Saethre-Chotzen syndrome (ACS III) in four generations

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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 prema- ture 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 acro- cephalo-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 syn- drome (ACS 11) and the Vogt cephalodac- tyly; secondly the Saethre-Chotzen syndrome (ACS 111), which includes the Waardenburg syndrome (ACS IV); and fi- nally the Pfeiffer syndrome (ACS V), involv- ing the Noack syndrome (ACPS I).

    However, the classification of these syn- dromes 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 acro- cephalosyndactylies 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 syn- drome), 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 hair- line, ptosis, defects of the vertebral column, variable brachydactyly and cutaneous syn- dactyly. In the present paper, a family is described, in which members of four gener- ations 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 acrocephalosyndac- tyly. 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 cor- onal 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 syn- dactyly of the 2nd and 3rd fingers and a small porus coccygeus. Chromosome analy- sis 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 syn- dactyly 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 su- tures 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 syn- drome: 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 asym- metry, 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 pro- bands (Fig. 4A) showed the typical facial features of the syndrome, involving acroce- phaly, low-set frontal hairline, broad nasal bridge, ptosis and a strong facial asym- metry. 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.


    In the past, different types of acrocephalo- syndactyly 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



    -, &>--

    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.


    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


    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 ce- phalodactyly is characterized by hand and foot malformations of the Apert type and fa- cial features of the Crouzon syndrome, indi- cating the similarity of the above-mentioned disorders. Frequently observed features in patients affected with Waardenburg syn- drome (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 be- tween 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 ob- served among different members of the same family (Jackson et al. 1976, Escobar & Bixler 1977).

    In the family reported in this paper, clin- ical findings were quite similar among the affected probands, although a varying de- gree of seventy of the phenotypic expression was observed. In this family, Apert syn- drome and Vogt cephalodactyly have been excluded from differ