister-Hall syndrome) and related diseases as Smith-Lemli-Opitz type 11,holoprosencephaly-polydactyly,orofaciodigital type VI and hydrolethalus syndromes are outlined. Two pathogenic mechanisms are discussed: a classical pleiotropic model and single sequence model. The latter is sufficient to delineate syndromal hypothalamic hamartoblastoma. With the former, syndromal hypothalamic hamartoblastoma cannot be clearly recognized in the absence of a CNS tumour, a child with syndromal hypothalamic hamartoblastoma cannot be reliably diagnosed as Pallister-Hall rather than another MCA syndrome, and, ultimately, the existence of Pallister-Hall syndrome could be questioned, as it could only be the extreme expression of one or several other syndromes. As this hypothesis cannot be proven or disproven at this point, the authors suggest creating the concept of multiplex phenotype. “Cerebro-Acro-VisceralEarly lethality multiplex syndrome” is suggested to encompass all the ambiguous cases. Within this complex, an operative classification key is proposed. 0 1992 Wdey-Liss,Inc.

Received for publication June 29,1990; revision received August 28, 1991. Address reprint requests to Dr. A. Verloes, Centre de GBnBtique, Pathologie B23, CHU Sart Tilman, (B)-4000 Liege, Belgium.

0 1992 Wiley-Liss, Inc.

KEY WORDS: genitopalatocardiacsyndrome, holoprosencephaly - polydactyly syndrome, holoprosencephaly sequence, hydrolethalus syndrome, hypothalamic hamartoma, lethal acrodysgenital dwarfism, orofacio-digital syndrome type VI, Pallister-Hall syndrome, Rutledge syndrome, SmithLemli-Opitz syndrome type 11, Varadi-Papp syndrome

INTRODUCTION The first descriptions of the association between a hypothalamic hamartoblastoma and a malformation were given in the early 1950s. A more severe syndrome was further delineated in 1980 by Hall et al. and is currently known as Pallister-Hall syndrome. Recently, we observed a new severely affected patient, who was previously classified as holoprosencephaly-polydact yly syndrome. CLINICAL REPORT GD (Genetic file # 5136) was the first boy of nonconsanguineous parents of Belgiadtalian ancestry. Father’s age was 38. Family history was not remarkable. The mother had no upper lateral incisors. Prenatal diagnosis of IUGR and holoprosencephaly was made at 34 weeks by date. The child was born at 38 weeks, with a weight of 1,960 g, a length of 44 cm, and an OFC of 28.8 cm. He had premaxillary agenesis (hypotelorism, single nostril, median cleft of the lip, cleft palate (Fig. 11, normal tongue, bilateral microphthalmia, tetramelic postaxial polydactyly, and penile hypoplasia. Anus was patent and normally placed. Limbs were not short. GTGbanded chromosomes were normal. CT scan showed an alobar holoprosencephalywith an enlarged median ventricle and 2 diverging posterior horns, but failed to dem-

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Fig. 1. Face of the patient (at 2 months):premaxillaryagenesis and hypotelorism.

onstrate any expansive process in the brain stem. Hence, the diagnosis of holoprosencephaly-polydactyly syndrome was suggested for this child [Ramaekers et al., 19901. Recto-sigmoidal Hirschsprung disease was diagnosed soon after birth. Death at 2.5 month was attributed to peritonitis following intestinal perforation. Radiographs confirmed complete duplication of the 5th digits (3 phalanges visible in hands, 2 phalanges visible on feet) with enlarged to bifid distal 5th metacarpals and metatarsals. The 4th metacarpals were not short (Fig. 2). Spine, pelvis, and ribs were not remarkable. Necropsy confirmed aganglionosis of the distal colon. Heart, lungs, trachea, kidneys, and adrenals were macroscopically and microscopically normal. Thyroid was not examined. The univentricular brain weighed only 190 g. Olfactive tracts were absent. A large tumour (35 x 25 mm) bulged from the base of the brain and distorted the pons and cerebellum (Fig. 3). Hypophysis was present. Vermis was not hypoplastic. An hypothalamic hamartoblastoma lacking neoplastic changes was confirmed by microscopic examination.

DISCUSSION Some years ago, syndromologists and clinical geneticists were pleasantly divided into splitters (who cut defined entities in several subgroups) and lumpers (who merge in a single entity several previously independent syndromes). With the increasing bulk of reported congenital anomalies, 2 new categories may be delineated. The “stretchers” are mainly preoccupied with extending the limits of a given phenotype, by adding milder or unusually severe variants. The cut-and-pasters displace

the same atypical or borderline cases from one syndrome to another. Gene-based classification of syndromes tends to gather every clinical expression of a single gene in a unique nosologic box; for nonmendelian syndromes, the key for grouping is the pathogenic mechanism (e.g., sequences and spectra). For mendelizing disorders, this scientific approach has proven to be very powerful, as seen in the invaluable and universally accepted McKusick catalog. Although very important, this classification is not always so rewarding, and even may be of little practical value for clinical practice. When dealing with patients, or for basic genetic counseling, who could consider, e.g., Duchenne and Becker muscular dystrophies as the same disease, although the same gene is involved? P-Thalassaemia major and sickle cell anaemia, or benign hyperphenylalaninaemia vs phenylketonuria are other situations were an operative nongenomic classification remains necessary within a single MIM entry. What is true for well-known, nonheterogeneous monogenic diseases is still more important in the clinical workup of dysmorphic/MCA syndromes, which for the number of involved loci or the coexistence of nongenetic “phenocopies” is poorly known. For those syndromes, the attempts to split, lump, stretch, or cut-andpaste individual reports or series to match a limited number of predefined (presupposed?) genotypes may sometimes look like an intellectual but fruitless game. The primary task for a dysmorphologist consists in matching a given constellation of defects observed in a patient with a previously described syndrome. As none of its manifestations is mandatory, a syndrome is usually represented as an ideal template, and accepting or rejecting a diagnosis obeys empiric rules. The first step of validation is fulfilled if a minimal number of items among a list are present. The use of electronic databases clearly shows that the true mental workup in diagnosing MCA goes far beyond this simple combinatory list checking. A second and very important step is a form of “Gestalt” pattern recognition, through which a diagnosis is felt to be dubious or obviously false, even if the “checklist” test has been’ conclusive. This step unfortunately is highly subjective or intuitive, and escapes any attempt a t scientific modelisation. During the last 15 years, a number of severe MCA syndromes affecting brain, limb, and viscera have been delineated, which show an extreme phenotypic overlap: Smith-Lemli-Opitz (SLO) type I1 (lethal acrodysgenital dwarfism) [Curry et al., 1987;Le Merrer et al., 19881, hydrolethalus syndrome [Salonen et al., 1981; Salonen and Herva, 19901, orofaciodigital (OFD) type VI (Varadi-Papp syndrome)[Varadi et al. 1980; Mattei and Ayme, 19831, holoprosencephaly-polydactyly (pseudotrisomy 13) [Young and Madders, 1987;Verloes et al., 1991; Cohen and Gorlin, 19911, and Pallister-Hall syndrome. SLO syndrome type I1 has been variably considered as a separate entity or as the severe expression of the “common” SLO syndrome. Similarly, acrocallosal syndrome is felt by some authors to represent the milder expression of hydrolethalus syndrome. Considerable confusion has arisen from this “syndrome burst.”

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Fig. 2. (a-d) Posaxial polydactyly with duplication of the 5th ray

The first, and major difficulty in syndrome recognition lies in the definition of those minimal criteria of inclusion. The definition of the limits of a syndrome depends for an appreciable part on its original description and on the filters set by the authors to accept or reject a case in their series, which in turn lead to the definition of the first syndrome “template.”A clear illus-

tration of possible selection bias in syndrome delineation is given by SLO type 11: among the 27 new cases collected by Curry and Le Merrer, 22 are 46,XY, and all of them have some degree of sexual ambiguity. Does that mean that SLO type I1 cannot be seen without genital anomalies in males, and that it occurs 5 time less frequently in females, or does it signify that affected

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Fig. 3. (a)AP view: the tumour bulges from the mesencephalic area. (b)Sagittal section of the cerebral peduncles showing the enlarged brain stem and the cerebellum.

females and less ambiguous males have been missed, rejected, or assigned other diagnoses in the centres that collaborated on the 2 works? This involuntary shift toward an initial pattern results in a form of “founder effect,” which as much chance to perpetuate that the set of patients cited for the initial delineation is large and concordant. Subsequent lumping of highly concording syndromes with others will always generate pros and cons, depending on their appreciation of the discriminating value of the various signs. Difficulties in coping with “founder effect”are illustrated by the discussion on the independence of genitopalatocardiac syndrome (Gardner-Silengo-Wachtel syndrome [Greenberg et al., 198711, based on the presence of gonadal dysgenesis, or Rutledge syndrome [Rutledge et al., 19841 based on rhizomelic shortening of the arms and gallbladder aplasia, from SLO type I1 [Opitz and Lowry, 1987; Gorlin et al., 19901,or the differentiation of SLO type I1 and holoprosencephaly-polydactyly syndrome [Verloes et al., 1991; Cohen and Gorlin, 19911. Illustration of the founder effect in the delineation of “independent” syndromes later proved to be identical are numerous: Coffin syndrome and Lowry syndrome, Stickler syndrome, micrognathic dwarfism, and Weissenbacher-Zweymuller syndrome. Later recognition of the genetic uniqueness of several phenotypically distinct syndromes does not mean that the previous classification must be discarded, if there is no or very rare intrafamilial variation, because genetic counseling, strategies of prenatal diagnosis, and attitude toward decision of abortion may be modulated by the clinical form of the disorder. If intrafamilial variation is the rule, and for the same reasons, a definite lumping is more rewarding. We shall first review the literature on Pallister-Hall

syndrome and other MCA with hypothalamic hamartoblastoma, and propose a graded classification based on its variability. Then, we shall give evidence that suggests it is impossible to solve the heterogeneity question in Pallister-Hall syndrome, to recognize it when the tumour is lacking, and for the subjectivity of differential diagnosis between it and other sublethal MCA syndromes. Finally, we shall outline a possible operative and purely phenotypic classification, based on the concept of multiplex syndrome.

SYNDROMES WITH HYPOTHALAMIC HAMARTOBLASTOMA Review Twenty-eight patients with hamarto(b1ast)oma and associated defects have been reported, including our case. Those cases may be subdivided into 4 sets. Cases reported before 1980. The first possible case of hypothalamic tumour and polydactyly was described by Bertelotti [1914] in a dwarfed child with polydactyly, mental retardation, obesity, retinitis pigmentosa, optic nerve atrophy, and a tumour of the hypothalamic region which was not clearly characterized (this child also could have been affected with BardetBiedl syndrome). Brouwer [1950] reported a mentally deficient boy with hypothalamic tumour consisting mainly of poorly differentiated “embryonic” neurons, obesity, precocious puberty, and tetramelic polysyndactyly with metacarpal synostosis, who died at age 20 years. Stotijn and Nauta [19501 described a nondysmorphic boy with premature puberty who died at 10 years; he had a hypothalamic tumour, brachydactyly, partial duplication of the nail of the thumb, funnel chest, spina bifida occulta, and mental retardation and regression. Marcuse et al. [19531 pointed out the asso-

Syndromal Hypothalamic Hamartoblastoma ciation of a hypothalamic tumour with extracephalic malformations: Fallot tetralogy in one case, cleft palate in another. In both cases, tumours were described as hamartomas, and were not invasive but accompanied by signs of compression. The family history of case 1 of Marcuse et al. [19531 is most interesting: one sib died with “internal hydrocephalus”; another one had the same dramatic clinical course as the propositus and died at 2 months, but was not necropsied; a child born to the father’s brother and mother’s sister died with a tumour of the pons, “the section [of which resembled1those of the hamartoma presented here by the presence of mature ganglion cells. . . . A possible origin from the hypothalamus cannot be ruled out” [Marcuse et al., 19531. A hamartoma was observed in a boy with a complex form of holoprosencephaly (double proboscides, arhinencephaly, and agenesis of the corpus callosum) without associated anomalies [Rosen and Gitlin, 1959; Gitlin and Behar, 19601. The tumour was “similar in some respects to the large midline hamartoma of the hypothalamus described by Marcuse . . . the surface of which also had the gross appearance of cortical tissue” [Gitlin and Behar, 19601. Within an area of the tumour, the hamartoma had undergone anaplastic change and invaded the meninges. Bach et al. [19691 described a girl with a diencephalic tumour (considered to be a hamartoma), Dandy-Walker malformation, parietooccipital meningocele, hemivertebrae, and absent first rib. In their textbook, Warkany et al. [19811 illustrated a stillborn infant with midbrain hamartoma, cleft palate, polysyndactyly, and signs of hypopituitarism. Pallister-Hallsyndrome. Hall et al. [19801brought to light the importance of this MCA syndrome and its variability through the description of 6 severely malformed patients. Clarren et al. [1980], stressing the immaturity of the tumour structures, recommended the name “hypothalamic hamartoblastoma.” Several cases were reported since 1980, as “Hall-Pallister” or “Pallister-Hall” syndrome [Huff and Fernandes, 1982; Winter et al., 1982; Culler and Jones, 1984; Nurbhai et al., 1985; Graham et al., 1986; Iafolla et al., 1989; Pallister et al., 19891. Hypothalamic hamartoblastoma in MCA not considered as Pallister-Hall. Winter et al. [19821 reported a girl who was studied a t 111h years, because of precocious puberty, whose only extracerebral manifestation was a single central incisor (considered a mild form of holoprosencephaly). Her tumour was classified as a hamartoma by the authors, and quoted as hamartoblastoma by Cohen [19891. Hennekam et al. [1986] reported a “congenital hypothalamic hamartoma associated with severe midline defect” in a child with median facial cleft syndrome, tongue tumour, complex heart defect, corpus callosum agenesis, and arhinencephaly. Anyane-Yeboa et al. [19871reported as hydrolethalus syndrome a child with a large hypothalamic hamartoma, arhinencephaly, fused thalami, vermis hypoplasia, Dandy-Walker cyst, cleft palate, and polysyndactyly; a previous sib had huge hydrocephaly due to aqueductal stenosis, and preaxial polysyndactyly, including hallux duplex, but brain anatomy was not inves-

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tigated. None of them had polyhydramnios; corpus callosum agenesis and key-hole shaped foramen magnum were not observed in the necropsied child. The authors rejected the diagnosis of syndromal hypothalamic hamartoblastoma because the tumour “was a malformation without neoplastic elements,” but, recently, Salonen and Herva [19901 excluded the diagnosis of hydrolethalus syndrome for this case. Munke et al. [19901 described as OFD syndrome type VI a 10 year, ataxic but mentally normal child, with multiple lingual frenula and sublingual masses, central and postaxial polydactyly of the upper limbs, preaxial polydactyly of the lower limbs, vermis hypoplasia, and growth hormone deficiency. MRI imaging disclosed “an isointense mass within the hypothalamus, most consistent with a hypothalamic hamartoma.” The authors discarded the diagnosis of Pallister-Hall syndrome, because of the hypoplastic vermis. Purported Pallister-Hall syndrome with incomplete/insufficient diagnosis. In 3 reports, a histological diagnosis was not made but the tumour was radiologically observed: the patient of Bach et al. [19691, case 2 of Pallister et al. [19891, case 1of Munke et al. [1990] and one of the children reported by AnyaneYeboa et al. [19871, who had an affected sib. ‘hmour was not substantiated, even by CT scan, in case 3 of Pallister (who had compatible phenotype associated with large subarachnoideal cyst), case 3 of Graham et al. [19861, and case 6 of Hall et al. [19801. Classification of Syndromes With Hypothalamic Hamartoblastomas Considered as a whole, the patients with hypothalamic hamartoblastoma appear to illustrate a continuous spectrum of defects in which no “natural” and clear subset can be delineated on objective grounds. The tumouritselfisnot useful for the classification of hypothalamic hamartoblastoma syndromes. In all cases of hypothalamic hamartoblastoma with associated defects, the tumour bulges at the diencephalicmesencephalic junction in the interpeduncular cistern, and may extend to the pituitary stalk (hence the hypopituitarism), but histological features vary. The tumour is basically described as a heterotopic and usually, at least for term newborn, insufficiently differentiated mass of neural tissue. Clear neoplastic changes were observed only once [Gitlin and Behar, 19601. The neoplastic nature of the tumour in cases 1,2 and 4 of Hall et al. [19801 was “suggested by the size of the mass and its invasion and destruction of more peripheral hypothalamic nuclei,’’but “no mitotic figures or pleomorphic elements were found” [Clarren et al., 19801. Most histological records since 1980 refer to Clarren’s description but do not indicate if anaplasia is present. The degree of differentiation of the tumour toward normal mature gray matter is quite variable and may change (and maturate) with time. Discordance in the maturation between cell lines in a single tumour is common. In case 1 of Iafolla et al. [19891, the tumour consisted of heterotopic but histologically normal tissue. For clinical classification, the formal splitting between hamartoblastoma and hamartoma is useless, as both forms may be seen

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with extracerebral malformations. More mature nodules and hypothalamic ectopia are reported in PallisterHall cases [Pallister et al., 1989, patient 21, oligosymptomatic forms [Marcuse et al., 19531, and even with isolated holoprosencephaly [Iafolla et al., 19891, and an aggressive tumour was reported in the case of Gitlin and Behar [19601. We suggest a division of reported cases of hypothalamic hamartoblastoma into 3 or 4 clinically distinct phenotypes: syndromal hypothalamic hamartoblastoma, hypothalamic hamartoblastoma associated with malformations, and isolated hypothalamic hamartoblastoma. The fourth category, build for one patient, should be considered provisional (Table I). Syndromal hypothalamic hamartoblastoma. This is the association of a proved hypothalamic hamartoblastoma with malformations in a t least 2 out of 4 classes: craniocerebral, cardiorespiratory, genitourinaryfdigestive, or skeletal. This definition encompasses most of the children reported after 1980 as Pallister-Hall syndrome, our patient, and the cases reported by Warkany et al, [19811, Munke et al, [19901or Anyane-Yeboaet al. E19871. The report of Anyane-Yeboa et al. [19871 is compatible with autosomal recessive inheritance, but no other familial cases support this hypothesis to now, and the possibility of further heterogeneity within this category should not be overlooked. The clinical spectrum is as proteiform as the tumour. The face often seems characteristic: flat, with short upturned nose, long philtrum, misshaped or posteriorly rotated ears, gingival frenula, hypoplastic alveolar ridge, microglossia, and micrognathia. Holoprosencephaly was observed twice [Hall et al., 1980; this report] and may indicate a specific subset. Postaxial polydactyly due to duplication of the 4th or 5th ray is common, but central polydactyly with bifid third metacarpal, preaxial polydactyly, and syndactyly were observed, as well as oligodactyly. Lack of ossification of the distal phalanges was pointed out several times. Brachymelia, hip, elbow, or knee luxation, and club feet have been observed. Soft tissue anomalies included epiglottic and laryngeal clefts, abnormal lung segmentation, urinary malformations, micropenis, and various heart defects. Imperforate anus is common, and TABLE I. Classification of Hypothalamic Hamartoblastoma Svndromes Isolated hamartoblastoma l a With endocrine dysfunction l b Without Associated hamartoblastoma 2a With locoregional anomalies (dysmorphismholoprosencephaly sequence) 2b With malformation of one other system (head structure excluded) Syndromal hamartoblastoma 3a Pallister-Hall syndrome 3b SLO syndrome, type 11” 3c OFD syndrome, type VI” 3d Hydrolethalus syndrome” 3e Holoprosencephaly-polydactyly syndrome” 4 Hamartoblastoma-frontonasal dvsulasia svndrome “Diagnosessuggested in the literature but true differential diagnosis still pending (see discussion).

aganglionosis coli was observed in Hall et al. [19801as in our propositus. Early death is a consequence of the severe cardiorespiratory malformations, of brainstem compromise due to the expanding tumour, or of secondary adrenal insufficiency, but long survival is possible [Culler and Jones, 1984; Miinke et al., 1989; Iafolla et al., 19891. The single severely malformed patient with frontonasal dysplasia and complex heart disease, reported by Hennekam et al. [1986], could represent a separate category, following Gorlin et al. [19901, but no other similarly affected children are known. Besides the syndromes discussed here, trisomy 13, Meckel syndrome, Opitz trigonocephaly syndrome, McKusick-Kaufman hydrometrocolpos-polydactyly, and even Ellis Van Crevelt and Fryns syndromes have overlapping features with the syndromal hypothalamic hamartoblastoma, but hypothalamic hamartoblastoma was never observed among them, and anomalies specific to each usually permit accurate differential diagnosis. Associated hypothalamic hamartoblastoma. These are cases in which hypothalamic hamartoblastoma coexists with developmental abnormalities belonging to one other class. Patients of Stotijn and Nauta [19501, Brouwer [19501, Gitlin and Behar [19601, Marcuse et al. [19531, Winter et al. [19821, and patient 2 of Iafolla et al. 119891 belong to this entry. This group may be further subdivided into 2 sets. The first one groups “nonsyndromal” children with hypothalamic hamartoblastoma and craniofacial anomalies, for which the onset of the tumour may be suspected to occur during the very first step of fetal development, inducing a disruptive pattern of anomalies. The second one includes the other patients, for which 2 separate abnormal developmental events occurred. Graham et al. [19861 reported possible familial occurrence (the aunt of his female case 2 could have been affected). Family history of case 1of Marcuse et al. [1953] is evocative of autosomal recessive inheritance. Isolated hypothalamic hamartoblastoma. This was reported in more than 50 patients with hypothalamic hamartoblastoma, associated or not with endocrine dysfunction (often with delayed onset). This clinically clearly delimited set of patients has been reviewed by Zuniga et al. [1983]. As for the previous categories, this grouping does not preclude genetic or pathogenetic heterogeneity. Pathogenesis: Pleiotropic Syndrome or Disruptive Sequence? The pathogenic mechanism of the syndromal hypothalamic hamartoblastoma has been discussed by Hennekam et al. [19861, who consider it to be primarily a midline field defect [Opitz and Gilbert, 19821. Slight differences in the time of onset and random variability in the expression (as suggested in Kurnit’s [19871 stochastic theory on gene expression in morphogenesis) could explain variations in expressiveness. Two mechanism could be set forth to account for the whole svndrome: in a “traditional” view. manifestations of the hndromes result from the pleiotropic action of a

Syndromal Hypothalamic Hamartoblastoma gene (or of an environmental agent). Some of the primary defects may then induce secondary sequences. We could suggest a less classical interpretation, in which syndromal hypothalamic hamartoblastoma is a single disruptive sequence. Disruption easily explainsthe anomalies: the tumour arises from the primary hypothalamic plate and affects the differentiation, migration, and/or stereotactic relationships between the embryonic structures of the cephalicpole. Holoprosencephalyresults when the hamartoblastomatous process occurs during the 4th5th week. Very little is known of the other possible consequences of early tumour formation, but several congenital anomalies of the syndromal hypothalamic hamartoblastoma may be speculated to be initially a consequence of the primitive hit of the neural plate. Hall et al. [1980] already pointed to the central role of abnormal development or migration of the cells of the anterior neural crest for the pathogeny of Hirschsprung disease or imperforate anus. “NOcomponent of a dysplasialmalformation in any syndrome is obligatory (i.e., present in every case) or pathognomonic (i.e., present in that syndrome only)”. This axiom of variability is obviously correct in the traditional approach of syndromal hypothalamic hamartoblastoma, but does not fit perfectly the disruptive model, which predicts that the syndrome cannot be expressed without the presence of the tumour. With this model, the “law” would apply to all manifestations, the tumour excepted, hypothalamic hamartoblastoma would be the only specificity of the diagnosis, and it should be an obligate feature.

DIFFERENTIAL DIAGNOSIS OF PALLISTER-HALL SYNDROME Syndromal Hypothalamic Hamartoblastoma Without Hypothalamic Hamartoblastoma Pallister-Hall syndrome, described a priori as hypothalamic hamartoblastoma within an MCA context, OFD syndrome type VI, and hydrolethalus syndrome were independently reported within one year, so that there were no crossed studies, SLO syndrome type 11, and holoprosencephaly-polydactyly delineated from 1987 onward only. Donnai et al. [1987] suggested that syndromal hypothalamic hamartoblastoma and SLO syndrome type I1 were the same disorder. Hypothalamic tumour was never reported among the latter cases, which could be a clue for considering the syndromes independent or another illustration of the founder effect in syndromes. If syndromal hypothalamic hamartoblastoma is seen as a nonsequential MCA syndrome, to which the axiom of variability applies totally, we must question how it could be recognized when hamartoma is lacking. Visceral malformations (some of them relatively uncommon, as tracheopulmonary anomalies) are seen in Meckel, SLO type 11, hydrolethalus, holoprosencephaly-polydactyly, and OFD type VI. In some patients reported with Pallister-Hall syndrome, unusual features such as Hirschsprung disease and nesidioblastosis reminds us of SLO syndrome type 11,which is conceivable without sex reversal, cleft palate, or micrognath-

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ism. Would lingual hypoplasia, abnormal frenula (noted in the original paper of Hall et al. [19801), and lingual hamartomas (patient 1 of Huff and Fernandes [19821) not have been sufficient for suggesting OFD syndrome if the authors had not stressed hypothalamic tumour? Central polydactyly and/or distal duplication of the 4th metacarpal present in patients 1,2, and 4 of Hall et al. [19801 are also features of Varadi-Papp syndrome (in which vermian agenesis is certainly not mandatory). The cases collected as “other diagnosis” (see above) are other examples. Without neuroradiologic or neuropathologic investigations, differential diagnosis is impossible: SLO type I1 may not be ruled out for patient 6 of Hall et al. [19801,Varadi-Papp syndrome was another possibility for patient 3 of Graham et al. [19861, SLO syndrome may perhaps be suggested for patient 3 of Pallister et al. [19891, and our case was previously published as holoprosencephaly-polydactyly syndrome, and fits also a diagnosis of SLO syndrome type I1 with holoprosencephaly . We are driven to 3 uncomfortable conclusions: 1. A child with syndromal hypothalamic hamartoblastoma cannot be reliably diagnosed as PallisterHall rather than another MCA syndrome with casual CNS tumour. 2. Pallister-Hall syndrome cannot be specifically recognized in the absence of a CNS tumour. 3. If the single disruptive sequence model is considered, Pallister-Hall syndrome deserves delineation, even if differential diagnosis is difficult. But if the pleiotropic model is favoured, Pallister-Hall syndrome could even not exist per se but represent an extreme expression of one or several other syndromes.

Although no answer is amenable for the existence of a separate Pallister-Hall syndrome, as long as the pathogeny will stay “in limbo” and identification of the gene defects for all those birth defects be achieved, we think that keeping several clinical categories brings more information and clarity for dysmorphologists and clinical geneticists and that the hamartoblastoma is specific enough to sustain the basis of a separate syndrome.

The Concept of Multiplex Syndrome The insolvable overlap prompts us to introduce a more neutral, purely phenotypic stage of classification: the “multiplex syndrome.” It may be defined as a clinical frame encompassing an unknown number of genetic and/or nongenetic MCA syndrome, for which differential diagnosis cannot be performed unequivocally. An individual syndrome may be totally merged with the multiplex syndrome, or only for its more extreme expression. Within the complex,patients may be further classified in clinical forms based on phenotypic particularities with the knowledge that the categorization of a given patient remains arbitrary. Suggested rules for internal classification of the multiplex syndrome advocated here are given in Table 11, and we suggest calling it the Cerebro-Acro-Viscera1 Early lethality (CAVE)

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Verloes et al. TABLE 11. Operative Nested Classification of the CAVE Multiplex Syndrome

Forms with hypothalamic hamartoblastoma Syndromal hypothalamic hamartoblastoma form Frontonasal dysplasia (Hennekam) form Holoprosencephalic form Forms without hypothalamic hamartoblastoma With holoprosencephaly (and inconstant hypogenitalism in male) Holoprosencephaly-polydactyly form Without holoprosencephaly Hydrocephaly, midline CNS defect and deep set eyes Hydrolethalus form Oral anomalies. cerebellar defect, forked third metacarpal Orofaciodigital type VI form Typical facies, hypogenitalism, syndactyly 11-111 of toes Smith-Lemli-Opitztype I1 forms Male with normal testicles Lethal acrodysgenital dwarfism form Rutledge form Male with dysgenetic testicles Genitopalatocardiac form Encephalocele Meckel form

multiplex syndrome. Syndromal hypothalamic hamartoblastoma or holoprosencephaly-polydactyly does not exist outside the CAVE multiplex syndrome: if the CNS malformation is not considered essential, several other diagnoses are always possible. Most cases of hydrolethalus, OFD type VI, or Smith-Lemli-Opitz cases clearly belong to one syndrome, but the diagnosis of some very severe, unusual, or partially investigated cases remains ambiguous, and falls within the scope of the CAVE multiplex syndrome. For instance, a child with an association of retrognathism, postaxial polydactyly, IUGR, severe hypospadias, and normal CNS is a case of SLO type 11. But if he has holoprosencephaly,the diagnosis should be CAVE multiplex syndrome, holoprosencephaly-polydactyly type. A child with polydactyly, cleft palate, microcephaly, and occipital encephalocele whose kidneys were not examined could be diagnosed as CAVE complex syndrome, Meckel form, rather than “possible Meckel syndrome.”

CONCLUSION As this time no definite answer will be reached concerning the existence of Pallister-Hall as an independent entity within the framework of syndromal hamartoblastomas, concerning its clinical variability and heterogeneity. Differential diagnosis with phenotypically related syndromes (as SLO syndrome 2, hydrolethalus, holoprosencephaly-polydactyly, or OFD syndrome type VI) will remain a matter of personal subjective appraisal. Here we have advocated the delineation of 4 clinical phenotypes for hypothalamic hamartomas (irrespective of the genetic or environmental background) for clinical work-up and genetic counseling, and we have suggested the creation of a new nosologic class be used as long as DNA and embryological studies are unable to provide a pathogenic and ge-

netic classification of the entities included in the CAVE multiplex syndrome.

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NOTE ADDED IN PROOF A group of papers falling in the scope of the CAVE complex have been published since submission of our

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manuscript. Greenhaw et al. [19911 reported on a slightly retarded boy aged 24 with Pallister-Hall syndrome, whose tumour was detected at 18. Two children with hamartoma and prexillary agenesis had combined 3p trisomy and 7q monosomy [Golabi et al., 19911.Finnigan et al. [19911,described as Pallister-Hall syndrome two unrelated children with MCA, polymicrogyria, Dandy-Walker malformation, neuronal heterotopias and no hamartoma, thus resembling a patient described as hylethalus by Krassikoff ~ 9 8 7 1Encha-Razavi . et al. [1992] reported on 3 unrelated cases, the third one presenting with hamartoma and encephalocele. The problems of differential diagnosis have been further illustrated and discussed in several revcent case reports [Hingoraniet al., 1991;Muenke et al., 1991;Hennekam et al., 19911.

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