Clinical Genetics 1977: 12: 169-178

On the classification of the acrocep ha losyndactyly syndromes

VICTOR ESCOBAR AND DAVID BIXLER

Departments of Oral-Facial and Medical Genetics, Indiana University Medical Center, Indianapolis, U.S.A.

This report describes a family in which two different types of acrocephalosyndactyly (ACS) were clinically identified. The proband presented with the classic stigmata of Pfeiffer syndrome, while her cousin was considered to be a typical case of Apert syndrome. Seven other family members also have unusually shaped heads and the facial appearance rerninis- cent of Crouzon disease.

From the observations made in this family and from previous reports in the literature, we feel there is substantial reason to re-evaluate the ACS classification and to consider that the Apert and Pfeiffer types of ACS may be one and the same.

Received 7 March, revised 31 March, accepted f o r publication 6 April 1977

In 1960, after examining 54 cases of ACS, Blank divided them into typical and atyp- ical types. He concluded that typical ACS was a dominant trait, as originally described by Apert (1906) and later by others (Book & Hesselvick 1953, Buchanan 1968, Mathur et al. 1968, Dodson et al. 1970, Hoover et al. 1970, Roberts & Hall 1971 and Scott 1972). The variations designated as atypical were subclassified according to the pattern of inheritance, presence of polydactyly, severity of syndactyly and associated anom- alies. These atypical variations have been discussed by Saethre (1931), Chotzen (1932), Vogt (1933). Waardenburg (1934a), Noack (1959), Pfeiffer (1964) and Tem- tamy (1966). There is so much overlap in phenotypic expression among these dis- orders that some ACS types originally be- lieved to be discrete entities have now been reclassified as an already existing type. In 1968, McKusick listed seven types of ACS, some with and some without polydactyly.

In 1975, McKusick listed only five types, and the literature (Pruzansky et al. 1975, Robinow & Sorauf 1975 and Jackson et al. 1976) further suggests that one of these (Type 111) is probably a variant of the Pfeiffer syndrome. Because of the very close clinical similarity between the Pfeif- fer and the Apert types of ACS, Degenhart (1950) has suggested that they may actually be variations of a single gene defect. In support of this contention, we present here a family in which classic clinical forms of the Pfeiffer and Apert syndromes as well as transitional types have occurred. Inter- estingly, several members of the family bear a facial resemblance to patients with Crouzon disease.

Family History

The proband in this family is a 24-month- old white female (Fig. 1, individual IV-2) first seen at 5 months of age for evaluation

170 E S C O B A R A N D B I X L E R

D O M I N A N T ACROCEPHALOSY NDACTYLY

1 2 3 4

I

I 1 2 I V

X-Ray Manifestations Only Unusual Head Shape

Digital Anomaiies Preaxial Polydactyly Reported i n 2 Sibs.

0 Deceased Examined

Fig. 1. Pedigree of family with ACS

of possible premature craniosynostosis and multiple anomalies of the hand and foot.

Pregnancy, labor and delivery, and past medical history are unremarkable. Her hand and foot deformities have been pres- ent since birth. She has had serial skull X-rays made since birth without evidence for premature sutural closure until about 14 months of age. Her developmental mile- stones have been reached at appropriate ages.

At the time of the proband’s birth, the mother was 24 years old and the father 25. They deny consanguinity. T h e patient has a n older sib (Fig. 1 , IV-1) who is without any cranial or hand-foot deformities.

Physical examination of the proband a t 14 months revealed an alert, active female infant. The OFC was 49.5 cm (+ 2.2 s.d.); height 74 cm (mean) and weight 12 kg

(+ 1.8 s.d.1. Physical findings included bilateral epicanthal folds, somewhat low-set, large ears with anteverted pinnae and a tower-shaped appearance t o the skull with a high prominent forehead (Fig. 2). There was no palpable sutural ridging, and the anterior fontanelle was closed. Radiographs showed all cranial sutures open (Fig. 2).

Clinocamptodactyly of all fingers was present bilaterally (Fig. 2), the middle pha- langes being dysplastic. Both distal pha- langes of digit one were shortened and tri- angular shaped. There was a striking poly- dactyly of both feet and syndactyly of all toes (Fig. 2). Metatarsus adductus was also present.

Chromosome analysis showed a normal female (46XX) karyotype. Her dermato- glyphic findings were compatible with her clinical deformities and were unremarkable.

A C R O C E P H A L O S Y N D A C T Y L Y S Y N D R O M E S

Fig. 2. Patient with Pfeiffer syndrome (Fig. 1 : IV-2)

171

172 E S C O B A R A N D B I X L E R

Fig. 3. Father of the proband (Fig. 1: 111-12)

Examirlation of the proband’s father showed that he has an unusually shaped head with an increased biparietal diameter (Fig. 3). X-rays showed a thickened cal- varium, but there was no residual evidence of premature synostosis. His OFC was 56.5 cm. His hands and feet were without ob- vious clinical or radiographic abnormality.

Further family study revealed that, in addition to the proband and her father, se- ven other family members also have an un- usual head shape and facial appearance reminiscent of that seen with Crouzon dis- ease. This facies is characterized as a middle-third deficiency with flattened nose and very short philtrum. Their clinical find- ings are summarized in Table 1.

Although Pfeiffer syndrome was the ob- vious diagnosis for the proband, the ACS type represented by these other individuals was unclear since the phenotypic expression of the particular trait was so variable. This can best be illustrated by the fact that one female 18 years old (Fig. 4) was severely retarded, obese, had marked acrocephaly with severe mid-facial hypoplasia, and had

almost complete syndactyly of the digits of both hands and feet, resembling the “mitten”-type configuration (Fig. 4).

The grandfather of the proband (Fig. 1 , 11-15) reportedly also has an unusual head shape like his son, but has no obvious hand and foot abnormalities. We have not been able to examine him.

The great-grandfather (Fig. 1 , 1-1) was reported t o have the characteristic unusual family head and face. H e reportedly had no hand and foot deformities. Three of his seven sons have shown the unusual head shape but have no clinically apparent ab- normalities of the extremities. One of his daughters, a great-aunt of the proband (Fig. 1, 11-13) has a normal clinical and roent- genographic skull appearance. We consider her to be an obligate gene carrier for this trait since she has affected brothers, and because her older son presented the charac- teristic clinical and radiographic skull find- ings noted in family members who were diagnosed as affected. A cephalometric study of all available members in this family was undertaken and showed that not only

A C R O C E P H A L O S Y N D A C T Y L Y S Y N D R O M E S 173

Table 1

Summary of most common clinical findings encountered in ACS Types I and V

Findings

Cranlofacial: Acrocephaly Craniosynostosis Maxillary hypoplasia Deep-flattened nasal bridge Flat occiput Parrot-beaked nose Hydrocephalus Deviation of nasal septum

Anomalies of external ear (low-sethnalformed)

Hypertelorism Antimongoloid slant Exophthalmos Ptosis Strabismus

Oral structures: Cleft palate Highly arched palate

Limited joint movement Genu valgum

Syndactyly - partial webbing Syndactyly - "mitten" type Bony (fusion) abnormalities Absent phalanges Brachydactyly Big thumbs Varus deformity of thumbs Clinodactyly (5th fingers) Camptodactyly

Syndactyly - partial webbing Syndactyly - "mitten" type Big toes (duplication) Haliux valgus Broad short first metatarsal

Low IQ Heart defects Dermatoglyphic alterations Seizures

Ears:

Eyes:

Skeleton:

Hand:

Feet:

Other:

100 45 45 82 14 23 14

5

+ - + + - + + + + - - - + + - + - - - - + + + + + + + + + + + - + + - - + - + - + - + + - - - + + - - - + + - + - - - - - - + - - - - - - - - + + + + + + + + +

100 100 100 80 70 50 50

?

30 18 + - + + + + + - + -

100 80 90 50 60

40 30

86 73 18 27 18

5 64

+ - + + - + + - + - - + + + + + + - + - - - + - - - - - - - + - + + - + - - + - - - + - - - - - - -

.. 23 23 .. 73

100 100 50 30 20 20 10

64 45

27 - +

-

+ 82

100 10 10 . r

55 59 45 + - + - - - - - - -

+ - + + - + - - + - 100 20

9

36 14

1 -ACS I: N = 10 (Book & Hosselvik 1953, Buchanan 1968, Mathur et al. 1968. Dodson et al. 1970, Roberts 8

2 -ACS V: N = 22 (Pfeiffer 1964, Asnes 8 Morehead 1969, Pfeiffer 1969, Martsolf 1971, Saldino et al. 1972, Hall 1971, Scott 1972).

Leonard 1974, Temtamy 1974). ' * - Reported sporadically.

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Fig. 4. Patient wi th Apzrt syndrome ( F g 1' III-2)

the maxilla but also the mandible is small, Also prominent was a marked upward slant both in ramus height and in body length. to the lesser sphenoid wings, a depresscd

A C R O C E P H A L O S Y N D A C T Y L Y S Y N D R O M E S 175

sella turcica and a small posterior and anterior cranial fossa with a normal face height and normal posterior facial height (Escobar & Bixler 1977). A radio- graphic analysis of their hands was per- formed and it demonstrated a generalized brachydactyly (Escobar & Bixler 1977).

Discussion

With the exception of acrocephalopoly- syndactyly (ACPS) of the Carpenter type, which is a recessive disorder (Temtamy 1966), all other types have shown an auto- soma1 dominant mode of transmission. Penetrance is suggested to be complete, al- though gene expression is highly variable. Sporadic cases probably represent new dominant mutations, especially in the case of Apert syndrome. The reports of ACS type 111 (Waardenburg 1934b, Moffie 1950, Gellis & Feingold 1968, Pfeiffer 1969, Aase & Smith 1970, Bartsocas et al. 1970, Kreig- borg et al. 1972, Pantke et al. 1975, Pru- zansky et al. 1975) and Pfeiffer type (De- genhart 1950, Lenz 1957, Manns & Bopp 1965, Asnes & Morehead 1969, Pfeiffer 1969, Zippel & Schiiler 1969, Martsolf et al. 1971, Saldino et al. 1972) have been mostly familial, although sporadic cases have been reported (Asnes & Morehead 1969, Zippel & Schiiler 1969, Leonard 1974). In spite of the considerable pheno- type overlap, these ACS syndromes are con- sidered by most investigators to be the result of different (although possibly al- lelic) genes.

The findings in this family demonstrate how variation in gene expression could produce attempts to split the ACS disorders into multiple etiologic types. On the basis of clinical appearance alone, the proband has Pfeiffer syndrome, her cousin has Apert syndrome and other cousins (Fig. 1, 111-3, 7, 8) appear to have a variant of Crouzon disease (see Fig. 5 ) , without any

clinical abnormality of hands and feet. One more cousin (Fig. 1, 111-1) in another sib- ship was originally tentatively diagnosed as affected because of her clinical facial in- volvement. Cephalometric analysis con- firmed her craniofacial abnormality, and the metacarpophalangeal profile index sup- ported her assignment as affected with Pfeiffer syndrome (Escobar & Bixler 1977).

The data summarized in Table 1 show that the malformations consistently present in both Apert and Pfeiffer syndromes are the same, with the possible exception of anomalies of the hands and feet. However, even here the differences appear to be of degree and not of kind.

As a final comment on ACS nosology, it seems obvious from the literature that the absence of big thumbs and big toes can make the differential diagnosis of the Pfeif- fer and Chotzen syndromes very difficult. The reports of Robinow & Sorauf (1975) and Jackson et al. (1976) illustrate that problem. The former presented a single family in which there were patients diagnosed as hav- ing either the Chotzen or Pfeiffer syndro- mes. Other relatives presented phenotypic combinations of these two disorders. In the family reported by Jackson et al., the phenotypic expression was so variable that all dominant ACS types, except for the Apert type, were seen. In their conclusions, Jackson et al. stated their uncertainty about whether they described a new syndrome or if the variation observed indicated that the ACS types previously described as separate entities were actually variable expressions of a single gene defect. The family reported here raises the important question of mini- mal diagnostic criteria to support the clas- sification of “affected.”

We believe that the single family with multiple affecteds is the most powerful tool to answer the question of gene expression and phenotypic heterogeneity. Therefore, when a single family is found in which

I76 E S C O B A R A N D B I X L E R

Fig. 5. Three slblings (Fig 1 Ill 3. 4, 7). cousins of the proband, who are affected wlth ACS

A C R O C E P H A L O S Y N D A C T Y L Y S Y N D R O M E S 177

there are two or more phenotypes which have already been reported as separate en- tities, it is time to re-examine the disease classification and to look for new, and hopefully definitive criteria for identifica- tion of affected. Our observations and those in the literature seem to indicate that there is no substantial reason to consider Apert, Pfeiffer and Chotzen types of ACS as dif- ferent nosologic entities.

Acknowledgment

This is publication no. 76-59 from the De- partment of Medical Genetics and was sup- ported in part by the Indiana University Human Genetics Center Grant PHS PO1 GM 21054 and the Oral-Facial Genetics Training Grant T22 DE 00007-02. This paper was presented in par t a t the Birth Defects Conference in Vancouver, British Columbia, June 1976.

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Address: Victor Escobar, D.D.S. M.S. Department of Oral-Facial Genetics Indiana University School o f Dentistry 1121 West Michigan Street Indianapolis. Indiana 46202 U.S.A.