Pedlar. Radiol. 2, 175--184 (1974) 9 by Springer-Verlag 1974

The So-called "Cloverleaf Skull Syndrome" A Report of Three Cases with a Discussion of Its Relationships with Thanatophoric Dwarfism and the Craniostenoses G. Iannaccone 1 and G. Gerlini ~ Dept. of Radiology, I. Pediatric Clinic1, and Institute of Child Healths, University of Rome, Italy Abstract. Three cases of cloverleaf skull are reported, one in a newborn with generalized bone changes suggesting thanatophoric dwarfism, one in an infant with acrocephalosyndactyly, and the other in an infant with several features of Crouzon's disease. The relationships between cloverleaf skull, on one side, and thanatophoric dwarfism and the severe craniostenoses, on the other, are discussed. The cloverleaf

deformity should be considered a purely morphologic feature in common to several diseases, and should no lorlger he considered a separate "syndrome".

"Kleeblattschiidel", meaning cloverleaf skull (C1. Sk.), is the German term first given by Holtermiiller and Wiedemann [20] to a deformity characterized by severe enlargement of the head, with grotesque trilobed configuration in the frontal view, resembling the three-leaved clover. The deformity is due to severe alterations in skull development with premature synostosis of some cranial sutures associated with marked hydrocephalus, resulting in a striking bulging of the head upward in the region of the anterior fontanel and laterally in the temporal regions, the latter forming the lateral lobes of the cloverleaf. In many patients a craniolacunar pattern ("Ltickenschfidel") is found in some areas of the vault, a further evidence of the developmental disturbances of the skull in these patients. Holtermiiller and Wiedemann [20] described one personal case of C1.Sk. with no other skeletal malformations outside the skull, but in reviewing the previous German literature back to 1849 they were able to find 12 additional cases of C1.Sk., 8 of which showed also alterations in the long bones classified as "chondrodystrophic". According to these authors, C1.Sk. represents a well defined syndrome, whose main features are: (1) cloverleaf deformity, the cardinal symptom; (2) facial malformations involving the orbits, nose and upper maxilla; (3) occasionally, chondrodysplastic changes affecting the limbs and the spine; (4) severe hydrocephalus; (5) poor prognosis due to progressive intracranial hypertension. In 1970, Bloomfield [4] reported a case of C1.Sk. associated with skeletal changes identified as typical of thanatophoric dwarfism (Th.Dw.). In 1971, Partington et al. [40], in a critical review of the previously reported cases of C1.Sk., empha-

sized the high frequency (9 out of 23 cases) with which C1.Sk. was associated with generalized bone lesions which recall the picture of Th.Dw. These authors added 4 cases of C1.Sk., all of them with generalized chondrodysplastic changes considered as typical of Th.Dw., and arrived at the conclusion that the CI.Sk. might be a previously unrecognized feature of Th.Dw., and that there may be three distinct syndromes in patients with the Cl.Sk. deformity: (a) C1.Sk. associated with T h . D w . ; (b) C1.Sk. associated with other minor localized malformations; (c) CI.Sk. without other skeletal abnormalities. More recently (1972) Hall et al. [18] reported a case of C1.Sk. in a boy w h o was the 13th child in a large pedigree of classical Crouzon's disease, and raised the possibility that some cases of what has been called the "C1.Sk. syndrome" may in fact represent a severe form of Crouzon's cranio-facial dysostosis, and that in some instances the two entities represent one and the same disease. The purposes of this paper are: (a) to report three new cases of C1.Sk., a newborn with Th.Dw., an infant with acrocephalosyndactyly, and an infant with several features of Crouzon's disease; (b) to show evidence that C1.Sk. has close relationships not only with Th.Dw. but also with the severe craniostenoses; (c) to emphasize that C1.Sk. represents only a peculiar " d e f o r m i t y " of the skull and not a specific "syndrome".

Key ,vords: "Kleebfattschfidel" syndrome, cloverleaf skull, thanatophoric dwarfism, acrocephalosyndactyly, Crouzon's disease, Apert's disease, craniostenoses.

Report of Cases Case 1. M. De R., a newborn female, deceased 5 hours after birth with signs of severe respiratory difficulty. Father 35 years old, mother 34, para-6, gravida-6. Family history revealed no consanguinity, malformations or here-

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Fig. 1 a and b. Case 1. Marked trilobed configuration in the a-p view, with bulging unossified vertex, widely open squamosal sutures and eversion of the temporal squamae. Flattening and gross streaky structure ("LiXckensch{idel" appearance) of the occipital bone ditary disorders. Pregnancy was complicated by polyhydramnios. Birth was spontaneous after a 40-week gestation.

Ciin#alfindings. Weight 2.100 g, length 38 cm. The baby showed severe micromelic dwarfism, narrow elongated chest, marked bulging of the frontal and both temporal regions with a striking trilobed configuration of the head. Head circumference 33 cm at the level of the parietal bones, and 35 at the level of the bulging soft temporal regions. Both ears were low-placed. Nasal root was flattened. The upper limbs were 10 cm tong, the lower extremities only 9 cm. Soft tissues of the extremities and trunk showed several gross folds. Radiologica] findings. X-rays were taken immediately after death.

Skull (Fig. 1 a--b). Striking trilobed deformity in the a-p view. The frontal bone is very thin and bulges upward and forward, the large anterior fontanel extends forward and bilaterally into widely open metopic and coronal sutures, the temporal sutures are widely separated and the temporal squamae almost horizontal. The occipital bone is flattened and grossly thickened with dense bony ridges giving a craniolacunar appearance. Chesl, spine, pelvis and long bones (Figs. 2 and 3) all show findings consistent with the diagnosis of Th.Dw.

Fig. 2a and b. Case 1. Ribs are short and thin, with flared sternal ends. Vertebral bodies are small and flat, U-shaped in the a-p view, with beak-like projections in the lateral view. Intervertebral spaces are all abnormally wide. Interpediculate distances at the lumbar level are decreased. Iliac wings are broadened, pubic and ischial bones abnormally short, ischial notches very small

Pathologic findings. A detailed microscopic, histochemical and ultrastructural study on some bones in this patient has been reported elsewhere by Bonucci E. and Nardi F. [Virchows Arch. path. Anat. A 357, 199 (1972)]. Endochondral ossification was abnormal, due to absence of the seriated cartilage, irregularities in the morphology and distribution of the chondrocytes, poorly formed and irregularly oriented calcified trabeculae. These findings were similar to those described in Th.Dw. [22].

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Fig. 3a--c. Case ;1. Abnormally shortened long hones, with flared metaphyses. Femurs and tibiae are also slightly bowed and show thorn-like projections, more evident at the proximal femoral ends

Case 2. C. S., a newborn female baby admitted to the hospital because of hydrocephalus, exophthalmus and abnormally shaped head. Family history revealed no consanguinity. The 33-year-old father showed bilateral membranous syndactylism of the toes. The 25-year-old mother was para-1, gravida-1. Pregnancy was normal and followed by spontaneous delivery. Clinical findings. On admission weight was 3.400 g, length 48 cm. The head showed a striking triangular shape with marked turricephaly and severe bulging of Both temporal regions, where a soft mass of about 3 • 5 cm, corresponding to the widened and tense squamosat sutures, could be fett on palpation. The occipital region was flattened. Head circumference at the level of the temporal regions was 36 cm. The anterior fontanel was obliterated. There was bilateral exophthalmus. B o t h ears were displaced downward. Reflexes were all normal. Laboratory examinations were within normal limits. Both feet showed membranous syndactylism affecting the 1 st and 2nd toes. Since the exophthalmus progressed and the head continued to enlarge upward and bitemporally, at the age of 2 months the Eaby was submitted to neurosurgery. Subsequent to the opening of the sagittal suture cranial hypertension was much relieved, but the shape of the skull gradually shifted to a quadrangular configuration. At present, the child is 6 years of age, is 108 cm tall, shows marked turricephaly, with steep frontal bone, bulging of both temporal regions not as marked as at birth, moderate exophthalmus, no significant mental retardation. Radiological findings. O n admission the skull (Fig. 4a--b) showed marked bulging of the frontal bone upward, diastasis of Both squamosal sutures and eversion of the temporal squamae, a small anterior cranial fossa, a markedly enlarged and deeply situated middle cranial fossa, "Lilckensch{idel" structure of the fronto-parietal region, flattened and thickened occipital bone. 12 Pedlar. Radiol. Vol. 2

feet. The first metacarpals show widening and exostosislike projections at the base. The distal phalanges of the first toes are short and stubby. C-hest, spine, pelvis, long bones show no bone alterations. C~ase 3. M. V., a newborn male, born at term by forceps delivery, after an uneventful gestation. Father 34 years old, mother 35, para-1, gravida-2. A previous pregnancy had been complicated by gestosis followed by spontaneous abortion. Family history revealed no consanguinity, malformations or hereditary diseases.

Clinical findings. On admission soon after birth, weight was 3.500 g, iength 53 cm. The most striking features were a large trilobed head (Fig. 5) due to marked soft bulging of the anterior fontanel and both temporal regions, severe exophthalmus with dislocation of the eyeballs, and prominent scalp veins. Head circumference: 30 cm at the level of the parietal bones, and 38 cm at the level of the temporal regions. Other features included: flat occiput, flat nasal root, marked hypoplasia of the upper maxilla, prognathism and thickened alveolar ridges. Upper limbs were 14 cm long and permanently flexed, due to ankylosis of both elbow joints. Lower limbs were 18 cm long. There was membranous syndactylism affecting the 2nd and 3rd toes bilaterally. Chest was normal. The umbilical cord showed a single umbilical artery. Laboratory examinations, including chromosome analysis, were all within normal limits. The baby was fed by gastric catheter. Respiration was difficult since birth due to nasal obstruction, arid several episodes of respiratory infection occurred. The exophthalmus and the protrusion of the bregmatic fontanel and both temporal encephaloceles increased during the last week of life. Death occurred at the age of 4 months. Autopsy showed marked generalized hydrocephalus, with striking dilatation of the temporal ventricles, and invagination of the cerebellar tonsils into the foramen magnum. The pathologic findings are still under study and will be published in detail elsewhere.

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Fig. 4a and b. Case 2. At 1 day of age. Marked acrocephaly, synostosis of the sagittal and coronalsutures ,wide separation of both squamosal sutures, downward displacement of the temporal squamae, and crenated structure of the fronto-parietal region resembling craniolacunia

Fig. 5a and b. Case 3 at 2 months of age. Marked macrocephaly with striking cloverleaf deformity, dislocation of the eyeballs, marked hypoplasia of the maxillae and flattening of the occiput

Radiological findings. Skull (Fig. 6a--b). The vault is very thin at the frontal level and bulges upward through a wide anterior fontanel and bilaterally in the temporal regions, the temporal squamae are displaced in an almost horizontal position and all bony structures of the middle cranial fossa are pushed downward. Lambdoidal suture as well as portions of the sagittal and coronal sutures are closed. The occipital bone is flattened and thickened, with heavy streaky structure ("Ltickensch~idel" appearance), which involves also the posterior portions of the parietal bones. Dense bone struts

extend anteriorly into the sphenoid areas and in the a-p view seem to constrict the vault at its base. The upper maxilla shows severe hypoplasia, the orbital cavities are extremely shallow.

Spine (Fig. 7). Some vertebral bodies are hypoplastic and grossly triangular in the lateral view, others are broadened or increased in height. Partial fusion of C4--Cs--C6, and complete fusion of C7--D1, Da--D4, S2--Sa. The sacrum is hook-shaped.

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Fig. 6 a and b. Case 3. Wide separation of the temporal sutures and downward displacement of the petrous bones and temporal squamae. Flattening and gross streaky structure of the occipital bone with dense bony struts extending anteriorly into the sphenoid areas : in the a--p view- these seem to constrict the vault on each side of the parietal region, exaggerating the trilobed deformity. Extreme hypoplasia of the upper maxilla and the orbits

Upper limbs (Fig. 8). Typical findings of complete congenital ankylosis of the elbows. Chest, pelvis, lower limbs do not show significant bony alterations.

Postmortem opaque ventriculography is illustrated in Fig. 9.

Discussio,

Since the original report by Holtermilller and Wiedemann in 1960 [20], 25 new cases of C1.Sk. have been reported [1, 4, 5, 9, 11, 18, 27, 29, 35, 36, 37, 40, 46, 47, 51, 52, 53], most of them under the heading % y n d r o m e " and in patients from Germany or of German descent. Our three cases, all of Italian origin, make a total of 41 cases of C1.Sk. so far reported. The actual number of true C1.Sk., however, is difficult to assess since some of the reported cases do not fit the definition of C1.Sk. as a trilobed skull with prominence of the vertex and both temporal regions. In reviewing the literature one is impressed by the fact that in some cases the trilobed or grossly triangular shape of the skull is lacking ([35], [53]: case 1), or not so evident ([18], [37], [40]: case 3, [52] : case 1), while in others the skull is so distorted that no defined geometrical figure can be identi12"

Fig. 7a and b. Case 3. Abnormal shape of several vertebral bodies, fusion of C4--C6, C7--D1, Da--Da. $2--S.3. The sacrum is bent upward-

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G. Jannaccone and G. Geriini: Cloverleaf Skull Syndrome fled ([29], [47], [51]: case 1). In one of these cases [37] the bulging in the temporal regions, a conclifton for the formation of the lateral lobes of the trifoil, was consistently absent since birth. In another case, a specimen from a Pathology Museum, no X-rays were taken ([51]: case 2). Improper terminology and the inclusion of questionable cases probably adds difficulties when trying to set limits on what actually represents the C1.Sk,

Fig. 8. Case 3. Shortening, widening and complete fusion of the humerus, radius and utna at the elbow. Hypoplasia of some phalanges

Fig. 9. Case 3. Postmortem opaque ventriculography, showing severe generalized hydrocephalus and protrusion of enormous elongated temporal horns through the widely separated squamosal sutures

Cloverleaf skull and thanatophoric dwarfism. Our case 1 shows features consistent with the diagnosis of Th.Dw., as confirmed by Maroteaux [33] and other colleagues, even though the vertebral bodies in this patient are not as much flat as in some cases of severe Th.Dw. and a form of severe achondroplasia might also be suspected according to the convincing arguments recently pointed out by Silverman [48] and which could probably lead in the future to a new labelling of many cases of Th.Dw. so far reported. Since this differentiation does not seem strictly necessary to the purpose of our discussion, we believe that the diagnosis of Th.Dw. in our case 1 may be provisionally maintained according to the currently accepted diagnostic criteria [14, 19, 22, 24, 26, 31, 32, 33, 44]. This patient confirms that C1.Sk. may be found in assodation with Th.Dw. or similar conditions. And such an occurrence is easily understood if one considers that Th.Dw. is characterized by severe alterations in the ossification process of the skull base, hydrocephalus and protrusion of the frontal region: in such conditions it is highly probable that whenever the developmentai alterations of the crania1 base and the hydrocephalus are particularly severe, bulging through the squamosal sutures may occur, giving rise to the C1.Sk. configuration. In order to evaluate if C1.Sk. does represent a feature of Th.Dw. as suggested by Partington eta]. [40], it would be interesting to assess the real frequency of Th.Dw. changes in patients with C1.Sk. and, conversely, the incidence of C1.Sk. in patients with Th.Dw. The existence of several improperly termed cases of C1.Sk. on one hand, and the relatively recent recognition of Th.Dw. as a disease distinct from achondroplasia on the other, make this a difficult task. However, including case 2 reported by Feingold et al. [11], which seems to be an obvious instance of Th.Dw., and our case 1, it appears that 9 of the 41 cases of C1.Sk. so far reported were affected by Th.Dw., and in 8 more cases quoted by Holtermiiller and Wiedemann [20] from the old

G. Iannaccone and G. Gerlini: Cloverleaf Skull Syndrome German literature there were "achondroplastic" changes which in retrospect might probably be referred to Th.Dw. or similar conditions. This makes a total of 17 cases of C1.Sk. with generalized dysplastic bone alterations, while more frequently (24 out of 41 cases) C1.Sk. is not associated with "chondrodysplastic" or other systemic bone changes. As for the incidence of C1.Sk. in patients with Th. Dw. it is noteworthy that in reviewing the 61 cases of Th.Dw. to our knowledge described under this specific label since the original report by Maroteaux et ak in 1967, and including Feingold's case and our case 1, we found that the great majority (54 out of 63) only showed a more or less marked "large head" with no trifoil configuration [2, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 19, 21, 22, 23, 24, 26, 28, 30, 31, 32, 34, 38, 39, 41, 42, 43, 44, 50, 53], while only 9 would be classifiable as Th.Dw. with C1.Sk. ([4]: one case, [11]: one case, [40]: four cases, [53]: two cases, and our case 1). An interesting point is that all cases of C1.Sk. associated with Th.Dw. show a strikingly similar aspect in the lateral view, having in common some peculiar features which are basically present in all patients with Th.Dw., i.e. marked reduction in the a-p diameter, flattened occiput and a constant severe forward bulging of the frontal bone, with an overall configuration that recalls the lateral diagram of the skull in a 40 mm human embryo [4]. This makes the lateral shape in these patients usually different from other forms of C1.Sk. without Th.Dw. Cloverleaf skull and the craniostenoses. The so-called "isolated" or "incomplete" forms of C1.Sk., i.e. those without systemic changes of the chondrodystrophic type, are all characterized by marked hydrocephalus and exophthalmus, premature fusion of some sutures and wide opening of the others, bulging in the temporal regions being a condition for the tri]obed configuration. The case originally described by Holtermiiller and Wiedemann [20] and some of the most spectacular trifoil deformities of the head reported in the literature ([1]: case 1, [9], [11]: case 1, [51]: case 2, our case 3) belong to this group of the "isolated" C1.Sk. In reviewing these forms of C1.Sk. one is impressed by the many features they have in common with known types of craniostenoses: (a) In the "isolated" forms of C1.Sk. the shape of the head, although usually of the acrocephalic type, is quite variable. Such a variability is also a striking feature in all forms of congenital craniostenoses, even those so far considered as having peculiarly

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diagnostic head configuration [25], the ultimate shape of the skull being determined by which cranial suture closes first, how many sutures close, and how severe is the hydrocephalus [25]. (b) As in the severe forms of aerocephalic craniostenoses, patients with "isolated" C1.Sk. always show marked to severe exophthalmus, mainly due to the frequent association of marked hypoplasia of the anterior cranial fossa and upper maxilla, respectively the roof and the floor of the orbit. (c) Many cases of "isolated" C1.Sk. show also minor localized anomalies, such as membranous or bony syndactyly ([1], [9], [36], [46], and our cases 2 and 3), ankylosis of the elbows ([1,] [5], [9], [29], and our case 3) or knees [9], cleft lip [47], hip dislocation [29], and malformations affecting the ribs [37], the feet [51], the fingers [47], the elbow nuclei [11], the spine ([20] and our case 3). It is worth noting that these same anomalies are quite frequent also in Crouzon's disease, Apert's disease and other similar forms of severe craniostenoses [3, 25, 45]. (d) Also the evolution of some "isolated" C1.Sk. is in favour of their close relationships with the craniosynostoses. In fact, some of the "isolated" C1.Sk. who survive, later in life show the features of Crouzon's cranio-facial dysostosis ([1]: case 2, [11]: case 1, [18]), while others show features which make a retrospective diagnosis of Apert's disease quite reasonable ([1]: case 1, [9], [36], [46]). Case 1 described by Feingold et aL [11] seems particularly interesting: in this patient the trilobed configuration present at birth was lost at 13 years of age, when he only showed extreme frontal bulging with no lateral expansion of the head, and one would have classified the case as a severe form of acrocephaly with many features of Crouzon's disease. In their case 1, characterized by severe trilobed skull, webbing of the toes and elbow synostosis, Angle et al. [1] raised the possibility of a phenotypic overlap between the so-called "isolated" forms of C1.Sk. and acrocephalosyndactyly. Our case 2, showing webbing of the toes and evolution toward a marked turricephaly with peculiar facial features, clearly indicates that acrocephalosyndactyly may well present at birth with the clinical and radiological picture of CI.Sk. As for our case 3, who shows striking similarities with the original case described by Holtermiiller and Wiedemann [20], webbing of the toes, severe maxillary hypoplasia, prognathism and extreme exophthalmus make a diagnosis of Crouzon's disease quite likely according to modern diagnostic

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criteria [25], although m o s t of these anomalies m a y be f o u n d also in A p e r t ' s disease, while others, such as block misshaped vertebrae and thickened alveolar ridges, are considered c o m m o n findings in some socalled "atypical f o r m s " or " v a r i a n t s " of acrocephalosyndactyly [3, 45]. W h a t e v e r the exact d i a g n o s i s , our case 3 confirms that a trilobed deformity of the skull m a y well represent the initial stage of some severe f o r m s of craniosynostosis of the a c r o c e p h a l i c type, such as Crouzon's disease or a f o r m of acrocephalosyndactyly.

Conclusions T h e following conclusions seem possible: (a) C1.Sk. is often (17 out of 41 cases) associated with generalized " c h o n d r o d y s p l a s t i c " changes, and in 9 of the 17 cases these changes m i g h t be interpreted as due to T h . D w . according to the currently accepted diagnostic criteria. (b) I n T h . D w . , however, a simple "large h e a d " with no trifoil configuration is far m o r e c o m m o n (54 out of 63 cases) than a true C1.Sk. (c) T h e "isolated" or " i n c o m p l e t e " f o r m s of C1.Sk. seem to fall into the wide g r o u p of the congenital craniostenoses, usually of the acrocephalic type, sometimes with the peculiar features of Crouzon's or A p e r t ' s diseases, or similar conditions. (d) B o t h in cases of C1.Sk. with T h . D w . and in those due to congenital craniosynostosis, the trilobed deformity is the result of severe alterations in skull d e v e l o p m e n t associated with m a r k e d hydrocephalus and cranial bulging t o w a r d the vertex and bitemporally, the latter being a condition for the trifoil configuration. (e) T h e trilobed deformity of the skull appears to be a purely m o r p h o l o g i c feature, which is in c o m m o n to several diseases, and is also quite variable in shape, size and evolution. As such, C1.Sk. deformity cannot be taken as a basis to define a specific entity and should, therefore, no longer be considered a separate syndrome.

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