Letters 405 26 Finnilä S, Hassinen IE, Majamaa K. Restriction fragment 29 Macaulay V, Richards M, Hickey E, Vega E, Cruciani F, J Med Genet analysis as a source of error in detection of heteroplasmic Guida V, Scozzari R, Bonné-Tamir B, Sykes B, Torroni A. 2001;38:405–409 mtDNA mutations. Mutat Res 1999;406:109-14. The emerging tree of west Eurasian mtDNAs: a synthesis 27 Richards MB, Macaulay VA, Bandelt HJ, Sykes BC. Phylo- of control-region sequences and RFLPs. Am J Hum Genet geography of mitochondrial DNA in Western Europe. Ann 1999;64:232-49. Department of Hum Genet 1998;62:241-60. Paediatrics, University 30 Johns DR. Seminars in medicine of the Beth Israel Hospital, 28 Tanno Y, Okuizumi K, Tsuji S. mtDNA polymorphisms in Boston. Mitochondrial DNA and disease. N Engl J Med Japanese sporadic Alzheimer’s disease. Neurobiol Aging Hospital of Innsbruck, 1995;333:638-44. Austria 1998;19(suppl):S47-51. E Haberlandt H Fischer P Heinz-Erian T Müller Split hand/split foot malformation associated with Institute of Medical Biology and Human Genetics, University of sensorineural deafness, inner and middle ear Innsbruck, Schöpfstrasse 41, 6020 malformation, hypodontia, congenital vertical Innsbruck, Austria J Löffler talus, and deletion of eight microsatellite markers G Utermann A R Janecke in 7q21.1-q21.3 Departments of Hearing, Speech and Voice Disorders/ENT, Edda Haberlandt, Judith LöZer, Almut Hirst-Stadlmann, Bernd Stöckl, Werner Judmaier, University Hospital of Helmut Fischer, Peter Heinz-Erian, Thomas Müller, Gerd Utermann, Richard J H Smith, Innsbruck, Austria Andreas R Janecke A Hirst-Stadlmann Department of Orthopaedics, University Hospital of EDITOR—The split hand/split foot malforma- The classical features of the autosomal domi- Innsbruck, Austria tion (SHFM, MIM 183600) is a central reduc- nant inherited EEC syndrome are ectrodactyly, B Stöckl tion defect of the hands and feet and occurs ectodermal dysplasia, and clefting of the Institute of MR both as an isolated malformation and as part of lip/palate. In most patients, there are additional Imaging and several syndromes including the EEC syn- anomalies typically aVecting the urogenital and Spectroscopy, drome (MIM 129900). We report ona2year lacrimal systems.12 Some patients also have University Hospital of old boy with SHFM associated with features of dysmorphic facies, a tendency to infectious dis- Innsbruck, Austria W Judmaier ectodermal hypoplasia, a submucous cleft pal- ease, endocrine disorders, and mental retarda- ate, congenital vertical talus, malformations of tion. This phenotypic variability has become Department of the middle ear, profound sensorineural hearing increasingly apparent over the last 15 years34 Otolaryngology, loss resulting from Mondini dysplasia, and a de and numerous related and overlapping syn- University of Iowa novo deletion of the paternal chromosome dromes have been delineated by many investi- Hospitals, Iowa City, 5 USA 7q21.1-q21.3. This patient with syndromic gators. In an attempt to clarify classification, R J H Smith SHFM represents a case of atypical EEC major and minor criteria for the diagnosis of syndrome, but also displays abnormalities EEC syndrome have been elaborated.34 Correspondence to: Dr Janecke, previously not associated with SHFM or EEC Dominant inheritance of EEC has been [email protected] syndrome. documented in several large multigenerational Figure 1 The proband aged 18 months. (A, B) Note facial dysmorphism (see text). (C) He cannot stand unsupported. www.jmedgenet.com 406 Letters Figure 2 Right foot of the patient. (A) Ectrodactyly (split foot malformation) with apparent absence of the 2nd toe and syndactyly of toes 3 to 5. (B) Radiograph showing syndactyly of the first and second metatarsals and absence of the second phalanges and malformation of the third to fifth phalanges.(C) Ectrodactyly and pes planovalgus (severe talus verticalis deformity). families.6 At least 15 patients have been Case report reported to have cytogenetic abnormalities of Our patient is the fifth child of healthy, consan- chromosome 7q21.2-7q22.1, including nine guineous, fourth cousin, Austrian parents. The patients with interstitial deletions.7–9 In addi- father and the mother were 41 and 36 years, tion, mutations in the gene encoding the trans- respectively, at the time of his birth. His four activation factor p63 on chromosome 3q27 sibs are healthy. He was born after an unevent- have been identified in familial and sporadic ful pregnancy in the 41st week of gestation and cases of EEC syndrome.10 A third locus was weighed 2840 g (10th centile), was 48 cm long mapped to chromosome 19q,11 further delin- (10th centile), and had a head circumference of eating the genetic heterogeneity of this syn- 31.5 cm (10th centile). Ectrodactyly of the drome. The reason for the phenotypic right foot was noted and transient evoked heterogeneity in EEC syndrome patients with otoacoustic emission screening indicated hear- 7q abnormalities is unclear but may relate to ing impairment. Further examinations were at the size of the deletion. first declined by the mother. At 15 months of asc asc co va es co Figure 3 Inner ear of the patient. A 3D reconstruction of a coronal MRI scan shows Mondini type malformation on both sides. (A) Right ear: overall dilated and plump structures of the inner ear. asc denotes the anterior semicircular canal, va the vestibular aqueduct with saccule and utricle, and co the cochlea showing a reduced number of coils. (B) Left ear: a large endolymphatic sac is shown (es). (C) Schema of the normal inner ear. 1. Anterior semicircular canal. 2. Membranous ampulla (MA) of the anterior semicircular canal. 3. MA of the lateral semicircular canal. 4. Saccule. 5. Cochlear canal. 6. Helicotrema. 7. Lateral semicircular canal. 8. Posterior semicircular canal. 9. MA of the posterior semicircular canal. 10. Vestibular window. 11. Cochlear window. 12. Scala vestibuli. 13. Scala tympani. 14. Utricule. www.jmedgenet.com Letters 407 B Distance D7S2506 3 2 1 4 cM Mb D7S663 3 2 4 1 8.5 D7S2455 3 1 2 4 10.3 D7S634 1 2 2 3 2.8 D7S2443 2 2 1 3 0.7 D7S524 2 1 2 3 3.7 D7S492 2 2 1 2 3.1 D7S2410 1 1 1 1 3.5 D7S657 1 1 3 2 1.5 D7S2482 1 3 2 3 2.8 A D7S527 2 1 3 2 0.2 D7S1812 3 3 2 1 0.1 D7S821 2 2 1 3 0.2 D7S2539 3 3 2 1 0.3 D7S479 1 2 3 2 <0.1 D7S491 3 3 2 1 0.1 0.1 D7S1796 2 3 2 1 1.3 D7S2480 1 2 2 2 0.5 D7S647 2 2 1 2 7.8 q21.1 D7S501 1 1 2 3 0.8 D7S692 3 2 1 3 q21.3 F M MFSL SL D7S2506 3 1 D7S663 3 4 7 der(7) D7S2455 3 2 D7S634 ? 2 D7S2443 2 1 D7S524 ? 2 D7S492 - 1 D7S2410 ? 1 De novo D7S657 - 3 deletion of D7S2482 - 2 about 8.9 D7S527 ? 2 to 17.0 cM D7S1812 - 2 D7S821 - 1 D7S2539 - 2 D7S479 - 3 D7S491 - 2 D7S1796 ? 2 D7S2480 1 2 D7S647 2 1 PDS gene D7S501 1 2 D7S692 3 1 Figure 4 Cytogenetic and molecular findings. (A) High resolution cytogenetic analysis of both chromosomes 7 of the patient. The deletion is indicated by the arrow. (B) Preliminary analysis of microsatellite markers from chromosome 7q in the family of the patient. The deleted interval spans at least 8.9 cM on the paternal chromosome flanked by microsatellite markers D7S2443 and D7S2480. Data regarding microsatellite mapping are compiled from Dib et al12 and Crackower et al.13 14 The arrow indicates the position of the gene mutated in Pendred syndrome. age, he was referred to the hospital because of patient haplotypes and found that for the eight failure to thrive (weight 7200 g, below the 3rd markers flanked by D7S2443 and D7S2480, centile; length 70 cm, below the 3rd centile; the patient had a deletion of the paternal allele head circumference 43 cm, below the 3rd cen- (fig 4B). Two markers within the interval tile). Physical examination showed arched eye- (D7S2410 and D7S527) were uninformative, brows, a small triangular nose with a depressed as were two flanking markers (D7S524 and nasal bridge, and ears with overfolded helices D7S1796). These data define a deletion of 8.9 and attached earlobes (fig 1). He also had to 17 cM , which includes the critical interval hypertelorism, a large biparietal diameter, of <1 Mb on 7q21.3 previously associated with hypopigmented retina, micrognathia, a submu- either SHFM or EEC syndrome.7913 cous cleft palate, carious primary teeth and hypodontia, sparse, light hair, pale skin, Discussion cryptorchidism, and bilateral severe congenital Extensive investigations have not been able to vertical talus, in addition to the previously support any of several hypotheses to connect noted ectrodactyly of the right foot (fig 2). CT the chromosomal aberrations with the occur- and MRI scans showed Mondini dysplasia of rence and varying characteristics of syndromic the inner ear (fig 3) and cochlear implanting SHFM .13 15 Given the rare occurrence of cyto- showed fixation of the ossicular chain. Audio- genetic abnormalities in persons with syndro- metric examinations were consistent with these mic and non-syndromic SHFM, the fact that findings and showed conductive and profound the deletion we report includes the critical sensorineural hearing loss. Laboratory investi- region previously described in patients with gations showed partial deficiency of growth SHFM emphasises the importance of this hormone secretion. Mental and psychomotor chromosome 7 interval in the pathogenesis of developmental delay was noted. SHFM/syndromic SHFM. Furthermore, we On GTG banding, we observed an intersti- believe that the range of phenotypic findings in tial deletion of chromosome 7 confined to the SHFM patients with aberrations of interval q21.1-q21.3 (fig 4A); parental karyo- chromosome 7q favours a contiguous gene types were normal.