American Journal of Medical Genetics 120A:381– 385 (2003)
A New Syndrome of Symphalangism, Multiple Frenula, Postaxial Polydactyly, Dysplastic Ears, Dental Anomalies, and Exclusion of NOG and GDF5 Piranit N. Kantaputra,1* Yupada Pongprot,2 Oranud Praditsap,3 Theeraphong Pho-iam,3 and Chanin Limwongse3 1
Department of Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand Division of Pediatric Cardiology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 3 Molecular Genetic Unit, Department of Research and Development, Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand 2
A Thai girl with a unique combination of limb and craniofacial anomalies is reported. Manifestations include blepharoptosis; prominent nose; hypodontia; multiple, hyperplastic frenula; and dysplastic ears. Limb anomalies include short stature, postaxial polydactyly of both hands and the left foot, proximal and distal symphalangism of fingers, and congenital absence of the distal phalanges of toes 2–5. Mutation analyses of NOG and GDF5, the genes responsible for symphalangism-related syndromes, were negative. ß 2003 Wiley-Liss, Inc. KEY WORDS: absent distal phalanges; blepharoptosis; hypodontia; microdontia; one-rooted molar; short stature
INTRODUCTION Symphalangism, characterized by fusion of the phalanges, is a rare anomaly. Proximal and distal symphalangism are defined as fusion between the proximal and middle phalanges and between the middle and distal phalanges, respectively. Proximal symphalangism is more common than distal and both have been reported in association with many syndromes such as proximal symphalangism (SYM1; OMIM 185800), facio-
Grant sponsor: The Thailand Research Fund (TRF); Grant sponsor: Mahidol University. *Correspondence to: Dr. Piranit N. Kantaputra, Department of Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand. E-mail: [email protected] Received 22 October 2002; Accepted 17 December 2002 DOI 10.1002/ajmg.a.20040
ß 2003 Wiley-Liss, Inc.
audio-symphalangism syndrome, tarsal-carpal coalition syndrome (TCCS; OMIM 186570), and multiple synostosis syndrome (SYMS1; OMIM 186500). Heterozygous mutations of the NOG gene are known to cause these proximal symphalangism-associated syndromes [Gong et al., 1999; Dixon et al., 2001]. Multiple synostosis, type 2, (SYNS2) is caused by a missense mutation in growth/differentiation factor 5 (GDF5) or cartilagederived morphogenetic protein-1 (CDMP1) [Akarsu et al., 1999]. Here, we describe a Thai patient with a unique combination of limb and craniofacial anomalies. Manifestations include blepharoptosis; prominent nose; hypodontia; multiple, hyperplastic frenula; and dysplastic ears. Limb anomalies include short stature, postaxial polydactyly of both hands and the left foot, and proximal and distal symphalangism of the fingers. NOG and GDF5 are known to play crucial roles in normal joint development [Akarsu et al., 1999; Gong et al., 1999; Tsumaki et al., 2002]. Because our patient had symphalangism, we thought that the phenotype might be caused by a mutation in NOG or GDF5. However, molecular studies did not identify any mutations in those genes. CASE REPORT The patient was a 12-year-old Thai girl, who was the first child of non-consanguineous, healthy parents (Fig. 1A). The patient was noted to have disproportionately short stature. Intelligence was normal. Her height, weight, and head circumference were 138 cm (3rd–10th centile), 36 kg (50th centile), and 51.5 cm (50th–75th centile), respectively. Hair and skin appeared normal. She had dolichocephaly, bilateral blepharoptosis, highly arched eyebrows, and sloping shoulders. Broad, prominent nasal bridge was observed. The philtrum was broad. The lower part of helices and lobules were hypoplastic (Fig. 1A). Hearing and echocardiography were unremarkable. Oral examination showed multiple, hyperplastic frenula and highly arched palate (Fig. 1B). The primary
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Fig. 1. A: Patient at the ages of 8, 11, and 12 years. B: Large maxillary permanent central incisor. Multiple, hyperplastic frenula. C: Panoramic radiograph at the age of 8 years showed hypodontia, short-rooted incisors, and premolars.
and permanent molars were small. The shape of the mandibular second premolar and first permanent molar resembled that of the mandibular second primary molar and mandibular second permanent molar, respectively. The maxillary first permanent molars and all second permanent molars had one root. Congenital absence of the maxillary permanent lateral incisors, and mandibular permanent central incisors were noted (Fig. 1C). The hands were small with bilateral postaxial polydactyly. The polydactylous fingers could not be moved voluntarily. Brachydactyly and tapering of all fingers were noted (Fig. 2A). Flexion at the interphalangeal joint (IPJ) was possible only at the distal interphalangeal joint (DIPJ) of the third fingers, making it impossible for her to make a fist. No cutaneous creases were observed over the dorsum of the affected joints. Fingernails were unremarkable (Fig. 2A). Roentgenograms of the hands at the age of 12 years showed normal appearance of the thumbs, short fourth and fifth metacarpals, and fusion of proximal interphalangeal joint (PIPJ) and DIPJ of fingers 2, 4, and 5. The DIPJ of the third fingers appeared normal. All phalanges of the polydactylous fingers were fused with rudimentary metacarpals. Metacarpophalangeal joints (MPJ) of the second and third fingers were narrow bilaterally (Fig. 2B). Hand radiography at the age of 7 years
showed brachymesophalangy of fingers 2–5. Coneshaped epiphyses of the middle phalanges 2–5 were observed. The PIPJ of fingers 2–5 were narrow. The DIPJ of all fingers were wider than the proximal ones and narrower than those seen at the age of 12 years. Symphalangism was seen only at the PIPJ of the polydactylous fingers. All toes were short. Postaxial polydactyly was found on the left foot; it could not be moved voluntarily. The first toes were broad with slightly dysplastic nails (Fig. 3A). Radiograph of the feet showed congenital absence of the distal phalanges of toes 2–5. The tufts of the distal phalanges of both great toes were not evident. The polydactylous toe appeared to have two phalanges but its metatarsal was absent (Fig. 2B). The metatarsal and tarsal bones appeared normal. A pelvic radiograph was unremarkable. MUTATIONAL ANALYSIS OF NOG AND GDF5 Genomic DNA was isolated from peripheral blood samples for mutation analysis of NOG and GDF5. NOG and GDF5 contain only 1 and 9 coding exons, respectively. Amplification of the entire coding sequence of NOG was performed using primers NOG1/NOG5. PCR
New Symphalangism-Craniofacial Anomaly Syndrome
Fig. 2. A: Postaxial polydatyly of hands. B: PA radiograph of hands at the age of 12 years. Note proximal and distal symphalangism. C: PA radiograph at the age of 7 years. Short middle phalanges of all fingers. All IPJ spaces are visible except for that of the proximal IPJ of the polydactylous one.
conditions for NOG have been described elsewhere [Gong et al., 1999]. Direct sequencing did not identify a pathogenic mutation in NOG and GDF5. DISCUSSION Symphalangism, a striking finding in this patient, is rare. Proximal symphalangism-associated syndromes
are caused by heterozygous mutations in NOG [Gong et al., 1999]. Congenital stapes ankylosis syndrome with no symphalangism has recently been found to be caused by heterozygous nonsense and frameshift mutations in NOG [Brown et al., 2002]. Noggin, the protein product of NOG, is essential for human joint morphogenesis. It binds and inactivates members of the TGFb superfamily, such as BMP4 [Brunet et al., 1998; Gong et al.,
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Fig. 3. A: Short toes. Postaxial polydactyly of the left foot. B: Short and broad distal phalanges of the great toes. Proximal IPJ spaces are narrow. Absence of the distal phalanges of toes 2–5. The polydactylous toe lacks metatarsal bone.
1999]. Patients with facio-audio-symphalangism syndrome and multiple synostosis syndrome, unlike those of proximal symphalangism syndrome, have facial manifestations, including a broad hemicylindrical nose, hypoplastic nasal alae, and a short upper lip [da-Silva et al., 1984; Hurvitz et al., 1985]. Symphalangism of both PIPJ and DIPJ in the same patient as reported here is very rare. Comparing the hand radiographs at the age of 7 and 12 years shows that symphalangism proceeds progressively in ulnar-radial [Strasburger et al., 1965; Polymeropoulos et al., 1995; Dixon et al., 2001] and proximo-distal directions [Krakow et al., 1998]. Proximal symphalangism, facioaudio-symphalangism syndrome, symphalangism with tarsal and carpal coalition, and multiple synostosis syndrome may have distal symphalangism as a rarely associated anomaly [Strasburger et al., 1965; Geelhoed et al., 1969; da-Silva et al., 1984; Drawbert et al., 1985; Hurvitz et al., 1985]. Similarly, distal symphalangism, as a distinct autosomal dominant disorder, may rarely have proximal symphalangism as an associated anomaly [Poush, 1991]. Although no mutations were found in NOG and GDF5, symphalangism in our patient could have resulted from overactivity of BMPs; increased BMP activity results in excess cartilage and failure in joint formation [Dixon et al., 2001; Tsumaki et al., 2002]. Morimoto et al.  reported a patient sharing many similarities with our patient: proximal symphalangism of fingers 2–5, blepharoptosis, malformed ears, short stature, microdontia, high-arched eyebrows, and a prominent nose. However, distal symphalangism; multiple, hyperplastic frenula; hypodontia; malformed molars; polydactyly; absent distal phalanges of toes; absence of mental retardation, chronic renal failure, and hearing loss in our patient distinguish her from having the same syndrome reported by Morimoto et al. . Finger symphalangism of all IPJ, except for the third DIPJ found in our patient has been described in 9 members of a family [Moumoumi et al., 1991]. Distal symphalangism of the third finger appears to be the
rarest form of the symphalangism [Letts et al., 1999]. Thus, we think the pathogenesis in our case may be different from others. Although some of the manifestations in our patient can be found in Ellis–van Creveld syndrome [da-Silva et al., 1980], Pallister–Hall syndrome [Biesecker et al., 1996], or oral-facial-digital syndromes [Toriello, 1993], the pattern of anomalies in our patient is at variance with these conditions. ACKNOWLEDGMENTS We thank the patient and her family for allowing us to perform the clinical examination as well as the molecular studies. We also thank Dr. Nurten Akarsu for her expert advice on GDF5 molecular analysis. REFERENCES Akarsu N, Haque MF, Ahmad W, et al. 1999. Multiple synostosis type 2 (SYNS2) maps to 20q11.2 and caused by a missense mutation in growth/ differentiation factor 5 (GDF5). Am J Hum Genet ( Suppl).65:A281. Biesecker LG, Abbott M, Allen J, Clericuzio C, Feuillan P, Graham JM Jr, Hall J, Kang S, Olney AH, Lefton D, Neri G, Peters K, Verloes A. 1996. Report from the workshop on Pallister–Hall syndrome and related phenotypes. Am J Med Genet 65:76–87. Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lespeerance MM. 2002. Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet 71:618–624. Brunet LJ, McMahon JA, McMahon AP, Harland RM. 1998. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280:1455–1457. da-Silva EO, Janovitz D, De Albuquerque SC. 1980. Ellis–van Creveld syndrome: Report of 15 cases in an inbred kindred. J Med Genet 17:349– 356. da-Silva EO, Filho SM, de Albuquerque SC. 1984. Multiple synostosis syndrome: Study of a large Brazilian kindred. Am J Med Genet 18:237–247. Dixon ME, Armstrong P, Stevens DB, Bamshad M. 2001. Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med 3:349–353. Drawbert JP, Stevens DB, Cadle RG, Cadle RG, Hall BD. 1985. Tarsal and carpal coalition and symphalangism of the Furhmann type. J Bone Joint Surg 67A:884–889.
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