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Original Articles Evidence for Digenic Inheritance in Some Cases of Antley

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Original Articles Evidence for Digenic Inheritance in Some Cases of Antley 26 J Med Genet 2000;37:26–32 Original articles J Med Genet: first published as 10.1136/jmg.37.1.26 on 1 January 2000. Downloaded from Department of Clinical Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Evidence for digenic inheritance in some cases of W Reardon M Baraitser Antley-Bixler syndrome? R M Winter Molecular Genetics Unit, Institute of Child Health, London, UK William Reardon, Anne Smith, John W Honour, Peter Hindmarsh, Debipriya Das, A Smith Gill Rumsby, Isabelle Nelson, Sue Malcolm, Lesley Adès, David Sillence, I Nelson Dhavendra Kumar, Celia DeLozier-Blanchet, Shane McKee, Thaddeus Kelly, S Malcolm Wallace L McKeehan, Michael Baraitser, Robin M Winter Department of Chemical Pathology, University College London Hospitals, London, UK J W Honour Abstract The Antley-Bixler syndrome represents the D Das The Antley-Bixler syndrome has been severe end of the spectrum of syndromic G Rumsby thought to be caused by an autosomal craniosynostosis. Many such patients have London Centre for recessive gene. However, patients with this choanal atresia and severe respiratory distress, Paediatric often resulting in early death. In contrast with Endocrinology, phenotype have been reported with a new University College dominant mutation at the FGFR2 locus as most clinically similar forms of syndromic Hospital, London, UK well as in the oVspring of mothers taking craniosynostosis, which are transmitted in an P Hindmarsh the antifungal agent fluconazole during autosomal dominant manner, Antley-Bixler Departments of early pregnancy. In addition to the cranio- syndrome has been thought to be an autosomal Clinical Genetics and recessive disorder.7 This is based upon three Paediatrics and Child synostosis and joint ankylosis which are the 8–10 Health, New Children’s clinical hallmarks of the condition, many reports of aVected sibs and the birth of Hospital, Parramatta, patients, especially females, have genital aVected subjects to consanguineous par- NSW 2124, Australia ents.91112It should be noted that joint ankylo- abnormalities. We now report abnormali- L Adès sis in the context of craniosynostosis is not D Sillence ties of steroid biogenesis in seven of 16 exclusive to Antley-Bixler syndrome and is also patients with an Antley-Bixler phenotype. Centre for Human seen in some cases of PfeiVer syndrome, many Genetics, SheYeld Additionally, we identify FGFR2 mutations Children’s Hospital, of which arise as new autosomal dominant 117 Manchester Road, in seven of these 16 patients, including one mutations.13–15 However, unlike Antley-Bixler SheYeld S10 5DN, UK patient with abnormal steroidogenesis. http://jmg.bmj.com/ D Kumar syndrome, genital malformations are not char- These findings, suggesting that some cases acteristic of PfeiVer syndrome. Similarly, femo- Division of Medical of Antley-Bixler syndrome are the outcome ral bowing with craniosynostosis can be seen in Genetics, University of Geneva CMU, 1 rue of two distinct genetic events, allow a some cases of thanatophoric dysplasia, again Michel-Servet hypothesis to be formulated under which without accompanying genital anomalies. An CH-1211, Geneva 4, we may explain all the diVering and seem- important observation common to all three Switzerland C DeLozier-Blanchet ingly contradictory circumstances in which sibships with recurrence of Antley-Bixler syn- the Antley-Bixler phenotype has been rec- drome is the concordance of genital abnormali- on September 28, 2021 by guest. Protected copyright. Clinical Genetics Unit, 8–10 Birmingham Women’s ognised. ties in all six cases. Hospital, Edgbaston, (J Med Genet 2000;37:26–32) Mutation of members of the fibroblast Birmingham B15 2TG growth factor receptor gene family (FGFR) has UK Keywords: Antley-Bixler syndrome; FGFR; congenital S McKee been established as the basis of several adrenal hyperplasia; CYP21 deficiency autosomal dominant forms of cranio- Division of Medical 16–18 Genetics, University of synostosis. Other mutations of this gene family have been established as the cause of Virginia School of In 1975 Antley and Bixler1 reported a patient Medicine, several variants of skeletal dysplasia, including with craniosynostosis, radiohumeral synosto- Charlottesville, VA, thanatophoric dysplasia.19–21 As the eVects of USA sis, and femoral bowing. A further 24 cases T Kelly FGFR mutation on receptor function have have since been added, showing that humero- become clearer, it has been suggested that Center for Cancer ulnar synostosis and straight femora may also Biology and Nutrition, 2 these mutant forms are viable only in the Institute of Biosciences be consistent with the condition, although the heterozygous state and that homozygosity for and Technology, Texas exact nosology can be controversial on FGFR mutation would be lethal.18 A&M University, 3–5 System Health Science occasion. An intriguing aspect of these New dominant mutations at the FGFR2 Center, 2121 Holcombe reports is the frequency of genital abnormali- locus have been observed in patients with a Blvd, Houston, TX ties among aVected subjects, 14 of whom were phenotype very similar to that of Antley-Bixler 77030, USA 15 22–24 W L McKeehan noted to have this feature. Of these 14 cases, 10 syndrome, although the genitalia in these were females with clitoromegaly, fusion of the Correspondence to: reports, which included three females, did not Dr Reardon labia minora, and hypoplasia of the labia show evidence of clitoromegaly. Genital abnor- majora.26Against this, eight females have been malities are not characteristic of syndromes Revised version received described in whom the genitalia were normal, arising as a result of FGFR mutation and the 19 August 1999 Accepted for publication 27 or not thought worthy of comment by the high prevalence of such anomalies, especially August 1999 authors. among female infants, is an unexplained aspect Digenic inheritance in Antley-Bixler syndrome? 27 J Med Genet: first published as 10.1136/jmg.37.1.26 on 1 January 2000. Downloaded from Figure 1 Characteristic craniofacial features of Antley-Bixler syndrome in patient SP of this report (A). The characteristic fixed elbow joint of Antley-Bixler syndrome is shown (B). The genital malformations are illustrated to document the cliteromegaly and hooded prepuce observed in SP (C). (Photographs reproduced with permission.) of the Antley-Bixler syndrome. Another clue to gest that the genital malformations of Antley- the aetiology of Antley-Bixler syndrome might Bixler syndrome may be the result of abnor- be the observation that the phenotype has been malities of steroidogenesis and that the severe reported in the oVspring of women taking high skeletal phenotype reflects an exaggerated dose fluconazole, an antifungal agent, during response to FGFR mutation, at least in some pregnancy. To date, four instances of this have cases. Finally, these observations oVer a model been recorded.25–27 under which the fluconazole induced cases of http://jmg.bmj.com/ The observation of abnormalities of steroid Antley-Bixler syndrome may be explained. biosynthesis suggestive of heterozygosity for a 21-hydroxylase (CYP21) deficiency in a patient Materials and methods with classical Antley-Bixler syndrome (fig 1) Sixteen patients (4M, 12F) were available for has led us to evaluate 15 further patients with study, all of whom had confirmed craniosynos- craniosynostosis and joint fusion for abnor- tosis and ankylosis of the elbow joints. Five of malities of steroid biosynthesis and for FGFR2 the 12 female cases showed variable degrees of on September 28, 2021 by guest. Protected copyright. mutations. Based on our observations, we sug- malformation of the external genitalia (table Table 1 Summary of clinical, biochemical, and molecular findings in 16 patients with Antley-Bixler syndrome Patient Chromosomes Steroid profile FGFR2 mutation Genitalia NC (16666) 46,XY Not available for analysis S351C Normal male ID (20554) 46,XX Normal S351C Normal female HD (14506) 46,XX Normal S351C Normal female MN (15441) 46,XY Normal C342R Normal male MR (14837) 46,XX Not available for analysis P276V Normal female DW (11314) 46,XX Normal C342S Normal female MA 46,XY Abnormal T290C Normal male JH (24019) 46,XX Abnormal None established Vestigial uterus30 Small vagina Vulval septum SP (14683) 46,XX Abnormal None established Clitoromegaly (1 cm) Hooded prepuce Fused labia (fig 1) BM 46,XX Abnormal Not available for analysis Clitoromegaly Fused labia BW (24872) 46,XY Abnormal None established Normal male DK 46,XX Abnormal Not available for analysis Ambiguous genitalia Fused labia Clitoromegaly MJ 46,XX Abnormal Not available for analysis Ambiguous genitalia Chordee KM 46,XX Normal None established Normal female RS 46,XX Normal None established Normal female MF 46,XX Normal None established Normal female29 28 Reardon, Smith, Honour, et al 1). Two patients have been the subject of 123456 J Med Genet: first published as 10.1136/jmg.37.1.26 on 1 January 2000. Downloaded from previous clinical reports.28–30 Urine steroid metabolites were analysed by gas chromatography/mass spectrometry (GC/ MS) after processing of the urine samples as follows. Solid phase C18 SEP-PAK silica cartridges (Waters Associates, Harrow, Mid- dlesex) and ethanol were used for extraction of free steroids and steroid conjugates from the urine. The extract was dried and dissolved in 10 ml acetate buVer (0.5 mol/l, pH 4.6) to which was added 25 mg of enzyme powder, Sigma Sulfatase EC 3.1.6.1, type H-1 from Helix Pomatia (containing a sulphatase activity of 375-1000 units, and a â-glucuronidase activ- ity of 7500 units). The sample was incubated at 37°C for 18 hours for hydrolysis to take place. After further extraction using an ethanol primed C18 SEP-PAK cartridge internal standards, Exp: 8/30 Sec B: 187 W:248 G:1.25 Date: 06-01-1999 Time: 14:19 D 016-02701 File: A: D androstanediol (A), stigmasterol (S), and Figure 2 FGFR2 mutation in MA is shown. The mutation G882C causes Trp 290Cys substitution.
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