European Journal of Medical Genetics 57 (2014) 133e137
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Novel SOST gene mutation in a sclerosteosis patient from Morocco: A case report Mohamed Reda Belkhribchia a, *, Corinne Collet b, Jean-Louis Laplanche b, Redouane Hassani c a b c
Service de Neurologie, Centre Hospitalier Provincial Hassan II, Dakhla, Morocco UF de Génétique Moléculaire, Hôpital Lariboisière, Paris, France Cabinet ORL et Chirurgie Cervico-faciale, Casablanca, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 December 2013 Accepted 9 February 2014 Available online 1 March 2014
Sclerosteosis (OMIM 269500) is a rare autosomal recessive condition characterized by increased bone density associated with syndactyly. It is linked to a genetic defect in the SOST gene coding for sclerostin. So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis. Recently, two mutations in LRP4 gene underlying sclerosteosis were identified, reflecting the genetic heterogeneity of this disease. We report here a 30-years-old Moroccan man presented with typical clinical and radiological features of sclerosteosis who carries a novel homozygous mutation in the SOST gene, characterized as a nonsense mutation (c.79C > T; p.Gln27*) in exon 1 of the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Sclerosteosis SOST gene LRP4 gene Sclerostin Nonsense mutation North Africa
1. Introduction Sclerosteosis (OMIM 269500) is a rare autosomal e recessive disorder in which progressive bone overgrowth leads to gigantism, distortion of the facies, and entrapment of cranial nerves. This disorder is associated with syndactyly and digital malformation. Potentially lethal elevation of intracranial pressure is a frequent complication of this disease [Beighton and Hamersma, 1979; Beighton et al., 1976]. The estimated prevalence of sclerosteosis is very low but reaches 1 in 75,000 persons in the Afrikaner population in South Africa [Beighton, 1988]. It was described in 1958 by Truswell (1958) as osteopetrosis with syndactyly in two unrelated South African girls. In 1967, Hansen (1967) introduced the term sclerosteosis to designate this rare but severe skeletal disorder characterized by progressive bone overgrowth. Skeletal radiographs of sclerosteosis patients are virtually normal in early childhood, but thereafter bone widening and
* Corresponding author. Service de Neurologie, Centre Hospitalier Provincial Hassan II, Dakhla, Morocco. E-mail address: [email protected] (M.R. Belkhribchia). http://dx.doi.org/10.1016/j.ejmg.2014.02.007 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
sclerosis become increasingly evident. Patients display a generalized hyperostosis of the skeleton, clinically this is most evident in the skull and mandible where it results in considerable facial distortion in adulthood, and bony encroachment on the cranial nerves can lead to facial palsy, deafness, trigeminal neuralgia and loss of vision. The hyperostosis leads to characteristic facial features such as a broad, squared mandible, hypertelorism, a flat nasal bridge, frontal prominence and proptosis [Beighton, 1988]. Sclerosteosis is rare, but reaches a comparatively high prevalence in the Afrikaner community of South Africa [Hamersma et al., 2003]. A small number of individuals and families with sclerosteosis has been reported in other parts of the world, including, Spain [Bueno et al., 1994], Brazil [Paes-Alves et al., 1982], United States [Higinbotham and Alexander, 1941; Stein et al., 1983], Germany [Pietruschka, 1958], Japan [Sugiura and Yasuhara, 1975], Senegal [Tacconi et al., 1998], Turkey [Piters et al., 2010], and India [Bhadada et al., 2013]. Sclerosteosis is clinically and radiologically related to Van Buchem disease [Beighton et al., 1984]. Van Buchem disease, first described in 1955 [Van Buchem et al., 1955], is marked by a milder phenotype than sclerosteosis without syndactyly [Beighton et al., 1984]. Genetic studies have shown that these disorders are allelic, and linked to a genetic defect in the SOST gene coding for sclerostin [Balemans et al., 1999; Van Hul et al., 1998].
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M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137
So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis [Balemans et al., 2001, 2005; Bhadada et al., 2013; Brunkow et al., 2001; Kim et al., 2008; Piters et al., 2010]. The physiological role of sclerostin is most likely the suppression of bone formation. Therefore, the identification of sclerostin as an important protein in bone metabolism might become an important tool in the development of therapeutic strategies to prevent and treat osteoporosis [Balemans and Van Hul, 2004]. Recent data indicated that the interaction of sclerostin with LRP4 gene is required to mediate the inhibitory function of sclerostin on bone formation and found two mutations in LRP4 gene underlying sclerosteosis [Leupin et al., 2011]. Here we describe a Moroccan sclerosteosis patient with a novel mutation in the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa. 2. Clinical report A 30-years-old Moroccan man, a single brother, from a nonconsanguineous marriage, with a right acute otitis media with tympanic membrane perforation at the age of 1 year, presented with a history of recurrent bilateral attacks of facial palsy throughout childhood and a 18 years history of significant decreased hearing necessitating the provision of a hearing aid. He complained also of headache, bilateral papilledema, paroxystic pain in the right side of the face and excessive lacrimation for 2 years. He had normal neonatal and infantile course and no other significant medical history. There was no family history of deafness or visual loss. Both the parents and his brother had a normal phenotype with no symptoms or signs suggestive of sclerosteosis. After examination, his height was 174 cm and his weight was 64 kg. His speech was impaired. He had frontal bossing, broad flat root of the nose, broadened mandible and bilateral partial facial palsy (Fig. 1). Examination of the oral cavity found several teeth extracted. He had a diminished sensation in all three divisions of trigeminal nerve on right side. There was a syndactyly of 2nd and 3rd fingers of both hands which have been repaired; with a radial deviation of the terminal phalanges of the left 2nd finger (Fig. 2). He had also syndactyly involving the right 3rd and 4th toes and the left 4th and 5th toes, dysplastic nails on the great toes and swelling of soft tissue of all finger and toe tips (Fig. 3). Ophthalmic examination revealed a bilateral papilledema. The remainder of the systemic examination was normal. Investigations revealed normal complete haemogram. His albumin adjusted serum calcium, phosphate, alkaline phosphatase and 25 (OH) D were normal. Skeletal survey by plain radiographs revealed generalized increased bone density with thick cortices and narrow medullary canal particularly of long bones (Fig. 4). Computerized tomography (CT) of head showed thickened calvarium. Also, the skull base and the exit foramina of the skull base appeared to be narrower than usual (Fig. 5a and b). Audiogram showed bilateral mixed-type hearing loss.
Fig. 1. Clinical photograph of face: Facial distortion with bilateral partial facial palsy.
3. Molecular analysis Blood samples were drawn for diagnostic purposes after informed consent and written permission to publish the clinical photographs. DNA was extracted using a QIAamp blood kit (Qiagen, Courtaboeuf, France). SOST (exons 1e2) was amplified and sequenced directly on both strands (Life technologies, Courtaboeuf,
Fig. 2. Clinical photograph of hand: Radial deviation of the terminal phalanges of the left 2nd finger.
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137
135
Fig. 3. Clinical photograph of feet: Syndactyly and dysplastic nails.
France) then analyzed using Sescape (Life Technologies) and Alamut software (Interactive Biosoftware, Rouen, France). The NCBI reference sequences were as follows: SOST (NM_025237.2) for c.DNA and for exon numbering SOST (NG_008078.2). The mutation nomenclature was based on HGVS nomenclature guidelines [http:// www.hgvs.org/mutnomen].
Fig. 5. a and b: CT skull coronal and axial view: thickened skull vault and base of skull.
Molecular screening of SOST detected the apparently homozygous c.79C > T (p.Gln27*) mutation in exon 1 (Fig. 6). This undescribed nonsense mutation p.Gln27* was not found in 1000 Genomes (http://www.1000genomes.org/) and in the Exome Variant Server (http://evs.gs.washington.edu/EVS/). 4. Discussion
Fig. 4. X-ray pelvis: thickened cortices and narrow medullary canal of femur.
The patient had typical features of sclerosteosis in the form of facial distortion, syndactyly, dysplastic nails, radial deviation of the
136
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137
Fig. 6. Partial sequence chromatogram displaying the DNA sequence of a control individual and the patient .The arrowhead indicates the position of the homozygous c.79C > T, p.Gln27* mutation.
terminal phalanges of the affected digits, facial palsy, deafness, raised intracranial pressure and no history of fracture. He had an involvement of the trigeminal nerve which is a less common complication in sclerosteosis [Beighton et al., 1976]. There was also an excessive lacrimation due to bone obstruction of the tear ducts which can be seen in 28% of patients with sclerosteosis [Beighton and Hamersma, 1985]. The only symptom that seems to be absent is the tall stature of sclerosteosis patients. However, this could be due to the ethnic background since Moroccan people are in general smaller than some other ethnicities. Radiographs of skull and appendicular skeleton revealed increased bones’ density with a loss of medullary canal and increased the thickness of the cortical bone suggestive of a sclerosing bone dysplasia. Haematology and urinalysis are usually normal in this disease. Serum calcium and phosphorus are usually normal but the alkaline phosphatase level may be slightly raised [Beighton et al., 1976]. We reported a novel nonsense homozygous mutation p.Gln27* in exon 1 of SOST corresponding to the sclerostin domain. This mutation, located just downstream to the signal peptide (aminoacid 1e23), leads to a loss-of-functional sclerostin. Previously, seven different mutations have been identified in the SOST gene underlying sclerosteosis from different geographical regions which include one missense [Piters et al., 2010], one frame shift [Bhadada et al., 2013], two splice site [Balemans et al., 2001, 2005], and three nonsense mutations [Balemans et al., 2001; Brunkow et al., 2001; Kim et al., 2008] (Table 1).
Table 1 Previously known and presently identified mutations in SOST gene associated with sclerosteosis. Geographical origin
Mutation in SOST gene
Mutation effect
Reference
Senegal United states of America South Africa
IVS1þ3A > T c.376C > T (p. Arg 126X) c.70C > T (p. Glu24X) IVS1þ1G > C c.372G > A (p.Trp124X) c.499T > C (p.Cys167Arg) c.296_297insC c.79C > T (p.Gln27*)
Splice site mutation Nonsense mutation
[Balemans et al., 2001] [Balemans et al., 2001]
Nonsense mutation
[Brunkow et al., 2001]
Splice site mutation Nonsense mutation
[Balemans et al., 2005] [Kim et al., 2008]
Missense mutation
[Piters et al., 2010]
Frame shift mutation Nonsense mutation
[Bhadada et al., 2013] Present study
Germany Brazil Turkey India Morocco
Recently, Leupin et al. (2011) reported the identification of two mutations in LRP4 gene (R1170W and W1186S) underlying sclerosteosis. In an interesting way, no case was described in North Africa and we reported the first case of a patient native of Morocco. As well, it’s seems that spontaneous mutations of the SOST gene randomly appear in the world population. Competing interest No competing interests. References Balemans W, Van Hul W. Identification of the disease-causing gene in sclerosteosisddiscovery of a novel bone anabolic target? J Musculoskelet Neuronal Interact 2004;4(2):139e42. Balemans W, Ende JVD, Paes-Alves AF, Dikkers FG, Willems PJ, Vanhoenacker F, et al. Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12eq21. Am J Hum Genet 1999;64:1661e9. Balemans W, Ebeling M, Patel N, Hul VE, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 2001;10:537e43. Balemans W, Cleiren E, Siebers U, Horst J, Van Hul W. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 2005;36:943e7. Beighton P. Sclerosteosis. J Med Genet 1988;25:200e3. Beighton P, Hamersma H. Sclerosteosis in South Africa. S Afr Med J 1979;55:783e8. Beighton P, Hamersma H. Ophthalmological complications in the sclerosing bone dysplasias. Ophthalmic Paediatr Genet 1985;6:129e34. Beighton P, Durr L, Hamersma H. The clinical features of sclerosteosis. A review of the manifestations in twenty-five affected individuals. Ann Intern Med 1976;84:393e7. Beighton P, Barnard A, Hamersma H, van der Wouden A. The syndromic status of sclerosteosis and van Buchem disease. Clin Genet 1984;25:175e81. Bhadada SK, Rastogi A, Steenackers E, Boudin E, Arya A, Dhiman V, et al. Novel SOST gene mutation in a sclerosteosis patient and her parents. Bone 2013;52:707e10. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 2001;68:577e89. Bueno M, Oliván G, Jiménez A, Garagorri JM, Sarría A, Bueno AL, et al. Sclerosteosis in a Spanish male: first report in a person of Mediterranean origin. J Med Genet 1994;31:976e7. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet 2003;63:192e7. Hansen HG. Sklerosteose. In: Opitz H, Schmid F, editors. Handbuch der Kinderheilkunde. Berlin: Springer; 1967. pp. 351e5. Higinbotham NL, Alexander SF. Osteopetrosis, four cases in one family. Am J Surgs 1941;53:444e54. Kim CA, Honjo R, Bertola D, Albano L, Oliviera L, Jales S, et al. A known SOST gene mutation causes sclerosteosis in a familial and an isolated case from Brazilian origin. Genet Test 2008;12:475e9. Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowthassociated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 2011;286:19489e500. Paes-Alves AF, Rubin JLC, Cardoso L, Rabelo MM. Sclerosteosis: a marker of Dutch ancestry? Rev Bras Genet 1982;4:825e34.
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137 Pietruschka G. Further information on marble bones (Albers-Schonberg disease) with remarks on differential diagnosis. Klin Monatsbl Augenheilkd Augenarztl Fortbild. 1958;132:509e25. Piters E, Culha C, Moester M, Bezooijen RV, Adriaensen D, Mueller T, et al. First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Hum Mutat 2010;31:1526e43. Stein SA, Witkop C, Hill S, Fallon MD, Viernstein L, Gucer G, et al. Sclerosteosis: neurogenetic and pathophysiologic analysis of an American kinship. Neurology 1983;33:267e77. Sugiura Y, Yasuhara T. Sclerosteosis, a case report. J Bone Jt Surg Am 1975;57:273e7.
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Tacconi P, Ferrigno P, Cocco L, Cannas A, Tamburini G, Bergonzi P, et al. Sclerosteosis: report of a case in a black African man. Clin Genet 1998;53:497e501. Truswell AS. Osteopetrosis with syndactyly; a morphological variant of Alberse Schonberg’s disease. J Bone Jt Surg Br 1958;40:209e18. Van Buchem FSP, Prick JJG, Jaspar HHJ. Hyperostosis corticalis generalisata familiaris (van Buchem’s disease). Acta Radiol 1955;44:109e20. Van Hul W, Balemans W, Van Hul E, Dikkers FG, Obee H, Stokroos RJ, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12eq21. Am J Hum Genet 1998;62:391e9.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
Novel SOST gene mutation in a sclerosteosis patient from Morocco: A case report Mohamed Reda Belkhribchia a, *, Corinne Collet b, Jean-Louis Laplanche b, Redouane Hassani c a b c
Service de Neurologie, Centre Hospitalier Provincial Hassan II, Dakhla, Morocco UF de Génétique Moléculaire, Hôpital Lariboisière, Paris, France Cabinet ORL et Chirurgie Cervico-faciale, Casablanca, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 December 2013 Accepted 9 February 2014 Available online 1 March 2014
Sclerosteosis (OMIM 269500) is a rare autosomal recessive condition characterized by increased bone density associated with syndactyly. It is linked to a genetic defect in the SOST gene coding for sclerostin. So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis. Recently, two mutations in LRP4 gene underlying sclerosteosis were identified, reflecting the genetic heterogeneity of this disease. We report here a 30-years-old Moroccan man presented with typical clinical and radiological features of sclerosteosis who carries a novel homozygous mutation in the SOST gene, characterized as a nonsense mutation (c.79C > T; p.Gln27*) in exon 1 of the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Sclerosteosis SOST gene LRP4 gene Sclerostin Nonsense mutation North Africa
1. Introduction Sclerosteosis (OMIM 269500) is a rare autosomal e recessive disorder in which progressive bone overgrowth leads to gigantism, distortion of the facies, and entrapment of cranial nerves. This disorder is associated with syndactyly and digital malformation. Potentially lethal elevation of intracranial pressure is a frequent complication of this disease [Beighton and Hamersma, 1979; Beighton et al., 1976]. The estimated prevalence of sclerosteosis is very low but reaches 1 in 75,000 persons in the Afrikaner population in South Africa [Beighton, 1988]. It was described in 1958 by Truswell (1958) as osteopetrosis with syndactyly in two unrelated South African girls. In 1967, Hansen (1967) introduced the term sclerosteosis to designate this rare but severe skeletal disorder characterized by progressive bone overgrowth. Skeletal radiographs of sclerosteosis patients are virtually normal in early childhood, but thereafter bone widening and
* Corresponding author. Service de Neurologie, Centre Hospitalier Provincial Hassan II, Dakhla, Morocco. E-mail address: [email protected] (M.R. Belkhribchia). http://dx.doi.org/10.1016/j.ejmg.2014.02.007 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
sclerosis become increasingly evident. Patients display a generalized hyperostosis of the skeleton, clinically this is most evident in the skull and mandible where it results in considerable facial distortion in adulthood, and bony encroachment on the cranial nerves can lead to facial palsy, deafness, trigeminal neuralgia and loss of vision. The hyperostosis leads to characteristic facial features such as a broad, squared mandible, hypertelorism, a flat nasal bridge, frontal prominence and proptosis [Beighton, 1988]. Sclerosteosis is rare, but reaches a comparatively high prevalence in the Afrikaner community of South Africa [Hamersma et al., 2003]. A small number of individuals and families with sclerosteosis has been reported in other parts of the world, including, Spain [Bueno et al., 1994], Brazil [Paes-Alves et al., 1982], United States [Higinbotham and Alexander, 1941; Stein et al., 1983], Germany [Pietruschka, 1958], Japan [Sugiura and Yasuhara, 1975], Senegal [Tacconi et al., 1998], Turkey [Piters et al., 2010], and India [Bhadada et al., 2013]. Sclerosteosis is clinically and radiologically related to Van Buchem disease [Beighton et al., 1984]. Van Buchem disease, first described in 1955 [Van Buchem et al., 1955], is marked by a milder phenotype than sclerosteosis without syndactyly [Beighton et al., 1984]. Genetic studies have shown that these disorders are allelic, and linked to a genetic defect in the SOST gene coding for sclerostin [Balemans et al., 1999; Van Hul et al., 1998].
134
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137
So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis [Balemans et al., 2001, 2005; Bhadada et al., 2013; Brunkow et al., 2001; Kim et al., 2008; Piters et al., 2010]. The physiological role of sclerostin is most likely the suppression of bone formation. Therefore, the identification of sclerostin as an important protein in bone metabolism might become an important tool in the development of therapeutic strategies to prevent and treat osteoporosis [Balemans and Van Hul, 2004]. Recent data indicated that the interaction of sclerostin with LRP4 gene is required to mediate the inhibitory function of sclerostin on bone formation and found two mutations in LRP4 gene underlying sclerosteosis [Leupin et al., 2011]. Here we describe a Moroccan sclerosteosis patient with a novel mutation in the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa. 2. Clinical report A 30-years-old Moroccan man, a single brother, from a nonconsanguineous marriage, with a right acute otitis media with tympanic membrane perforation at the age of 1 year, presented with a history of recurrent bilateral attacks of facial palsy throughout childhood and a 18 years history of significant decreased hearing necessitating the provision of a hearing aid. He complained also of headache, bilateral papilledema, paroxystic pain in the right side of the face and excessive lacrimation for 2 years. He had normal neonatal and infantile course and no other significant medical history. There was no family history of deafness or visual loss. Both the parents and his brother had a normal phenotype with no symptoms or signs suggestive of sclerosteosis. After examination, his height was 174 cm and his weight was 64 kg. His speech was impaired. He had frontal bossing, broad flat root of the nose, broadened mandible and bilateral partial facial palsy (Fig. 1). Examination of the oral cavity found several teeth extracted. He had a diminished sensation in all three divisions of trigeminal nerve on right side. There was a syndactyly of 2nd and 3rd fingers of both hands which have been repaired; with a radial deviation of the terminal phalanges of the left 2nd finger (Fig. 2). He had also syndactyly involving the right 3rd and 4th toes and the left 4th and 5th toes, dysplastic nails on the great toes and swelling of soft tissue of all finger and toe tips (Fig. 3). Ophthalmic examination revealed a bilateral papilledema. The remainder of the systemic examination was normal. Investigations revealed normal complete haemogram. His albumin adjusted serum calcium, phosphate, alkaline phosphatase and 25 (OH) D were normal. Skeletal survey by plain radiographs revealed generalized increased bone density with thick cortices and narrow medullary canal particularly of long bones (Fig. 4). Computerized tomography (CT) of head showed thickened calvarium. Also, the skull base and the exit foramina of the skull base appeared to be narrower than usual (Fig. 5a and b). Audiogram showed bilateral mixed-type hearing loss.
Fig. 1. Clinical photograph of face: Facial distortion with bilateral partial facial palsy.
3. Molecular analysis Blood samples were drawn for diagnostic purposes after informed consent and written permission to publish the clinical photographs. DNA was extracted using a QIAamp blood kit (Qiagen, Courtaboeuf, France). SOST (exons 1e2) was amplified and sequenced directly on both strands (Life technologies, Courtaboeuf,
Fig. 2. Clinical photograph of hand: Radial deviation of the terminal phalanges of the left 2nd finger.
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137
135
Fig. 3. Clinical photograph of feet: Syndactyly and dysplastic nails.
France) then analyzed using Sescape (Life Technologies) and Alamut software (Interactive Biosoftware, Rouen, France). The NCBI reference sequences were as follows: SOST (NM_025237.2) for c.DNA and for exon numbering SOST (NG_008078.2). The mutation nomenclature was based on HGVS nomenclature guidelines [http:// www.hgvs.org/mutnomen].
Fig. 5. a and b: CT skull coronal and axial view: thickened skull vault and base of skull.
Molecular screening of SOST detected the apparently homozygous c.79C > T (p.Gln27*) mutation in exon 1 (Fig. 6). This undescribed nonsense mutation p.Gln27* was not found in 1000 Genomes (http://www.1000genomes.org/) and in the Exome Variant Server (http://evs.gs.washington.edu/EVS/). 4. Discussion
Fig. 4. X-ray pelvis: thickened cortices and narrow medullary canal of femur.
The patient had typical features of sclerosteosis in the form of facial distortion, syndactyly, dysplastic nails, radial deviation of the
136
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137
Fig. 6. Partial sequence chromatogram displaying the DNA sequence of a control individual and the patient .The arrowhead indicates the position of the homozygous c.79C > T, p.Gln27* mutation.
terminal phalanges of the affected digits, facial palsy, deafness, raised intracranial pressure and no history of fracture. He had an involvement of the trigeminal nerve which is a less common complication in sclerosteosis [Beighton et al., 1976]. There was also an excessive lacrimation due to bone obstruction of the tear ducts which can be seen in 28% of patients with sclerosteosis [Beighton and Hamersma, 1985]. The only symptom that seems to be absent is the tall stature of sclerosteosis patients. However, this could be due to the ethnic background since Moroccan people are in general smaller than some other ethnicities. Radiographs of skull and appendicular skeleton revealed increased bones’ density with a loss of medullary canal and increased the thickness of the cortical bone suggestive of a sclerosing bone dysplasia. Haematology and urinalysis are usually normal in this disease. Serum calcium and phosphorus are usually normal but the alkaline phosphatase level may be slightly raised [Beighton et al., 1976]. We reported a novel nonsense homozygous mutation p.Gln27* in exon 1 of SOST corresponding to the sclerostin domain. This mutation, located just downstream to the signal peptide (aminoacid 1e23), leads to a loss-of-functional sclerostin. Previously, seven different mutations have been identified in the SOST gene underlying sclerosteosis from different geographical regions which include one missense [Piters et al., 2010], one frame shift [Bhadada et al., 2013], two splice site [Balemans et al., 2001, 2005], and three nonsense mutations [Balemans et al., 2001; Brunkow et al., 2001; Kim et al., 2008] (Table 1).
Table 1 Previously known and presently identified mutations in SOST gene associated with sclerosteosis. Geographical origin
Mutation in SOST gene
Mutation effect
Reference
Senegal United states of America South Africa
IVS1þ3A > T c.376C > T (p. Arg 126X) c.70C > T (p. Glu24X) IVS1þ1G > C c.372G > A (p.Trp124X) c.499T > C (p.Cys167Arg) c.296_297insC c.79C > T (p.Gln27*)
Splice site mutation Nonsense mutation
[Balemans et al., 2001] [Balemans et al., 2001]
Nonsense mutation
[Brunkow et al., 2001]
Splice site mutation Nonsense mutation
[Balemans et al., 2005] [Kim et al., 2008]
Missense mutation
[Piters et al., 2010]
Frame shift mutation Nonsense mutation
[Bhadada et al., 2013] Present study
Germany Brazil Turkey India Morocco
Recently, Leupin et al. (2011) reported the identification of two mutations in LRP4 gene (R1170W and W1186S) underlying sclerosteosis. In an interesting way, no case was described in North Africa and we reported the first case of a patient native of Morocco. As well, it’s seems that spontaneous mutations of the SOST gene randomly appear in the world population. Competing interest No competing interests. References Balemans W, Van Hul W. Identification of the disease-causing gene in sclerosteosisddiscovery of a novel bone anabolic target? J Musculoskelet Neuronal Interact 2004;4(2):139e42. Balemans W, Ende JVD, Paes-Alves AF, Dikkers FG, Willems PJ, Vanhoenacker F, et al. Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12eq21. Am J Hum Genet 1999;64:1661e9. Balemans W, Ebeling M, Patel N, Hul VE, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 2001;10:537e43. Balemans W, Cleiren E, Siebers U, Horst J, Van Hul W. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 2005;36:943e7. Beighton P. Sclerosteosis. J Med Genet 1988;25:200e3. Beighton P, Hamersma H. Sclerosteosis in South Africa. S Afr Med J 1979;55:783e8. Beighton P, Hamersma H. Ophthalmological complications in the sclerosing bone dysplasias. Ophthalmic Paediatr Genet 1985;6:129e34. Beighton P, Durr L, Hamersma H. The clinical features of sclerosteosis. A review of the manifestations in twenty-five affected individuals. Ann Intern Med 1976;84:393e7. Beighton P, Barnard A, Hamersma H, van der Wouden A. The syndromic status of sclerosteosis and van Buchem disease. Clin Genet 1984;25:175e81. Bhadada SK, Rastogi A, Steenackers E, Boudin E, Arya A, Dhiman V, et al. Novel SOST gene mutation in a sclerosteosis patient and her parents. Bone 2013;52:707e10. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 2001;68:577e89. Bueno M, Oliván G, Jiménez A, Garagorri JM, Sarría A, Bueno AL, et al. Sclerosteosis in a Spanish male: first report in a person of Mediterranean origin. J Med Genet 1994;31:976e7. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet 2003;63:192e7. Hansen HG. Sklerosteose. In: Opitz H, Schmid F, editors. Handbuch der Kinderheilkunde. Berlin: Springer; 1967. pp. 351e5. Higinbotham NL, Alexander SF. Osteopetrosis, four cases in one family. Am J Surgs 1941;53:444e54. Kim CA, Honjo R, Bertola D, Albano L, Oliviera L, Jales S, et al. A known SOST gene mutation causes sclerosteosis in a familial and an isolated case from Brazilian origin. Genet Test 2008;12:475e9. Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowthassociated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 2011;286:19489e500. Paes-Alves AF, Rubin JLC, Cardoso L, Rabelo MM. Sclerosteosis: a marker of Dutch ancestry? Rev Bras Genet 1982;4:825e34.
M.R. Belkhribchia et al. / European Journal of Medical Genetics 57 (2014) 133e137 Pietruschka G. Further information on marble bones (Albers-Schonberg disease) with remarks on differential diagnosis. Klin Monatsbl Augenheilkd Augenarztl Fortbild. 1958;132:509e25. Piters E, Culha C, Moester M, Bezooijen RV, Adriaensen D, Mueller T, et al. First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Hum Mutat 2010;31:1526e43. Stein SA, Witkop C, Hill S, Fallon MD, Viernstein L, Gucer G, et al. Sclerosteosis: neurogenetic and pathophysiologic analysis of an American kinship. Neurology 1983;33:267e77. Sugiura Y, Yasuhara T. Sclerosteosis, a case report. J Bone Jt Surg Am 1975;57:273e7.
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Tacconi P, Ferrigno P, Cocco L, Cannas A, Tamburini G, Bergonzi P, et al. Sclerosteosis: report of a case in a black African man. Clin Genet 1998;53:497e501. Truswell AS. Osteopetrosis with syndactyly; a morphological variant of Alberse Schonberg’s disease. J Bone Jt Surg Br 1958;40:209e18. Van Buchem FSP, Prick JJG, Jaspar HHJ. Hyperostosis corticalis generalisata familiaris (van Buchem’s disease). Acta Radiol 1955;44:109e20. Van Hul W, Balemans W, Van Hul E, Dikkers FG, Obee H, Stokroos RJ, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12eq21. Am J Hum Genet 1998;62:391e9.
