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Clinical Genetics 199 1 : 40: 27 1-276

Saethre-Chotzen syndrome four generations

(ACS 111) in

SUSANNE c . NIEMANN-SEYDE, STEFAN w. EBER' AND BARBARA ZOLL

Institut f5r Humangenetik und 'Kinderklinik der Universitat Gottingen, FRG

The acrocephalosyndactylies (ACS) are a group of inherited disorders characterized by premature fusion of cranial sutures in association with abnormalities of the hands and feet. Based on their clinical features, different types of ACS have been described. We here report on a family with 9 individuals affected with ACS 111 (Saethre-Chotzen syndrome), 5 of them severely. Clinical features of the patients are presented with regard to differential diagnostic delineations.

Received I7 December 1990, revised 4 April, accepted for publication 6 April I991

Key words: acrocephalosyndactyly; Saethre-Chotzen syndrome

Premature craniosynostosis and a varying degree of brachy- and syndactyly are the name-giving clinical signs of the acrocephalo-syndactyly syndromes. According to McKusick (1988), at least three distinct types of ACS have to be distinguished: first- ly the Apert syndrome (ACS I), clinical vari- ants of which are the Apert-Crouzon syndrome (ACS 11) and the Vogt cephalodactyly; secondly the Saethre-Chotzen syndrome (ACS 111), which includes the Waardenburg syndrome (ACS IV); and finally the Pfeiffer syndrome (ACS V), involving the Noack syndrome (ACPS I).

However, the classification of these syndromes is often complicated by the wide variability in clinical manifestation and a frequent overlap of the clinical features. Thus, in the past, the nosology of the acrocephalosyndactylies has been debated, and the present classification may not be the final one (Escobar & Bixler 1977, Rasmus- sen & Frias 1988).

The ACS I11 (Saethre-Chotzen syndrome), first described in the early 1930's (Saethre 1931, Chotzen 1932), is character-

ized by acrocephaly with asymmetry of the neurocranium and face, low-set frontal hairline, ptosis, defects of the vertebral column, variable brachydactyly and cutaneous syndactyly. In the present paper, a family is described, in which members of four generations showed clinical features of ACS I11 (Fig. 1).

Family History

Case 1 Ev. L. (Fig. 2), the first child of unrelated parents, was a full-tern baby of 3230 g weight and 55 cm length. Because of peri- natal complications (Apgar score: 3/6/8) and cranio-facial dysmorphic signs, she was referred to the University Children's Hospi- tal. Clinical findings included a brachytur- ricephaly, a flat receding forehead and a prominent bone crest on the middle of the forehead. The root of the nose was flat and sunken. There was asymmetry of the face caused by a lateral deviation of the nasal septum. A moderate protrusio bulbi and bilateral epicanthal folds were found. Sten-

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I +TQ

FIg. 1. Pedigree of the family with acrocephalosyndactyly. The proposita and her brother are marked with an arrow.

osis of the tear ducts was suspected. The ears were low set. The head circumference was 3 1 cm at birth (< 3rd percentile). Some of the cranial sutures were widely open: the sagittal suture up to 6 cm, the lambdoideal and the temporal sutures 1-2 cm; the coronal and the frontal sutures were partially synostosed. Roentgenological analysis of the skull demonstrated hypoplastic frontal bones and a shortened base of the skull (Eber et al. 1986). Significant digital im- pressions were found. Further clinical inves- tigations showed a bilateral cutaneous syndactyly of the 2nd and 3rd fingers and a small porus coccygeus. Chromosome analysis was normal.

Case 2 Er. L (Fig. 3), the brother of the proposita, was born by section in the 40th week of gestation because of imminent uterus rup- ture. Birth weight was 3850 g. and length 51 cm. Clinical features included acrocephaly with widely open anterior and posterior fon- tanelles, low-set frontal hairline, deep, flat- tened nasal bridge, parrot-beaked nose, antimongoloid slant of the palpebral fis- sures, hypertelorism, low-set ears, flat occi- put, slight prognathism and cutaneous syndactyly of the 2nd and 3rd fingers. Upon radiological examination, the skull showed irregularities similar to those of his sister: premature synostosis of the coronal suture,

widely open lambdoideal and sagittal sutures and marked hypoplasia of the frontal bones.

Further Family History Examination of the children's mother (Fig. 4C) revealed that she herself had a mild form of the acrocephalosyndactyly syndrome: she showed a slight flattening of the forehead and brachycephaly, hypertelorism with a protrusio bulbi on the left side, a highly arched palate, a slight facial asymmetry, caused by a deviation of the nasal septum, and a bilateral brachydactyly with a small cutaneous syndactyly between the 2nd and 3rd fingers.

Further family studies revealed that, to a varying extent, clinical signs of ACS I11 were found in 6 of the other family members. Their clinical findings are summarized in Table 1. The great-grandfather of the probands (Fig. 4A) showed the typical facial features of the syndrome, involving acrocephaly, low-set frontal hairline, broad nasal bridge, ptosis and a strong facial asymmetry. These clinical signs were found to a lower degree of expression in one of his sons (Fig. 4B). In addition to these facial features, he also had brachydactyly. One of his daughters (Fig. 1, 111-6) and her son (Fig. 1, IV-5) had slight mid-face hypoplasia in association with brachycephaly. Another daughter (Fig. 1, 111-2), in addition to the facial features, was mentally retarded. Her daughter (Fig. 1, IV-1) showed the typical flattening of the forehead, acrocephaly, midface-hypoplasia and ptosis.

Discussion

In the past, different types of acrocephalosyndactyly syndromes have been described and the existence of at least three distinct nosologic entities has been discussed.

According to McKusick (1988), Apert syn-

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 I l l 273

111 are

present.

NIEMANN-SEYDE ET AL. 274

-, &>--

flg. 3. Er. L. aa a newborn, showing features similar to those in his Sister.

flg. 4. a) Great-grandfather (1-1). b) grandfather (11-5) and c) mother Of the proposita. There is typical Intrafamlllal variability of the clinical features.

ACROCEPHALOSYNDACTYLY S Y N D R O M E I l l 275

Table 1

Frequency of clinical findings in Saethre-Chotzen syndrome

Frequency (%) according to Pantke et al. (1975)

Findings IV-10 IV-9 IV-5 IV-1 111-10 111-6 111-2 11-5 1-1

+ - + Lowset frontal hairline + - - - Acrocephaly Deviation of nasal septum

+ + ( + I + ( + I ( + I ( + I + + ( + I ( + I ( + I + - + + ( + I >75%

Ptosis of the eyelids + + + ( + I + + Parrot-beaked nose + + + ( + I

Brachydactyly + + + + + + + + Lowset ears 50-70% + + + - + Tear duct stenosis - ( + I Strabismus - - + - Facial asymmetry - + + ( + I ( + I ( + I + Highly arched palate ( + I ( + I Spinal anomalies 2540% - ( + I Dystopic canthus + + + - Anomalous m a . lat. incisors - Hypertelorism + ( + I Impaired hearing - Optic atrophy Soft tissue syndactyly of hands Clinodactyly + + + + + + + + Cleh palate Cryptorchidism - Heart murmur Renal anomalies infrequent Anus imperforate Mental retardation - - + - - + = present: (+ ) = moderate; - = absent: blank = unknown.

- - -

-

( + I -

+ - + - -

- - - + + + ( + I 25%

- - - - - - - _ _ - - - - - - - - - - - - -

drome, also called ACS I, is characterized by a special form of symmetrical syndactyly of all four limbs with a typical mid-digital hand mass (Allanson 1986). In the Apert-Crouzon disease (ACS 11), which belongs to the same nosologic entity as the Apert syndrome (Co- hen 1975), typical facial features are caused by a very hypoplastic maxilla. The Vogt cephalodactyly is characterized by hand and foot malformations of the Apert type and facial features of the Crouzon syndrome, indi- cating the similarity of the above-mentioned disorders. Frequently observed features in patients affected with Waardenburg syndrome (ACS IV) are plagiocephaly, absence of first metatarsal and bifid terminal phal- anges of the digits as well as cleft palate, car-

diac malformations or contractures. Based on the clinical findings, ACS IV has recentiy been subclassified to the ACS 111 syndrome. Finally, in Pfeiffer syndrome (ACS V) strik- ing features are short and broad thumbs and big toes, the proximal phalanx occasionally being fused with the distal phalanx. A clinical variant of ACS V, the Noack syndrome, dif- fers from the Pfeiffer syndrome in the pres- ence of polydactyly as an additional feature.

However, such a classification becomes complicated by the fact that distinction between individual cases and different types is often minimal. The wide variability in phenotypic expression and the frequent overlap of clinical signs has raised the ques- tion, whether the multiple ACS phenotypes

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might be a result of a single gene with a highly variable expression. This point of view has been supported by case reports, where multiple ACS-phenotypes were observed among different members of the same family (Jackson et al. 1976, Escobar & Bixler 1977).

In the family reported in this paper, clinical findings were quite similar among the affected probands, although a varying degree of seventy of the phenotypic expression was observed. In this family, Apert syndrome and Vogt cephalodactyly have been excluded from differential diagnostic evalu- ations, because of the lack of bone symphy- sis of fingers and toes, which are typical for these disorders. Further, the observed facial features were not suggestive of Crouzon disease; in particular, none of the affected family members showed the characteristic ex- ophthalmus and external strabismus, nor was hypoplastic maxilla and relative man- dibular prognathism found in the patients. In addition, the absence of specific ex- tremity malformations such as broad and short thumbs and toes did not suggest Pfeif- fer syndrome in the affected family; further- more, no polydactyly as in the Noack syndrome was observed. In contrast, differential diagnostic considerations showed that phenotypic signs of the affected family members were typical for Saethre-Chotzen syndrome (ACS 111). However. as the nosology of these syndromes is still being debated, the present classification may not be the final one and in future it may possibly need some modification.

Clinical features of the disorder could be minimal, underlining once more the need for careful examination for minor stigmata before providing genetic counselling (Le Merrer et al. 1988). Large pedigrees may help to clarify the genetic background of the ACS syndromes and can provide a powerful tool, e.g. for linkage analysis (Eastman et al. 1978).

References

Allanson, J. E. (1986). Germinal mosaicism in Apert syndrome. Clin. Genet. 29, 429-433.

Chotzen, F. (1932). Eine eigenartige familiire Entwicklungsstijrung (Akrocephalosyndak- tylie, Dysostosis craniofacialis und Hypertelo- rismus). Mschr. Kinderheilk. 55, 97-122.

Cohen, M. M. Jr. (1975). An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects XI (2). 137-1 89.

Eastman, J. R., V. Escobar & D. Bixler (1978). Linkage analysis in dominant acrocephalosyndactyly. J. Med. Genet. IS, 292-293.

Eber, S. W., H. G. Luhr, 0. Spoem, W. Weigel & M. Westmeier (1 986). Kraniofaziale Korrek- turoperation bei Akrozephalosyndaktylie- Syndrom (Saethre-Chotzen-Syndrom). Z. Kinderchir. 411, 263-266.

Escobar, V. & D. Bixler (1977). On the classification of the acrocephalosyndactyly syndromes. Clin. Genet. 12, 169-178.

Jackson, C. E.. L. Weiss, W. A. Reynolds, T. F. Forman & J. A. Peterson (1976). Cranio- synostosis, midfacial hypoplasia and foot abnormalities: an autosomal dominant pheno- type in a large Amish kindred. J. Pediatr. 88, 963-968.

Le Merrer, M., V. Ledinot, D. Renier, D. Mar- chac & M. L. Briard (1988). Conseil ghetique dans les craniostenoses. Bilan d’une 6tude pro- spective realike avec le g r o u p d’etudes sur les malformations craniofaciales. J. Genet. Hum. 35,295-306.

McKusick, V. (1988). Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Auto- soma1 Recessive, and X-Linked Phenotypes, 8th Edit. Baltimore, John Hopkins University Press.

Pantke, 0. A., M. M. Cohen, C. J. Witkop, M. Feingold, B. Schaumann, H. C. Pantke & R. J. Gorlin (1975). The Saethre-Chotzen syndrome. Malformation Syndromes, ed. D. Bergsma. Birth Defects: Original Article Series, Vol XI, No. 2, 226-237.

Rasmussen, S. A. & J. L. Frias (1988). Mild expression of the Pfeiffer syndrome. Clin. Genet. 33, 5-10.

Saethre, H. (1931). Ein Beitrag zum Turmschiidel- problem (Pathologie, Erblichkeit und Sympto- matologie). Drsch. Z . Nervenheilk. 117, 533-555.

Address: Dr. med. S. Niemann-Seyde Institut f6r Humangenetik GoJIerstraje I2d 0-3400 Gdttingen, Germany