Jf Med Genet 1994:31:393-396 393 Syndrome of the month J Med Genet: first published as 10.1136/jmg.31.5.393 on 1 May 1994. Downloaded from

Saethre-Chotzen syndrome

William Reardon, Robin M Winter

Clinical geneticists are inured to anecdotes Chotzen syndrome provides a perfect battle- recounting odd presentations of dysmorphic ground for "lumpers" and "splitters", a broad syndromes. Saethre-Chotzen syndrome is a consensus has now emerged as to the central case in point. A consultation for schizophrenia features of the condition. However, such is the led to the first report from the Norwegian degree of variability and overlap with other psychiatrist, Haakon Saethre, who identified a syndromes of craniofacial growth disturbance condition characterised by , that certain identification of the syndrome in a low frontal hairline, facial asymmetry, brachy- single case is often difficult, examination of dactyly, fifth finger , partial syn- other family members being required for con- dactyly, and vertebral column defects in his firmation in a suspected case. In addition clin- patient.' The patient's mother and half sister ically unaffected carriers have been noted also had and cranial abnormalities. several times7 and the response of the family to This initial report also included details of a the evaluation of other apparently well persons similar, apparently sporadic case. Within a may need to be considered.8 year, Chotzen2 reported a father and two sons who, in addition to craniosynostosis, had , facial asymmetry, palatal mal- Clinical features formation, , deafness, and mental Disturbed cranial development in Saethre- retardation. Chotzen syndrome results in a wide variety of This unusual variability in the phenotype craniofacial abnormalities, sometimes mani- delayed the emergence of a well defined syn- festing as frank craniosynostosis. However, the drome for 40 years until the report of Pantke et mildness of the skull irregularity in some in- al,3 whose systematic evaluation of six families stances may lead to underdiagnosis and, con- underlined the clinical range of the condition. sequently, the overall prevalence of craniosy- http://jmg.bmj.com/ Moreover, these authors retrospectively iden- nostosis within the syndrome is uncertain. If tified several published cases and pedigrees present, the craniosynostosis is variable and which had been misdiagnosed and reported as frequently asymmetrical. Premature fusion of other syndromes. the coronal suture, manifesting as brachyce- Meanwhile the confusion surrounding clin- phaly or , of the metopic suture, ical conditions comprising craniofacial and di- causing , and of the lambdoid

gital anomalies had been clarified by Blank4 suture causing occipital flattening have all on September 27, 2021 by guest. Protected copyright. whose study of 34 patients with "acrocephalo- been noted, in addition to frontal and parietal syndactyly" had clearly identified Apert syn- bossing. The disturbance of cranial develop- drome from non-Apert acrocephalosyndac- ment may be more subtle and late closing tyly. The changes in approach to classifying , parietal foramina (fig 1), and ossi- this group of disorders are well illustrated by fication defects, as well as hyperostosis of the comparing the approach adopted by McKu- calvarium have all been recorded. Common sick in 1966 with that of 1992.56 In the first clinical features resulting from abnormal cra- edition of Mendelian Inheritance in Man, six nial development, apart from craniosynostosis, separate categories of acrocephalosyndactyly are a flat forehead and a straight nasal bridge. were cited: type I or typical Apert syndrome, As noted by Saethre the frontal hairline may type II called Apert-Crouzon or Vogt syn- be low. Ptosis, hypertelorism, and facial asym- drome, type III consisting solely of the reports metry are well documented. The palate may be of Saethre and Chotzen without the use of arched or, rarely, cleft and the nasal septum their acronym, type IV or Mohr type, type V deviated from the midline. Lacrimal duct ab- or Waardenburg type, and type VI or Pfeiffer normalities are common. Typical facial syndrome. Nowadays, three rather than six features are illustrated in figs 2 and 3. Hearing Mothercare Unit of categories of acrocephalosyndactyly syn- impairment, thought to reflect nerve Paediatric Genetics compres- and Fetal Medicine, dromes are recognised separately: types II and sion, is an occasional finding. Mild external ear Institute of Child IV and Waardenburg have been eliminated malformation is common, typically manifest- Health, 30 Guilford and type III, now known after Saethre and ing as small round ears which may be poster- Street, London WClN 1EH, UK. Chotzen, has been greatly expanded. Pfeiffer iorly rotated, while some authors have noted W Reardon syndrome continues as a distinct entry but has the prominence of the crus helicis (fig 4). R M Winter become type V and Apert syndrome remains as Mild syndactyly of the second interdigital Correspondence to type I. space of the fingers was a feature of Saethre's Dr Reardon. Although the clinical variability of Saethre- description and has been reiterated by several 394 Reardon, Winter J Med Genet: first published as 10.1136/jmg.31.5.393 on 1 May 1994. Downloaded from

I

Figure 3 Adult patient with Saethre-Chotzen syndrome. Note the ptosis andfrontalis overactivity.

Differential diagnosis Some cases may be so mildly manifesting as to go undetected until evaluation of the whole family after identification of the syndrome in a child with frank craniosynostosis. In this con- nection it is surprising to note that Carter et al,9 in a review of craniosynostosis, identified nine probands with Saethre-Chotzen syn- Figure 1 Skull radiograph showing fusion of the lower drome but thought that only four were fami- part of the metopic suture, the upper end of which is lial. Our experience suggests that most cases of widely separated and continuous with large, symmetrical defects in the parietal bones, extending to the midline. Saethre-Chotzen syndrome are familial rather than sporadic, but the signs in other family members may be subtle. subsequent reports and by our own observa- Since craniosynostosis is the problem lead- tions (fig 5). Syndactyly of other fingers is ing to presentation in many families, differen- uncommon. The thumbs may be short and tial diagnosis will focus largely on craniosyno- angulated or flattened (fig 6). Cutaneous syn- stosis and its causes, whether simple or dactyly of toes 2 to 3 is well described and a syndromic. Craniosynostosis is an aetiologi- broad hallux with a valgus deformity is charac- cally heterogeneous end stage of several com- teristic of Saethre-Chotzen syndrome. We plex pathophysiological processes,'0 some http://jmg.bmj.com/ have observed instances of hallucal reduplica- cases of which have an underlying chromoso- tion in the context of a strong family history of mal abnormality. Among the autosomal dom- "classical" Saethre-Chotzen syndrome in three different families (fig 7). In addition, radiographs of clinically broad halluces may show notching of the terminal phalanges (fig

8). Other skeletal anomalies, much less fre- on September 27, 2021 by guest. Protected copyright. quent in prevalence, are radioulnar synostosis and vertebral fusion.

Figure 2 Typicalfacialfeatures of a child with Saethre-Chotzen syndrome. Note the acrocephaly, wide prominent forehead, depressed nasal bridge, and small ears with Figure 4 Prominent crus helicis in a patient with prominence of the crus. Saethre-Chotzen syndrome. Saethre-Chotzen syndrome 395 J Med Genet: first published as 10.1136/jmg.31.5.393 on 1 May 1994. Downloaded from

Figure 7 Hallucal reduplication observed in a single tient with Saethre-Chotzen patient from a family with Saethre-Chotzen syndrome. as a gene carrier.

varus deformity in Pfeiffer cases. Saethre- inant forms of syndromic craniosynostosis, Chotzen cases, in contrast, may have broad big Saethre-Chotzen syndrome is readily identifi- toes but with a characteristic valgus deformity

able from Apert syndrome by the absence of and the thumbs are not usually broad, al-

the characteristic skin and bony syndactyly of though may be flattened. Jackson-Weiss syn- the latter condition. is drome represents a highly variable phenotype, characterised by proptosis in almost all cases, a the craniofacial abnormalities covering the en- feature which is rare in Saethre-Chotzen syn- tire spectrum of acrocephalosyndactyly syn- drome pedigrees. Moreover the facial profile in dromes, associated with medial deviation of to a Apert and Crouzon syndromes tends show the big toes in some cases. Clearly the differen- more severe degree of midface hypoplasia than tiation between Saethre-Chotzen and Jack- is usual in Saethre-Chotzen syndrome. Al- like son-Weiss syndromes might be difficult, par- though patients with , ticularly in the single case. Indeed it has been have a de- Saethre-Chotzen cases, frequently suggested that these are allelic forms (see be- gree of soft tissue syndactyly as well as cranio- low).

synostosis, the constant feature on which the et identified distal hallucal Carter aP9 redup- http://jmg.bmj.com/ the differentiation may be based is presence of lication and a Saethre-Chotzen syndrome-like with a broad thumbs and big toes, usually facies in two probands, and suggested a separ- ate entity, called Robinow-Sorauf syndrome, on September 27, 2021 by guest. Protected copyright.

Figure 6 Short, angulated thumbs offather (below) Figure 8 Degrees of terminal hallucal phalangeal and son (above) with Saethre-Chotzen syndrome. notching in patients from different pedigrees. 396 Reardon, Winter

in recognition of the report from these authors don et aP4 citing the break at 7p21.2 and Reid of autosomal dominant craniosynostosis and et aP5 indicating 7p22 as the breakpoint. hallucal reduplication." Similar observations Whether these observations reflect the current

have been recorded by other authors'213 and limits of cytogenetic resolution or, as discussed J Med Genet: first published as 10.1136/jmg.31.5.393 on 1 May 1994. Downloaded from are probably also represented by another re- by Reid et al, possible molecular heterogeneity port labelled as Pfeiffer syndrome.'4 Bifid dis- for this syndrome, noteworthy for its clinical tal hallucal phalanges have also been observed variability, remains to be seen. in auralcephalosyndactyly syndrome in which , facial asymmetry, delayed su- Figure 1 is reproduced with the consent of Drs Thompson, ture closure, and small pinnae were seen in Baraitser, and Hayward and by the permission of the Editor. association with 4/5 cutaneous syndactyly of 1 Saethre H. Ein Beitrag zum Turmschadelproblem (Patho- the feet.'516 While some authors'5 suggested genese, Erblichkeit und Symptomologie). Dtsch Z Ner- this as a separate entity, others thought it fell venheilkd 1931;117:533-55. 2 Chotzen F. Eine eigenartige familiare Entwicklungsstor- within the Saethre-Chotzen spectrum.'6 Given ung. (Akrocephalosyndaktylie, Dystosis craniofacialis the inconstant finding of radiological redupli- und Hypertelorismus). Monatschr Kinderheilkd 1932;55:97-122. cation of the hallux in several of our own 3 Pantke OA, Cohen MM Jr, Witkop CJ Jr, et al. The pedigrees with classical Saethre-Chotzen Saethre-Chotzen syndrome. Birth Defects 1975;XI(2): 190-225. phenotype, it seems likely that these authors 4 Blank CE. Apert's syndrome (a type of acrocephalosyndac- were all describing variable expression of the tyly): observations on a British series of thirty nine cases. Ann Hum Genet 1960;24:151-64. Saethre-Chotzen gene.'0 16 McKusick6 con- 5 McKusick VA. Mendelian inheritance in man. 1st ed. Balti- tinues to afford Robinow-Sorauf syndrome a more: Johns Hopkins University Press, 1966. 6 McKusick VA. Mendelian inheritance in man. 10th ed. provisional discrete entry in his catalogue. In Baltimore: Johns Hopkins University Press, 1992. view of these observations, it seems unlikely 7 Cohen MM Jr. Syndromes with craniosynostosis. In: Cra- niosynostosis: diagnosis, evaluation and management. New that there is continued justification for this. York: Raven Press, 1986:413-590. 8 Hughes HE. Syndrome diagnosis: patient grief or physician glory? 5th Manchester Birth Defects Conference, 1992. 9 Carter CO, Till K, Fraser V, Coffey R. A family study of Gene localisation studies craniosynostosis, with probable recognition of a distinct syndrome. J Med Genet 1982;19:280-5. There is a significant association between 7p 10 Cohen MM Jr. Sutural biology and correlates of craniosy- deletion and craniosynostosis, 14 of 32 nostosis. Am J Med Genet 1993;47:581-616. 11 Robinow M, Sorauf TJ. Acrocephalosyndactyly, type reported cases having this feature.'7 The pre- Noack, in a large kindred. Birth Defects 1975;11(5):99- cise location of and extent of deletion required 106. 12 Young I, Harper PS. An unusual form of familial acroce- for craniosynostosis is the focus of some debate phalosyndactyly. J Med Genet 1982;19:286-8. among cytogeneticists,'8 19 some favouring 13 Kopysc Z, Stanska M, Ryzko J, Kulczyk B. The Saethre- Chotzen syndrome with partial bifid of the distal pha- 7pl5 as the likely critical area and others langes of the great toes: observations of 3 cases in one considering the 7p21 region to be more im- family. Hum Genet 1980;56:195-204. 14 Naveh Y, Freidman A. Pfeiffer syndrome: report of a family portant. Based on the frequency of craniosy- and review of the literature. J Med Genet 1976;13:277-80. nostosis among 7p deletion cases, Brueton et 15 Kurczynski TW, Casperson SM. Auralcephalosyndactyly: a new hereditary craniosynostosis syndrome. Jf Med Genet aP0 performed linkage studies, using biallelic 1988;25:491-3. http://jmg.bmj.com/ markers, on 16 pedigrees with autosomal dom- 16 Legius E, Fryns JP, Van Den Berghe H. Auralcephalosyn- dactyly: a new craniosynostosis syndrome or a variant of inant craniosynostosis segregating. Although the Saethre-Chotzen syndrome? J Med Genet 1989;26: recognising the clinical heterogeneity among 522-4. 17 Chotai KA, Brueton LA, van Herwerden L, et al. Six cases their patient cohort, they showed significant of 7p deletion: clinical, cytogenetic and molecular studies. linkage among their pedigrees with 7p Am J Med Genet (submitted). 18 Aughton DJ, Cassidy SB, Whiteman DAH, Delach JA, markers. This has now been corroborated in a Guttmacher AE. Chromosome 7p- syndrome: craniosy- nostosis with of Am Med Genet refined patient group from six carefully preservation region 7p2. J7 on September 27, 2021 by guest. Protected copyright. 1991;40:440-3. selected Saethre-Chotzen pedigrees and a 19 Kikkawa K, Narahara K, Tsuji K, Kubo T, Yokoyama Y, position of maximum likelihood refined Seino Y. Is loss of band 7p21 really critical for manifesta- tion of craniosynostosis in 7p-? Am J Med Genet around the locus D7S488 (Zmax 7.57, Omax 1993;45: 108-10. O.05).21 Broadly similar linkage data are emerg- 20 Brueton LA, van Herwerden L, Chotai KA, Winter RM. The mapping of a gene for craniosynostosis: evidence for ing from others investigating separate patient linkage of the Saethre-Chotzen syndrome to distal chro- cohorts.22 mosome 7p. J Med Genet 1992;29:681-5. 21 van Herwerden L, Rose CP, Reardon W, et al. Evidence for The true genetic basis for the clinical de- locus heterogeneity in acrocephalosyndactyly: a refined lineation of autosomal dominant syndromic localisation for the Saethre-syndrome locus on distal chromosome 7p and exclusion of Jackson-Weiss syn- forms of craniosynostosis has also been shown drome from craniosynostosis loci on 7p and 5q. Am J by linkage studies. Crouzon syndrome families Hum Genet (in press). 22 Lewanda AF, Cohen MM Jr, Jackson CE, et al. Genetic do not map to the region of 7p defining the heterogeneity among craniosynostosis syndromes: map- Saethre-Chotzen syndrome locus, nor is Jack- ping the Saethre-Chotzen syndrome locus between D7S513 and D7S516 and exclusion of Jackson-Weiss and son-Weiss syndrome allelic with Saethre- Crouzon syndrome loci from 7p. Genomics (in press). Chotzen syndrome.2223 23 Reardon W, van Herwerden L, Rose C, Jones B, Malcolm S, Winter RM. Crouzon syndrome is not linked to Saethre-Chotzen syndrome phenotype has craniosynostosis loci at 7p2l and 5qter. Jf Med Genet recently been described in association with de 1994;31:219-21. 24 Reardon W, McManus SP, Summers D, Winter RM. novo translocations of 7p by two independent Cytogenetic evidence that the Saethre-Chotzen syndrome reports2425 and four other such cases are now gene maps to 7p21.2. AmJ Med Genet 1993;47:633-636. 25 Reid CS, McMorrow LE, McDonald-McGinn DM et al. known to the authors. The breakpoints dif- Saethre-Chotzen syndrome with familial translocation at fered slightly in the two published cases, Rear- chromosome 7p22. Am Jf Med Genet 1993;47:637-9.