Syndromology: An updated conceptual overview. IV. Perspectives on malformation syndromes

Invited review

Syndromology:an updated conceptual overview

M. Michael Cohen, Jr. Department of Oral Biology, Faculty of Dentistry, Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

IV. Perspectives on malformation syndromes M. M. Cohen, Jr.: Syndromology: an updated conceptual overview. IV. Perspectives on malformation syndromes. Int. J. Oral Maxillofac. Surg. 1989; 18." 286-290. Abstract. In Part IV, the terms sequence and syndrome are defined and the difference between them is emphasized. Malformations and sequences are nonspecific; each may occur as an isolated defect and each may occur as a component part of various syndromes. True malformation syndromes are characterized by embryonic pleiotropy in which a pattern of developmentally unrelated malformations occurs, that is, the malformations that make up the syndrome occur in embryonically non-contiguous areas. It is emphasized that syndrome diagnosis is never made from obligatory anomalies, but from the overall pattern of defects. Finally, the relationships among etiology, pathogenesis, and the phenotype are discussed.

Perspectives on malformation syndromes The nature of malformation syndromes

To understand the nature of malformation syndromes, it is necessary to review the definitions of malformation and sequence, and the principle of nonspecificity. A malformation may be defined as a morphologic defect of an organ, part of an organ, or a larger area of the body resulting from an intrinsically abnormal developmental process (Spranger et al. 1982). Polydactyly, cleft palate, or renal agenesis serve as examples. Malformations may be relatively simple or complex. The later the defect is initiated, the simpler the malformation. Malfon~aations initiated earlier during organogenesis tend to have more far reaching consequences. A sequence may be defined as multiple defects derived from a single known or presumed structural defect (Spranger et al. 1982). The primary defect sets off a chain of secondary and tertiary events, resulting in what appear to be multiple anomalies. In holoprosencephaly, for example, the embryonic forebrain fails to cleave sagittally into cerebral hemispheres, transversely into telencephalon and diencephalon, and horizontally into olfactory and optic bulbs. Holoprosencephaly varies in its degree of severity. At the mild end of the spectrum is simple

absence of the olfactory tracts and bulbs. Holoprosencephaly is associated with facial dysmorphism which also varies from mild to severe expression

Key word: syndromes. Accepted for publication 25 April, 1989

(Fig. 17). A single eye or closely set eyes, proboscis formation, single nostril nose, flattened nose, and median cleft lip may be observed variably and in combi-

Fig. 17. Spectrum of dysmorphic faces associated with variable degrees of holoprosencephaly. A: Cyclopia without proboscis formation. Note single central eye. B: Cyclopia with proboscis. C: Ethmocephaly. D: Cebocephaly. Ocular hypotelorism with single-nostril nose. E: Median cleft lip, fiat nose, and ocular hypotelorism. F: Ocular hypotelorism and surgically repaired cleft lip. A, B, C, D, F from M. M. Cohen et al, Birth Defects 7 (7): 125-139, 1971 and M. M. Cohen, Jr., The chiM with multiple birth defects, Raven Press, New York, 1982. E. from W, E. DeMyer & W. Zeman. Confin. Neurol. 23: 1-36, 1963.

Syndromology: an updated conceptual overview

287

Table 11. Some syndrome-specific frequencies and syndrome-specific ranges of holoprosencephaly Condition

Estimated frequency of holoprosencephaly within diagnostic category~ (%)

Autosomal recessive holoprosencephaly

100t

Triso~y 13 syndrome

70

Autosomal recessive campomelic dysplasia

18

Deleti0~" 13q syndrome

10

Deletion t8p syndrome

10

Infants of di/tbetic mothers

1-2

Range of holoprosencephalic facial appearances within diagnostic categoryb wide range: cyclopia to median or lateral cleft lip wide range: cyclopia to median or lateral cleft lip narrow range: absent olfactory tracts and bulbs and nondiagnostic face for holoprosencephalyd narrow range: ocular hypertelorism, iris coloboma, minor facial dysmorphism wide range: cyclopia to median or lateral cleft lip wide range: cyclopia to median or lateral cleft lip

Frequency estimates. Autosomal recessive holoprosencephaly: Cohen et al. (1971); trisomy 13 syndrome: Taylor (1968); campomelic dysplasia: Hall & Spranger (1980); deletion 13q syndrome: Niebuhr & Ottesen (1973); deletion 18p syndrome: Schinzel (1984); infants of diabetic mothers: Barr et aL (1983). b Range estimates. Autosomal recessive holoprosencephaly: Cohen et al. (1971); trisomy 13 syndrome: Cohen et al. (1971); campomelic dysplasia: Hall & Spranger (1980); deletion 13q syndrome: Opitz (1969); Orbeli et al. (1971); deletion 18p syndrome: Grouchy (1969); Faust et al. (1976), Cohen et al. (1971); infants of diabetic mothers: Barr et al. (1983). ° Any sibship defined as autosomal recessive holoprosencephaly must have at least one case with a holoprosencephalic brain. If all cases are facial microforms such as cleft lip only, there is no way to be sure that the sibship represents holoprosencephaly. In practice, the autosomal recessive form usually has mostly severe cases (unlike the autosomal dominant form). d Campomelic dysplasia has some craniofacial features but none that predicts arhinencephaly. From Cohen (1989).

nation. All malformations encountered trace their origin developmentally to a single primary defect in morphogenesis thought to be an abnormality in the prechordal mesoderm. Malformations and sequences are non-specific. Each may occur as an isolated defect; each may also occur as a component part of various syndromes.

SEQUENCE

defect

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Basic

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SYNDROME

13 14

Fig. 18. Comparison of a malformation sequence (top) with a true malformation syndrome (bottom). Isolated holoprosencephaly is an example of a malformation sequence. The combination of holoprosencephaly, ventricular septal defect, and polydactyly, caused by trisomy 13, is a malformation syndrome (From Cohen (1982)).

Cleft palate, for example, may occur alone or as part of the autosomal domin a n t Stickler syndrome, a condition characterized by high myopia, retinal detachment, and various abnormalities of bones and joints. Because anomalies occur with various frequencies in different syndromes, they are facultative rather than obligatory; that is, they may or m a y not be present in a given example of a condition in which they are k n o w n to be features (Cohen 1982, Opitz et al. 1969). Although patients with the Rubinstein-Taybi syndrome, for example, usually have broad thumbs, patients are k n o w n with essentially normal thumbs. Single, pathognomic malformations for various syndromes are uncommon. Thus, syndrome diagnosis is made not from any one malformation but from the overall pattern of malformations. The same malformations may occur in a variety of different disorders. Each syndrome of k n o w n etiology has a syndrome specific frequency with which a given malformation occurs in the syndrome population. Furthermore, for some types of malformations, each syndrome of k n o w n etiology has a syndrome specific range of anatomic variation. Both syndrome specific frequencies and anatomic ranges of variation using holoprosencephaly as an example are illustrated in Table 11. Such esti-

mates for syndromes of u n k n o w n etiology (recurrent-pattern syndromes) are not possible for the reasons discussed in the section entitled "Population definition of a syndrome" (Part I). A syndrorde may now be formally defined as a pattern of multiple anomalies thought to be pathogenetically related a n d not representing a sequence (Benirschke et al. 1980). In a syndrome, the level of understanding of a pathoTable 12. Non-specific features of chromosomal syndromes Mental retardation Growth retardation Low birth weight Microcephaly Downward slanting eyes Upward slanting eyes Hypertelorism Microphthalmia Small palpebral fissures Strabismus Broad nasal bridge Cleft upper lip Cleft palate Micrognathia Low-set ears Short neck Clinodactyly Camptodactyly Congenital heart disease Cryptorchidism Elevated axial triradius Transverse palmar crease From Yunis & Lewandowski (1983).

288

Cohen

Table 13. "Discriminating" phenotypic tbatures of chromosomal syndromes

Table 14. Robin sequence

Chromosome imbalance

Phenotypic features

Monogenic

dup(lq21 ~qter) dup(lq25~qter) dup(3p21.31 -*pter) del(4p15.32)

thymic aplasia absent gallbladder hypoplastic penis marked delay in ossification of carpus, tarsus, pelvis laryngomalacia, premature graying of hair absent patella aniridia-Wilms tumor hypoplastic penis increased polymorphonuclear nuclear projections persistence of fetal hemoglobin retinoblastoma holoprosencephaly hypoplasia or aplasia of thumb synostosis of 4th and 5th metacarpals anal stenosis polydactyly orbital hypotelorism orbital hypotelorism hypoplasia of 1st metacarpal orbital hypotelorism anal stenosis hypoplasia of 4th and 5th metacarpals ovarian aplasia ovarian hypoplasia testicular aplasia

del(5p 15) trisomy 8 del(1 Ip13) dup( 11q23 ~ qter) dup(13ql 1~ q l 3) dup(13ql4) del(13ql4) dup(13q14) del(13q31 ~q32) del( 13q31 ~ 32) del(13ql4~qter) dup(13q31 ~q34) del(13q) del(l 8@ 1~ qter) del(18q21 --*qter) dup(21q22.3) dup(22pter -~q23) del(Xp) det(Xpl 1) del(Xp27~qter) del(Yp) From Yunis & Lewandowski (1983).

Andre syndrome Beekwith-Wiedemann syndrome Campomelic syndrome Carey neuromuscular syndrome Catel-Manzke syndrome Cerebrocostomandibular syndrome Congenital myotonic dystrophy Diastrophic dysplasia Donlan syndrome Nager acrofacial dysostosis Persistent left superior vena cava syndrome Postaxial acrofacial dysostosis Radiohumeral synostosis syndrome Robin-oligodactylysyndrome Spondyloepiphyseal dysplasia congenita Stickler syndrome Velocardiofacial syndrome Chromosomal

del(4q) syndrome dup(1 lq) syndrome Teratogenically induced

Fetal alcohol syndrome Fetal hydantoin syndrome Fetal trimethadione syndrome Disruption

Amniotic band sequence Unknown genesis

in which a pattern of developmentally unrelated malformation sequences occurs; that is, the malformations that make up the syndrome occur in embryonically non-contiguous areas. They are not related to one another at the descriptive embryonic level, but at a more basic level, the malformations have or are presumed to have a common cause and are thus pathogenetically related. The difference between a malfor-

genetically related set of anomalies is usually lower than in a sequence in which the initiating event and the cascading of secondary events are frequently known. A syndrome commonly, but not always, implies a unitary etiology, e.g., del(4p) syndrome; a sequence commonly has multiple causes, e.g., oligohydramnios sequence. A true malformation syndrome is characterized by embryonic pleiotropy

+O.lO.

+0.05"

0

0.00~

CHARGE association Femoral dysgenesis-unusual facies syndrome Martsolf syndrome Moebius sequence Robin/amelia association Updated from Cohen (1982).

marion sequence and a malformation syndrome is shown in Fig. 18. When holoprosencephaly occurs alone, it is a malformation sequence, but when it occurs with multiple non-contiguous anomalies in trisomy 13 syndrome or with multiple non-contiguous anomalies in the autosomal recessively inherited Meckel syndrome, it is a malformation syndrome composed of several malformation sequences (Cohen 1982). Malformation syndromes lack biochemical definition. The highest state in malformation syndrome delineation is a known genesis syndrome of the pedigree

Fig. 19. Cluster (principal coordinate) analy--0.005"

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--0.10

--0,05

0.00

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PRINCIPAL COORDINATE 1

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+0.20

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sis of the phenotypes of patients reported to have dup(9p) (closed circles) and del(9pter~p22) (open circles) based on the analyses of 178 phenotypic characters. The two outliers are considered to be cytogenetically different from the others, with the del(9p) outlier having a shorter deletion and the dup(9p) outlier actually having dup(6p). From Preus & Aym6 (1983).

Syndromology: an updated conceptual overview ETIOLOGY

PATHOGENESIS

PHENOTYPE

Jr C-

~22/

Fig. 20. Possible relationships between etiology, pathogenesis, and the phenotype. From Cohen (1982).

or chromosomal type. Pedigree syndromes may involve mutant embryonic proteins that are switched off before birth, thus masking the basic defect. Many other malformation syndromes remain unknown-genesis syndromes of the provisionally unique or recurrentpattern type (Cohen 1982, Herrmann & Opitz 1974). The study of malformation syndromes is impeded by an inability, at present, to reconstruct the pathogenesis of various syndromes. Other problems in their study include: 1) the non-specificity of malformations leading to similarity of different kinds of conditions, 2) variability of the phenotype, resulting in incomplete forms that are difficult to diagnose, 3) frequent, sporadic occurrence, and 4) an inability, at present, to detect cytological defects in some suspected chromosomal syndromes with very small deletions or duplications (Opitz et al. 1969).

suspected by good syndromologists because they think in terms of patterns of anomalies, not in terms of specific anomalies. Clinical diagnosis, based on pattern recognition is quite an informal process. However, formal analysis is possible, such as the investigation of Preus & Aym6 (1983). Using the method of cluster analysis, they showed that syndromes caused by dup(4p), del(4p), dup(gp) and (del(9p) respectively belonged to distinct phenotypic groups (Fig. 19). Pathogenetic heterogeneity

Many clinicians prefer the "spectrum thinking" of classical medicine to the "discontinuous thinking" of medical geneticists. The former emphasizes relationships and similarities between various disorders; the latter emphasizes differences and discontinuities of the same disorder. These seemingly differ-

289

ent perspectives are actually compatible. Disorders that are etiologically heterogeneous (discontinuous) may have similar or identical pathogenetic pathways. Etiology and pathogenesis of a disorder should be considered separately. Fig. 20 diagrams some possible relationships between etiology, pathogenesis, and the phenotype. Model I shows etiologically heterogeneous disorders with a common pathogenetic mechanism producing a single phenotype. Model II shows etiologically heterogeneous disorders with similar but not identical pathogenetic mechanisms and a single phenotype. Model III shows etiologically heterogeneous disorders with pathogenetically heterogeneous mechanisms resulting in the same phenotype (Cohen 1982). Evidence to date suggests that many malformations are pathogenetically heterogeneous, i.e., that several different mechanisms may be responsible for the

Syndrome diagnosis

It has already been indicated that syndrome diagnosis is made from the overall pattern of anomalies, but that nonspecificity of malformations and variability of the phenotype, especially incomplete forms, complicate the diagnostic process. Chromosomal syndromes are particularly instructive in this regard because the clinical diagnosis can be verified or negated by cytogenetic analysis. In a large number of chromosomal duplication and deletion syndromes, for example, Yunis & Lewandowski (1983) listed non-specific features found very commonly in a large number of such syndromes (Table 12). They also listed discriminating phenotypic features (Table 13) that, although not unique or pathognomonic, significantly limit the number of chromosomal syndromes that have to be considered. Even with mostly non-specific features, the correct clinical diagnosis is usually

Fig. 21. Robin sequence. A, B: Micrognathia and U-shaped palate. C, D: Same patient showing mandibular catch-up growth (From Cohen (1982)).

290

Cohen

ETIOLOGY

PATHOGENESIS

Oligohydramnios --

PHENOTYPE

---- Extrinsic mandibular deformation

Neurogenichypotonia ~

Lack of mandibular exercise Robin sequence

Growth deficiency

Connective tissue disorder

~

Intrinsic mandibular hypoplasia ~

"

~ Intrinsic mandibular hypoplasia and failure of connective tissue penetration across palate

Fig. 22. Etiologic heterogeneity suggests pathogenetic heterogeneity in the Robin sequence. The following pathogenetic possibilities should be considered. I: Oligohydramnios results in decreased amnionic fluid, compressing the chin against the sternum and thus restricting mandibular growth. II: If hypotonia restricts mouth opening during early fetal life prior to complete palatal closure, the Robin sequence might result from lack of mandibular exercise. III: Growth deficiency, as observed in chromosomal syndromes such as dup(1 lq) syndrome, may produce the Robin sequence by intrinsic mandibular hypoplasia. IV: In a connective tissue disorder such as the Stickler syndrome, the Robin sequence may result from intrinsic hypoplasia and failure of connective tissue penetration across the palate. From Cohen (1982).

same defect (Fig. 20, Model III). Consider holoprosencephaly, for example. The phenotype (P) (i.e., holoprosencephaly) is known to be etiologically heterogeneous (A,B,C) (e.g., may be caused in some cases by an autosomal recessive gene in the homozygous state, in other cases by trisomy 13, and in still other cases by the diabetic state of a pregnant woman). Etiologic heterogeneity suggests that the pathogenesis may also be heterogeneous (X,Y,Z) (e.g., may be based on an insult to the prechordal mesoderm in some instances, a slightly later insult to the neural plate in other instances, or an insult producing decreased cellular proliferation of all 3 germ layers simultaneously in still other instances). Although holoprosencephaly is known to be etiologically heterogeneous, in some cases the pathogenesis may be reduced to a common mechanism (X), as illustrated in Model I and in other cases may be reduced to a similar mechanism (X,X1), as illustrated in Model II (Cohen 1982). Consider Robin sequence (Fig. 21).

Table 14 lists some representative syndromes in which Robin sequence may be a feature with variable frequency. In Stickler syndrome, Robin sequence occurs in some instances (Herrmann et al. 1975). Since abnormalities of bones and joints are characteristic, the major pleiotropic effect appears to be on connective tissue. Thus, in this condition, Robin sequence may result from intrinsic mandibular hypoplasia and failure of connective tissue penetration across the palate (Cohen 1982). Another condition that may have Robin sequence is dup(1 lq) syndrome (Aurias & Laurent 1975). With the hypoplastic growth that accompanies most chromosomal syndromes, there may not be significant mandibular catch-up growth in patients with dup(1 lq) syndrome who survive. Therefore, to include such patients in a mandibular growth study of Robin sequence would be to study "fruit" since "oranges" are being confused with "apples" (Cohen 1982). Some instances of Robin sequence

have been associated with oligohydramnios. It is thought that reduced amnionic fluid results in compression of the chin against the sternum, restricting mandibular growth and impacting the tongue between the palatal shells. Because micrognathia is based on intrauterine molding, mandibular catch-up growth is expected after birth when intrauterine deforming forces are no longer acting. Poswillo (1966) produced a phenocopy of Robin sequence in rats by puncturing the amnionic sac prior to palatal closure. Some experimental animals also had anomalies of the limbs, ranging from clubfoot to ring constrictions and intrauterine amputations. Such limb abnormalities have also been observed with Robin sequence of humans. The association of amputations and/ or limb reduction defects in some human cases suggests that Robin sequence may occur on a disruptive basis. For example, an amnionic tear may cause oligohydramnios which can result in severe compressive disruption, causing limb reduction defects, and bands, causing amputations. Such primary disruption with oligohygramnios can also cause secondary deformation such as mandibular constraint, leading to Robin sequence. Finally, Robin sequence has been associated with congenital hypotonia. If neurogenic hypotonia occurred prior to complete closure of the palate, it is conceivable that Robin sequence might result from lack of mandibular exercise. Different etiologic and pathogenetic possibilities are summarized diagramatically in Fig. 22 (Cohen 1982). This is the end of Parts III and IV in a 10-part series. Parts V and VI will appear in the next issue. References will appear in Part X.