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Pediatrics International (2014) 56, e26–e29
doi: 10.1111/ped.12383
Patient Report
Case of Desbuquois dysplasia type 1: Potentially lethal skeletal dysplasia Shinkai Inoue,1,2 Atsushi Ishii,1 Goro Shirotani,1 Makoto Tsutsumi,1,2 Eiji Ohta,1,2 Masatoshi Nakamura,1,2 Toshiko Mori,1,2 Takahito Inoue,1 Gen Nishimura,4 Atsushi Ogawa3 and Shinichi Hirose1,2 1 Department of Pediatrics, School of Medicine, Fukuoka University, 2Division of Neonatology, Center for Maternal, Fetal and Neonatal Medicine, Fukuoka University Hospital, 3Department of Pediatrics, Fukuoka University Chikushi Hospital, Fukuoka and 4Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Abstract
We report a boy with Desbuquois dysplasia type 1. He had the typical skeletal changes: a “Swedish key” appearance of the proximal femora; advanced carpal ossification and other distinctive features of the hand, including an extraossification center at the base of the proximal phalanx of the index and middle fingers; dislocation of the metacarpophalangeal joint of the index finger; and bifid distal phalanx of the thumb. In addition, he presented with very severe prenatal growth failure, respiratory distress as a neonate, subsequent failure to thrive and susceptibility to airway infection, and sudden death in early childhood. Molecular analysis identified homozygous 1 bp deletion in the CalciumActivated Nucleotidase 1 gene (CANT1). To our knowledge, this is the first report of Desbuquois dysplasia type 1 in Japan. Our experience suggests potential lethality in the disorder.
Key words CANT1 gene, Desbuquois dysplasia, diagnosis, fatal outcome, radiographic characterization.
Desbuquois dysplasia (MIM 251450) is a rare skeletal dysplasia inherited as an autosomal recessive trait. Desbuquois et al. described two sisters with severe disproportionate dwarfism, joint laxity and dislocation, and disorganized ossification of the hands and feet.1 Thereafter, Beemer et al. and Meinecke et al. reported additional experiences, and ascertained the condition as a distinctive disease entity.2,3 Based on a large series of patients, Shohat et al. detailed the clinical, radiological, and morphological manifestations of the disorder.4 The clinical characteristics comprise short stature of prenatal onset, joint laxity and facial characteristics, including a round face with midface hypoplasia. The hallmarks of skeletal alterations include a “Swedish key” appearance of the proximal femur and advanced carpal and tarsal bone age. Another unique finding is an extra-ossification center distal to the second metacarpal termed “hyperphalangy of the index finger.” The hyperphalangy helps make a definitive diagnosis but its presence varies among patients;5 thus, Desbuquois dysplasia is subdivided into type 1 (with hyperphalangy) and type 2 (without hyperphalangy). Additionally, recent investigations have elucidated that both types are allelic and caused by homozygous or compound heterozygous mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1).6 We report here on a boy with Desbuquois dysplasia type 1; we reveal homozygous 1 bp deletion in CANT1. The case resulted in a fatal outcome in early Correspondence: Shinkai Inoue, MD, Department of Pediatrics, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Email address:
[email protected] Received 27 January 2013; revised 16 March 2014; accepted 20 March 2014.
© 2014 Japan Pediatric Society
childhood. Our experience suggests the potential lethality of the disorder.
Case report The patient was a boy, the first child of healthy, nonconsanguineous parents. His family history was unremarkable. Micromelia was noted at 29 weeks of gestation. The baby was delivered at 38 weeks of gestation. Birth length was 31.0 cm (−6.7 SD), weight was 1687 g (−3.8 SD), and head circumference was 32.3 cm (−0.6SD). He presented with multiple joint dislocations and facial features, including a round face, proptosis, and midface hypoplasia (Fig. 1). He showed tachypnea with chest retraction that required oxygen for 6 days without intubation. Laboratory examination was normal, and chromosome analysis showed a normal male karyotype. Parenteral nutrition was given for 9 days after birth. After that, he tolerated oral full-dose milk feeding, and gained weight +14.3 g per day. He was discharged from our hospital at 64 days of age. His weight was 2605 g at that time. Subsequently, however, he failed to thrive because of persistent respiratory problems with a heavy breathing workload and increased diaphoresis. Early psychomotor development was also remarkably delayed. He could not hold his head up at 14 months of age. He was initially diagnosed as having Larsen syndrome. Expert radiological consultation provided a diagnosis of Desbuquois dysplasia at 8 months of age. The radiological findings were a “Swedish key” appearance of the proximal femora, advanced carpal ossification, and other distinctive features of the hand, including an extra-ossification center at the base of the proximal phalanx of the index and middle fingers, dislocation of
Case of Desbuquois dysplasia type 1
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Fig. 1 Full-length and facial photographs taken on admission. (a) The patient had a markedly short stature and multiple joint dislocations in the hip, knee and elbow joints. (b) He had a round face, proptosis and midface hypoplasia.
the metacarpophalangeal joint of the index finger, and bifid distal phalanx of the thumb (Fig. 2). He necessitated short-term hospital stays twice because of bronchitis. At 16 months of age, he was admitted to the hospital for the treatment of upper respiratory infection. Intravenous fluids and antibiotics were administered. The next day, although his cough persisted, his fever went down and he gradually became able to drink fluids. That night, he suddenly suffered cardiopulmonary arrest, and died despite attempted resuscitation. Subsequently, a molecular analysis was performed to confirm the diagnosis. Genomic DNA was
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extracted from the umbilical cord using standard commercial kits. Polymerase chain reaction (PCR) amplification from the four exons constituting CANT1 (accession number; RefSeq: NM_138793.3) was performed with 13 primer pairs corresponding to each exon. Details of the PCR conditions and the primers used are available upon request. Both forward and reverse strands were directly sequenced using the ABI PRISM BigDye 3.1 terminator method (Applied Biosystems, Foster City, CA, USA) and the ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). A homozygous 1 bp deletion in exon 3 (c.805delC)
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Fig. 2 X-rays of the patient’s lower limbs (5 months) and hand (1 month). (a) The patient had a “Swedish key” appearance of the proximal femur and dislocation of the hip and knee joints. (b) He also had an extra-ossification center at the base of the proximal phalanx of the index and third fingers, bifid distal phalanx of the thumb and dislocation of the metacarpophalangeal joint of the index finger. © 2014 Japan Pediatric Society
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was identified. The mutation results in a frameshift and causes premature truncation of the protein (p.L269C fsX54) (Fig. 3).
Discussion Desbuquois dysplasia is subdivided into type 1 (with hyperphalangy) and type 2 (without hyperphalangy). Recent investigations have elucidated that both types are allelic and caused by homozygous or compound heterozygous mutations in the CANT1 gene.6 Until now, 28 patients have been reported with the CANT1 mutation, and 24 distinct CANT1 mutations have been reported throughout the gene; these include 11 nonsense mutations, 11 missense mutations, one large deletion in 5’UTR, and one splice site mutation.6–9 The arginine 300 substitution has been identified in 6/28 unrelated Desbuquois dysplasia type 1 patients (p.Arg300Cys [3/6], p.Arg300His [3/6]). The valine 226 substitution has been identified in five patients with a Kim variant phenotype from Japan/Korea, characterized by short metacarpals and elongated phalanges. No other obvious correlation between genotype and phenotype has been established. We identified a novel CANT1 mutation in our patient, located within exon 3 of the gene. It was a frameshift mutation with a predicted stop codon after 54 missense amino acid residues, and was expected to cause complete loss of protein function, probably through nonsense-mediated mRNA decay as the disease-causing mechanism. The frameshift mutation was found in homozygous 1 bp
Arg Ala Leu Ala Asn A A C G C C CT G C G G G C T
Control Leu Ala Cys Gly Asn A AC G CC TGC G G GC T G C del
c.805delC / p.L269C fsX54 Patient Fig. 3 Molecular diagnosis in the patient with Desbuquois dysplasia. Direct sequencing of the genomic DNA showed homozygous 1 bp deletion in exon 3 (c.805delC). The mutation results in a frameshift and causes premature truncation of the protein (p.L269C fsX54). © 2014 Japan Pediatric Society
deletion (c.805delC). The function of CANT1 is largely unknown, although recent investigations have suggested it plays a role in proteoglycan metabolism.10 We describe here our experience of a boy with Desbuquois dysplasia type 1. In addition to the typical skeletal changes, he presented with very severe prenatal growth failure, respiratory distress as a neonate, subsequent failure to thrive and susceptibility to airway infection, and sudden death in early childhood. Hall discussed the potential lethality of Desbuquois and reported minimum mortality of 33% (13 deaths among 39 liveborns) in the literature (mostly between birth and 7 months as a result of respiratory problems) and a high rate of sudden death later on,11 as was seen in the present patient. We propose that it would be prudent for apnea and bradycardia monitors to be routinely utilized during early childhood. Despite the clinical, radiological, and molecular clarifications, Desbuquois dysplasia has not gained much awareness from physicians. The disorder tends to be mistaken for other skeletal dysplasias with joint abnormalities and/or abnormal patterning of the short tubular bones (hyperphalangy, delta phalanx, and bifid thumb) – pseudodiastrophic dysplasia, diastrophic dysplasia, Catel–Manzke syndrome, and most often Larsen syndrome. In fact, our patient had been diagnosed as having Larsen syndrome until the definitive diagnosis was made on expert consultation. To our knowledge, this is the first report of Desbuquois dysplasia type 1 in Japan. Although this may suggest a rarity of the phenotype in the Japanese population, it is possible a number of cases may have gone undiagnosed. A common mutation related to Desbuquois type 2 is known in the East Asian population.8,12 The ethnicity-associated mutation not only increases likelihood of the disorder, but also, in combination with another mutation, may give rise to unexpected phenotypes of the disorder. Further clinical and molecular experiences are needed to thoroughly elucidate the incidence and phenotypic diversity of Desbuquois dysplasia in our country.
Acknowledgments The authors are indebted to all members of the patient’s family for their helpful cooperation in this study. The authors also thank Akiyo Hamachi and Minako Yonetani for their excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research (A) (21249062, to S.H.), a Grant-in-Aid for Challenging Exploratory Research (23659529, to S.H.), a Grantin-Aid for Young Scientists (B) (23791201, to A.I.) from the Japan Society for the Promotion of Science (JSPS), grants from Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP) Exploratory Research, Japan Science and Technology Agency (JSP), “Central Research Institute for the Molecular Pathomechanisms of Epilepsy of Fukuoka University”, Recommended Projects of Fukuoka University (117016). None of the funders had any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Case of Desbuquois dysplasia type 1
References 1 Desbuquois G, Grenier B, Michel J, Rossignol C. Nanisme chondrodystrophique avec ossification anarchique et polymalformations chez deux soeurs. Arch. Fr. Pediatr. 1966; 23: 573– 87. 2 Beemer FA, Kramer PP, van der Harten HJ, Gerards LJ. A new syndrome of dwarfism, neonatal death, narrow chest, spondylometaphyseal abnormalities, and advanced bone age. Am. J. Med. Genet. 1985; 20: 555–8. 3 Meinecke P, Spranger J, Schaefer E, Maroteaux P. Micromelic dwarfism with vertebral and metaphyseal abnormalities and advanced carpotarsal ossification: another observation. Am. J. Med. Genet. 1989; 32: 432–4. 4 Shohat M, Lachman R, Gruber HE et al. Desbuquois syndrome: clinical, radiographic, and morphologic characterization. Am. J. Med. Genet. 1994; 52: 9–18. 5 Faivre L, Cormier-Daire V, Eliott AM et al. Desbuquois dysplasia, a reevaluation with abnormal and “normal” hands: radiographic manifestations. Am. J. Med. Genet. A. 2004; 124A: 48– 53.
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6 Huber C, Oules B, Bertoli M et al. Identification of CANT1 mutations in Desbuquois dysplasia. Am. J. Hum. Genet. 2009; 85: 706– 10. 7 Faden M, Al-Zahrani F, Arafah D, Alkuraya FS. Mutation of CANT1 causes Desbuquois dysplasia. Am. J. Med. Genet. A. 2010; 152A: 1157–60. 8 Furuichi T, Dai J, Cho TJ et al. CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant. J. Med. Genet. 2011; 48: 32–7. 9 Laccone F, Schoner K, Krabichler B et al. Desbuquois dysplasia type 1 and fetal hydrops due to novel mutations in the CANT1 gene. Eur. J. Hum. Genet. 2011; 19: 1133–7. 10 Nizon M, Huber C, De Leonardis F et al. Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis. Hum. Mutat. 2012; 33: 1261–6. 11 Hall BD. Lethality in Desbuquois dysplasia: three new cases. Pediatr. Radiol. 2001; 31: 43–7. 12 Kim OH, Nishimura G, Song HR et al. A variant of Desbuquois dysplasia characterized by advanced carpal bone age, short metacarpals, and elongated phalanges: report of seven cases. Am. J. Med. Genet. A. 2010; 152A: 875–85.
© 2014 Japan Pediatric Society