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Original Article Molecular and Clinical Analysis in a Series of Patients with Pyknodysostosis Reveals Some Uncommon Phenotypic Findings

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Original Article Molecular and Clinical Analysis in a Series of Patients with Pyknodysostosis Reveals Some Uncommon Phenotypic Findings Int J Clin Exp Med 2014;7(11):3915-3923 www.ijcem.com /ISSN:1940-5901/IJCEM0002218 Original Article Molecular and clinical analysis in a series of patients with Pyknodysostosis reveals some uncommon phenotypic findings Margarita Valdes-Flores1, Alberto Hidalgo-Bravo1, L Casas-Avila1, Carmen Chima-Galan2, Eric J Hazan-Lasri1, Ernesto Pineda-Gomez1, Druso Lopez-Estrada1, Juan C Zenteno3 1Department of Genetics, National Institute of Rehabilitation, Mexico City, Mexico; 2Department of Genomic Medicine, National Medical Center 20th of November, ISSSTE, Mexico City, Mexico; 3Department of Biochemis- try, Faculty of Medicine, UNAM and Department of Genetics, Institute of Ophthalmology “Conde de Valenciana”, Mexico City, Mexico Received September 1, 2014; Accepted October 23, 2014; Epub November 15, 2014; Published November 30, 2014 Abstract: Pyknodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, deformity of the skull, osteosclerosis, hypoplasia of the clavicle, and bone fragility. Radiographs show increased bone density, osteosclerosis, and acroosteolysis of the terminal phalanges. The pycnodysostosis gene is located on chromosome 1q21 and encodes an enzyme called Cathepsin K. Cathepsin K is a cysteine protease lysosomal protein associated with the degradation of bone and cartilage. In the current study, the authors described the clinical, radiological and molecular features of a group of six Mexican patients, including two familial and two sporadic cases, with Pyknodys- ostosis. One of the patients presented hypoacusia, an unusual finding in this disease. Keywords: Pyknodysostosis, sclerosing, bone, dysplasia, Cathepsin K Introduction are abbreviated [6, 8, 9]. Short stature is an essential feature of the disease and it could be Pyknodysostosis is a rare autosomal recessive attributed not only to the sclerosing bone dys- skeletal dysplasia with complete penetrance plasia affecting long bones and vertebral col- [1]. To date, less than 200 patients have been umn, but also to associated anomalies such as reported in the literature. The estimated fre- congenital cardiopathy or malnutrition [10]. In quency is 1 to 1.7 per million. Both genders are addition, Soliman et al reported deficient growth affected equally and consanguinity has been hormone secretion in five of six patients with reported in about approximately 30% of the Pyknodysostosis in response to stimulation and cases [2]. The clinical manifestations were low IGF-1 concentration [10]. The physiologic described independently in 1962 by Maroteaux replacement with this hormone increased IGF-1 and Lamy [3] and by Andren et al [2]. The French concentration and improved linear growth in painter Henri de Tolouse Lautrec was retro- patients with Pyknodysostosis [6, 10]. Differ- spectively diagnosed with this disorder, howev- ential diagnosis includes osteopetrosis, acroos- er this has been subject of recent debate [4, 5]. teolysis, cleidocranial dysplasia, and mandibu- The principal clinical features of the disease loacral dysplasia [11]. are short stature, acroosteolysis of all distal phalanges, and bone fragility with frequent Linkage analysis in inbred Arab and Mexican fractures [6, 7]. Other features include delayed kindred previously showed that the Pykn- suture closure with skull deformities, promi- odysostosis locus was located on 1q21, a posi- nent nose, delayed teeth eruption, partial ano- tion from which the gene responsible of the dis- dontia, dental infections and short ramous of ease was subsequently cloned [12, 13]. The the mandible. Occasionally, exophthalmos and Pyknodysostosis gene, called Cathepsin K blue sclera are present. The trunk is not short- (CTSK), was originally cloned in osteoclasts ened although the metatarsals occasionally from rabbits and subsequently in several Uncommon features in Pyknodysostosis Table 1. Mutations described in the CTSK gene in patients with Pyknodysostosis. Taken from Xue et al. Orphanet J Rare Dis. 2011, 6: 20 and completed with data from Matsushita et al. Mol Syndromol 2011, 2: 254-258 and Zheng et al. Gene 2013, 521: 176-179 Genomic DNA Location Location in DNA Coding DNA Effect on First description sequence in protein sequence sequence amino acid variants variants sequence Missense Exon 2 g.1551T > C c.20T > C p.Leu7Pro Pre Donnarumma, et al., 2007 Exon 2 g.1557T > C c.26T > C p.Leu9Pro Pre Nishi, et al., 1999 Exon 3 g.2128C > T c.136C > T p.Arg46Trp Pro Schilling, et al., 2007 Exon 3 g.2227G > A c.235G > A p.Gly79Arg Pro Fratzl-Zelman, et al., 2004 Exon 3 g.2228G > A c.236G > A p.Gly79Glu Pro Hou, et al., 1999 Exon 4 g.2547G > A c.365G > A p.Arg122Gln Mature Zheng et al, 2013 Exon 4 g.2547G > C c.365G > C p.Arg122Pro Mature Matsushita et al, 2012 Exon 5 g.4120C > T c.422C > T p.Ala141 Val Mature Chavassieux, et al., 2008 Exon 5 g.4134G > C c.436G > C p.Gly146Arg Mature Gelb, et al., 1996 Exon 5 g.4192A > G c.494A > G p.Gln165Arg Mature Donnarumma, et al., 2007 Exon 5 g.4258A > C c.560A > C p.Gln187Pro Mature Li, et al., 2009 Exon 5 g.4278G > A c.580G > A p.Gly194Ser Mature Donnarumma, et al., 2007 Exon 6 g.8644A > G c.635A > G p.Tyr212Cys Mature Hou, et al., 1999 Exon 6 g.8737 G > A c.728G > A p.Gly243Glu Mature Khan et al., 2010 Exon 6 g.8755T > C c.746T > C p.Ile249Thr Mature Donnarumma, et al., 2007 Exon 6 g.8758A > G c.749A > G p.Asp250Gly Mature Donnarumma, et al., 2007 Exon 7 g.9109C > T c.830C > T pAla277Val Mature Gelb, et al., 1998 Exon 7 g.9109C > A c.830C > A p.Ala277Glu Mature Hou, et al., 1999 Exon 7 g.9171T > C c.892T > C p.Trp298Arg Mature Nishi, et al., 1999 Exon 8 g.9186G > A c.908G > A p.Gly303Glu Mature Toral-Lopez et al., 2010 Exon 8 g.11474T > C c.926T > C p.Leu309Pro Mature Haagerup, et al., 2000 Exon 8 g.11479G > C c.931G > C p.Ala311Pro Mature Nishi, et al., 1999 Exon 8 g.11482C > G c.934C > G p.Arg312Gly Mature Hou, et al., 1999 Exon 8 g.11501G > A c.953G > A p.Cys318Tyr Mature Bertola et al., 2010 Exon 8 g.11503G > T c.955G > T p.Gly319Cys Mature Donnarumma, et al., 2007 Nonsense Exon 3 g.2146A > T c.154A > T p.Lys52X Pro Hou, et al., 1999 Exon 5 g.4266C > T c.568C > T p.Gln190X Mature Hou, et al., 1999 Exon 6 g.8730C > T c.721C > T p.Arg241X Mature Gelb, et al., 1996 Frameshifts (duplication) Exon 2 g.1591-1592 dupGA c.60_61dupGA p.Ile21ArgfsX29 Pro Donnarumma, et al., 2007 Exon 4 g.2359 dupA c.282dupA p.Val95SerfsX9 Pro Donnarumma, et al., 2007 Frameshifts (deletion) Exon 3 g.2230delG c.238delG p.Asp80ThrfsX2 Pro Fratzl-Zelman, et al., 2004 Exon 5 g.4124delT c.426delT pPhe142LeufsX19 Mature Fujita, et al., 2000 Splicing Intron2 g.2112G > A c.121-1G > A p.del41Val-81Me Pro Haagerup, et al., 2000 Exon 7 g.9169G > A c.890G > A; 785_890de p.Gly262AlafsX70 Mature Donnarumma, et al.2007 Stop codon Exon 8 g.11538A > G c.990A > G p.X330TrpextX19 Mature Gelb. et.al., 1996 human tissues [13]. It is highly expressed in published in 2011, 33 mutations in the CTSK osteoclasts, osteoarthritic hipbones, and os- gene had been reported in patients with teoclastoma. Targeted mutation of the Cath- Pyknodysostosis [14], afterwards only two epsin K gene in mice resulted in many of the more mutations have been reported [15, 16] phenotypic features of Pyknodysostosis, includ- (Table 1). CTSK is a lysosomal cysteine prote- ing increased bone density and bone deformi- ase that is synthesized as a prepropeptid of 37 ties [4, 5, 13]. Subsequently, point mutations in kDa. The mature enzyme is a monomeric pro- the CTSK gene were detected in patients with tein of approximately 29 kDa. CTSK efficiently Pyknodysostosis [5]. In the review by Xu et al, cleaves peptide bonds in different proteins 3916 Int J Clin Exp Med 2014;7(11):3915-3923 Uncommon features in Pyknodysostosis Figure 1. Pedigrees of the two families with pyknodysostosis. A: Consanguinity is present in family A. B: In family B there is no documented evidence of consanguinity. Squares represent males; circles represent females; filled symbols are individuals with Pyknodysostosis; the arrow indicates the propositus (patient) in each family. Roman numerals on the left indicate each generation. Numbers above the symbols identify each individual. Numbers below indicate the age in years. including elastin and type I collagen, it is secret- Patient data ed to the sub-osteoclastic space where partici- pates in bone matrix degradation [17]. In the All patients were referred to the authors’ insti- current study the authors described the clini- tutions due to dysmorphic features. All were cal, radiological and molecular features of six Mexican mestizos and their ages ranged from 8 previously unreported Mexican patients (includ- to 53 years. The patients were informed about ing two familial and two sporadic cases) with the details and aims of the study and they Pyknodysostosis. agreed to participate by signing an informed 3917 Int J Clin Exp Med 2014;7(11):3915-3923 Uncommon features in Pyknodysostosis Table 2. Summary of the clinical and radiological features found in this series of patients Clinical Features Patient 1 Patient 2 Patient 3A Patient 3B Patient 4A Patient 4B Gender Male Female Female Female Female Female Age (years) 53 40 26 9 14 8 Presentation Sporadic Sporadic Familial Familial Familial Familial Parental consanguinity confirmed No No Yes Yes No No Height 1.53 m 1. 50 m 1.30 m 95 cm 1.27 m 97 cm Frequent fractures Yes Yes Yes No No No Increased bone density + + + + + + Frontal bossing + + + + + + Delayed suture closed + + + + + + Hypoplasia of the mandible + + + + + + Proptosis + + + + + + Blue sclera + + + + + + Prominent nose + + + + + + Delayed teeth eruption + + + + + + Malapposed teeth + + + + + + Enamel hypoplasia + + + + + + Clavicular dysplasia + + - - - - Short fingers (hands and feet) + + + + + + Acroosteolysis (distal phalanges) + + + + + + Dystrophic nails + + + + + + Conductive hypoacusia - - - - + - Methods Molecular analysis The study’s procedures were approved by the Institutional Review Board and informed con- sent form was obtained from each patient.
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