A family with Camurati-Engelman disease. The role of the missense p.R218C mutation in TGFB1 in bones and endocrine glands
-
Meropi Toumba
, Vassos Neocleous
, Christos Shammas , Violetta Anastasiadou , Jeremy Allgrove , Leonidas A. Phylactou und Nicos Skordis
Abstract
Objectives: Camurati-Engelmann disease (CED) is a rare form of progressive bone dysplasia due to mutations in the transforming factor gene TGFB1 on chromosome 19q13.1-q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty and hypogonadotrophic hypogonadism may be present.
Methods and results: Genetic analysis of the TGFB1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia and menstrual irregularity. The patient responded well to prednisone 5 mg/kg per day as well as calcium and vitamin D supplements.
Conclusions: The role of p.R218C in TGFB1 on the mechanism of the disease itself and the complications of it in bones and endocrine glands remain unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease is important for future treatment options and better quality of life of such patients.
Conflict of interest statement
The authors have no conflict of interests.
References
1. Cockayne EA. Case for diagnosis. Proc R Soc Med 1920;13:132–6.10.1177/003591572001301935Suche in Google Scholar
2. Camurati M. Di uno raro caso di osteite simmetrica ereditaria degli arti inferiori. Chir Organi Mov 1922;6:662–5.Suche in Google Scholar
3. Engelmann G. Ein Fall von Osteopathia hyperostotica (sclerotisans) multiplex infantilis. Fortschr Geb Roentgenstr Nukl 1929;39:1101–6.Suche in Google Scholar
4. Campos-Xavier B, Saraiva JM, Savarirayan R, Verloes A, Feingold J, et al. Phenotypic variability at the TGF-beta1 locus in Camurati-Engelmann disease. Hum Genet 2001;109:653–8.10.1007/s00439-001-0644-8Suche in Google Scholar PubMed
5. Janssens K, Vanhoenacker F, Bonduelle M, Verbruggen L, Van Maldergem L, et al. Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment. J Med Genet 2006;43:1–11.10.1136/jmg.2005.033522Suche in Google Scholar PubMed PubMed Central
6. Sparkes RS, Graham CB. Camurati-Engelmann disease. Genetics and clinical manifestations with a review of the literature. J Med Genet 1972;9:73–85.10.1136/jmg.9.1.73Suche in Google Scholar PubMed PubMed Central
7. Hanson W, Parnes LS. Vestibular nerve compression in Camurati-Engelmann disease. Ann Otol Rhinol Laryngol 1995;104:823–5.10.1177/000348949510401013Suche in Google Scholar PubMed
8. Wright M, Miller NR, McFadzean RM, Riordan-Eva P, Lee AG, et al. Papilloedema, a complication of progressive diaphyseal dysplasia: a series of three case reports. Br J Ophthalmol 1998;82:1042–8.10.1136/bjo.82.9.1042Suche in Google Scholar PubMed PubMed Central
9. Whyte MP, Totty WG, Novack DV, Zhang X, Wenkert D, et al. Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFbeta1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand. J Bone Miner Res 2011;26:920–33.10.1002/jbmr.283Suche in Google Scholar PubMed PubMed Central
10. Crisp AJ, Brenton DP. Engelmann’s disease of bone – a systemic disorder? Ann Rheum Dis 1982;41:183–8.10.1136/ard.41.2.183Suche in Google Scholar PubMed PubMed Central
11. Gupta S, Cheikh IE. Camurati-Engelmann disease in conjunction with hypogonadism. Endocr Pract 2005;11:399–407.10.4158/EP.11.6.399Suche in Google Scholar PubMed
12. Meczekalski B, Czyzyk A, Podfigurna-Stopa A, Rydzewski B, Sroczynski J, et al. Hypothalamic amenorrhea in a Camurati-Engelmann disease – a case report. Gynecol Endocrinol 2013;29:511–4.10.3109/09513590.2012.760196Suche in Google Scholar PubMed
13. Wallace SE, Lachman RS, Mekikian PB, Bui KK, Wilcox WR. Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati-Engelmann disease): report of a four-generation pedigree, identification of a mutation in TGFB1, and review. Am J Med Genet A 2004;129A:235–47.10.1002/ajmg.a.30148Suche in Google Scholar
14. Makita Y, Nishimura G, Ikegawa S, Ishii T, Ito Y, et al. Intrafamilial phenotypic variability in Engelmann disease (ED): are ED and Ribbing disease the same entity? Am J Med Genet 2000;91:153–6.10.1002/(SICI)1096-8628(20000313)91:2<153::AID-AJMG15>3.0.CO;2-USuche in Google Scholar
15. Janssens K, Gershoni-Baruch R, Van Hul E, Brik R, Guanabens N, et al. Localisation of the gene causing diaphyseal dysplasia Camurati-Engelmann to chromosome 19q13. J Med Genet 2000;37:245–9.10.1136/jmg.37.4.245Suche in Google Scholar
16. Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet 2000;26:19–20.10.1038/79128Suche in Google Scholar
17. Vaughn SP, Broussard S, Hall CR, Scott A, Blanton SH, et al. Confirmation of the mapping of the Camurati-Englemann locus to 19q13. 2 and refinement to a 3.2-cM region. Genomics 2000;66:119–21.10.1006/geno.2000.6192Suche in Google Scholar
18. Oida T, Weiner HL. Depletion of TGF-beta from fetal bovine serum. J Immunol Methods 2010;362:195–8.10.1016/j.jim.2010.09.008Suche in Google Scholar
19. Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming growth factor-beta1 to the bone. Endocr Rev 2005;26:743–74.10.1210/er.2004-0001Suche in Google Scholar
20. Oklu R, Hesketh R. The latent transforming growth factor beta binding protein (LTBP) family. Biochem J 2000;352(Pt 3):601–10.10.1042/bj3520601Suche in Google Scholar
21. Shi M, Zhu J, Wang R, Chen X, Mi L, et al. Latent TGF-beta structure and activation. Nature 2011;474:343–9.10.1038/nature10152Suche in Google Scholar
22. Sanchez-Capelo A. Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev 2005;16:15–34.10.1016/j.cytogfr.2004.11.002Suche in Google Scholar
23. Bensamoun SF, Hawse JR, Subramaniam M, Ilharreborde B, Bassillais A, et al. TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture. Bone 2006;39:1244–51.10.1016/j.bone.2006.05.021Suche in Google Scholar PubMed
24. Fox SW, Lovibond AC. Current insights into the role of transforming growth factor-beta in bone resorption. Mol Cell Endocrinol 2005;243:19–26.10.1016/j.mce.2005.09.008Suche in Google Scholar PubMed
25. Cicek M, Vrabel A, Sturchio C, Pederson L, Hawse JR, et al. TGF-beta inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways. PLoS One 2011;6:e17522.10.1371/journal.pone.0017522Suche in Google Scholar PubMed PubMed Central
26. Dabovic B, Chen Y, Colarossi C, Zambuto L, Obata H, et al. Bone defects in latent TGF-beta binding protein (Ltbp)-3 null mice; a role for Ltbp in TGF-beta presentation. J Endocrinol 2002;175:129–41.10.1677/joe.0.1750129Suche in Google Scholar PubMed
27. Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem 2003;278:7718–24.10.1074/jbc.M208857200Suche in Google Scholar PubMed
28. McLennan IS, Koishi K. The transforming growth factor-betas: multifaceted regulators of the development and maintenance of skeletal muscles, motoneurons and Schwann cells. Int J Dev Biol 2002;46:559–67.Suche in Google Scholar
29. Zamani N, Brown CW. Emerging roles for the transforming growth factor-{beta} superfamily in regulating adiposity and energy expenditure. Endocr Rev 2011;32:387–403.10.1210/er.2010-0018Suche in Google Scholar PubMed PubMed Central
30. Ingman WV, Robertson SA. Transforming growth factor-beta1 null mutation causes infertility in male mice associated with testosterone deficiency and sexual dysfunction. Endocrinology 2007;148:4032–43.10.1210/en.2006-1759Suche in Google Scholar PubMed
31. Memon MA, Anway MD, Covert TR, Uzumcu M, Skinner MK. Transforming growth factor beta (TGFbeta1, TGFbeta2 and TGFbeta3) null-mutant phenotypes in embryonic gonadal development. Mol Cell Endocrinol 2008;294:70–80.10.1016/j.mce.2008.08.017Suche in Google Scholar PubMed PubMed Central
32. Coya R, Alvarez CV, Perez F, Gianzo C, Dieguez C. Effects of TGF-beta1 on prolactin synthesis and secretion: an in-vitro study. J Neuroendocrinol 1999;11:351–60.10.1046/j.1365-2826.1999.00336.xSuche in Google Scholar PubMed
33. Sarkar DK, Chaturvedi K, Oomizu S, Boyadjieva NI, Chen CP. Dopamine, dopamine D2 receptor short isoform, transforming growth factor (TGF)-beta1, and TGF-beta type II receptor interact to inhibit the growth of pituitary lactotropes. Endocrinology 2005;146:4179–88.10.1210/en.2005-0430Suche in Google Scholar PubMed PubMed Central
34. Zatelli MC, Rossi R, degli Uberti EC. Androgen influences transforming growth factor-beta1 gene expression in human adrenocortical cells. J Clin Endocrinol Metab 2000;85:847–52.Suche in Google Scholar
35. Pisarev MA, Thomasz L, Juvenal GJ. Role of transforming growth factor beta in the regulation of thyroid function and growth. Thyroid 2009;19:881–92.10.1089/thy.2007.0303Suche in Google Scholar
36. Moritani M, Yamasaki S, Kagami M, Suzuki T, Yamaoka T, et al. Hypoplasia of endocrine and exocrine pancreas in homozygous transgenic TGF-beta1. Mol Cell Endocrinol 2005;229:175–84.10.1016/j.mce.2004.08.007Suche in Google Scholar
37. Sobrinho LG. Prolactin, psychological stress and environment in humans: adaptation and maladaptation. Pituitary 2003;6:35–9.10.1023/A:1026229810876Suche in Google Scholar
38. Li XF, Knox AM, O’Byrne KT. Corticotrophin-releasing factor and stress-induced inhibition of the gonadotrophin-releasing hormone pulse generator in the female. Brain Res 2010;1364:153–63.10.1016/j.brainres.2010.08.036Suche in Google Scholar
39. Beighton P. Sclerosing bone dysplasias. Prog Clin Biol Res 1982;104:173–94.Suche in Google Scholar
40. Yamada Y, Miyauchi A, Goto J, Takagi Y, Okuizumi H, et al. Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res 1998;13:1569–76.10.1359/jbmr.1998.13.10.1569Suche in Google Scholar
41. Ziv E, Kahn A, Cauley J, Morin P, Saiz R, et al. No association between the TGF-beta 1 Leu10Pro polymorphism and osteoporosis among white women in the United States. Am J Med 2003;114:227–31.10.1016/S0002-9343(02)01393-1Suche in Google Scholar
42. Inaoka T, Shuke N, Sato J, Ishikawa Y, Takahashi K, et al. Scintigraphic evaluation of pamidronate and corticosteroid therapy in a patient with progressive diaphyseal dysplasia (Camurati-Engelmann disease). Clin Nucl Med 2001;26:680–2.10.1097/00003072-200108000-00003Suche in Google Scholar PubMed
43. Cherie-Ligniere G, Santalena G, Parafioriti A. Pamidronate in the treatment of progressive diaphyseal dysplasia (Camurati-Engelmann disease). Clin Exp Rheumatol 1999;17:264.Suche in Google Scholar
44. Canalis E. Mechanisms of glucocorticoid action in bone. Curr Osteoporos Rep 2005;3:98–102.10.1007/s11914-005-0017-7Suche in Google Scholar PubMed
©2013 by Walter de Gruyter Berlin Boston
Artikel in diesem Heft
- Masthead
- Masthead
- Review article
- Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review
- Images in pediatric endocrinology
- Solitary median maxillary central incisor, a clinical predictor of hypoplastic anterior pituitary, ectopic neurohypophysis and growth hormone deficiency
- A rare case of granuloma annulare in a 6-year-old child with type 1 diabetes
- Original articles
- The arginine stimulation test: timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency
- The relationship between adiposity and stature in prepubertal children with celiac disease
- Influence of micronutrient status and socioeconomic gradient on growth indices of 2–18-year-old Indian girls
- Phosphotyrosine phosphatases in GH-stimulated skin fibroblasts from children with idiopathic short stature
- The relation between salivary cortisol and the metabolic syndrome score in girls
- Association of vitamin D concentrations with adiposity indices among preadolescent children in Korea
- Association of serum resistin levels with metabolic syndrome and early atherosclerosis in obese Chinese children
- Characteristics of infants at risk of hypoglycaemia secondary to being ‘infant of a diabetic mother’
- Parental dyadic coping in families of children and adolescents with type 1 diabetes
- Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome
- Effect of insulin therapy on IGF-1 level in children with new-onset type 1 diabetes mellitus: a comparison between DKA and non-DKA
- Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias
- Sexual development in prepubertal obese boys: a 4-year longitudinal study
- Genetic diagnosis of one family with incomplete clinical data
- Patient reports
- Complete androgen insensitivity syndrome and discordant Müllerian remnants: two cases with novel mutation in the androgen receptor
- Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture
- Ambiguous genitalia in a 48, XXYY newborn: a casual relationship or a coincidence?
- Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens
- Significant testicular enlargement in a 6.5-year-old boy with monorchism and testicular microlithiasis
- Report of the first case of precocious puberty in Rett syndrome
- Type II vitamin D-dependent rickets with diabetic ketoacidosis
- Pituitary gigantism presenting with depressive mood disorder and diabetic ketoacidosis in an Asian adolescent
- A rare association between Rathke’s cyst and hypophysitis in a patient with delayed sex development and growth failure
- Diabetes mellitus with Laron syndrome: case report
- Wegener granulomatosis as an uncommon cause of panhypopituitarism in childhood
- Rare cases of autoimmune hypothyroidism in young children
- Cushing syndrome related to leukemic infiltration of the central nervous system: a case report and a possible role of LIF
- Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy
- Identification of a novel homozygous mutation (S144I) in a Malay patient with maple syrup urine disease
- Virilization in two pre-pubertal children exposed to topical androgen
- A family with Camurati-Engelman disease. The role of the missense p.R218C mutation in TGFB1 in bones and endocrine glands
- Short communications
- Plasma ceramides are elevated in female children and adolescents with type 2 diabetes
- Assessment of contractility and myocardial function in small and appropriate for gestational age premature neonates using the stress-velocity relationship and tissue Doppler imaging immediately after birth
- Letter to the Editors
- Homeostasis model assessment of insulin resistance may not be reliable to evaluate insulin sensitivity in young obese children
- Type 1 diabetes in women with endometriosis: what is the risk of occurrence?
- How should we manage vitamin D-deficient adolescents?
- Should neonatal hyperparathyroidism associated with mucolipidosis II/III be treated pharmacologically?a
Artikel in diesem Heft
- Masthead
- Masthead
- Review article
- Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review
- Images in pediatric endocrinology
- Solitary median maxillary central incisor, a clinical predictor of hypoplastic anterior pituitary, ectopic neurohypophysis and growth hormone deficiency
- A rare case of granuloma annulare in a 6-year-old child with type 1 diabetes
- Original articles
- The arginine stimulation test: timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency
- The relationship between adiposity and stature in prepubertal children with celiac disease
- Influence of micronutrient status and socioeconomic gradient on growth indices of 2–18-year-old Indian girls
- Phosphotyrosine phosphatases in GH-stimulated skin fibroblasts from children with idiopathic short stature
- The relation between salivary cortisol and the metabolic syndrome score in girls
- Association of vitamin D concentrations with adiposity indices among preadolescent children in Korea
- Association of serum resistin levels with metabolic syndrome and early atherosclerosis in obese Chinese children
- Characteristics of infants at risk of hypoglycaemia secondary to being ‘infant of a diabetic mother’
- Parental dyadic coping in families of children and adolescents with type 1 diabetes
- Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome
- Effect of insulin therapy on IGF-1 level in children with new-onset type 1 diabetes mellitus: a comparison between DKA and non-DKA
- Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias
- Sexual development in prepubertal obese boys: a 4-year longitudinal study
- Genetic diagnosis of one family with incomplete clinical data
- Patient reports
- Complete androgen insensitivity syndrome and discordant Müllerian remnants: two cases with novel mutation in the androgen receptor
- Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture
- Ambiguous genitalia in a 48, XXYY newborn: a casual relationship or a coincidence?
- Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens
- Significant testicular enlargement in a 6.5-year-old boy with monorchism and testicular microlithiasis
- Report of the first case of precocious puberty in Rett syndrome
- Type II vitamin D-dependent rickets with diabetic ketoacidosis
- Pituitary gigantism presenting with depressive mood disorder and diabetic ketoacidosis in an Asian adolescent
- A rare association between Rathke’s cyst and hypophysitis in a patient with delayed sex development and growth failure
- Diabetes mellitus with Laron syndrome: case report
- Wegener granulomatosis as an uncommon cause of panhypopituitarism in childhood
- Rare cases of autoimmune hypothyroidism in young children
- Cushing syndrome related to leukemic infiltration of the central nervous system: a case report and a possible role of LIF
- Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy
- Identification of a novel homozygous mutation (S144I) in a Malay patient with maple syrup urine disease
- Virilization in two pre-pubertal children exposed to topical androgen
- A family with Camurati-Engelman disease. The role of the missense p.R218C mutation in TGFB1 in bones and endocrine glands
- Short communications
- Plasma ceramides are elevated in female children and adolescents with type 2 diabetes
- Assessment of contractility and myocardial function in small and appropriate for gestational age premature neonates using the stress-velocity relationship and tissue Doppler imaging immediately after birth
- Letter to the Editors
- Homeostasis model assessment of insulin resistance may not be reliable to evaluate insulin sensitivity in young obese children
- Type 1 diabetes in women with endometriosis: what is the risk of occurrence?
- How should we manage vitamin D-deficient adolescents?
- Should neonatal hyperparathyroidism associated with mucolipidosis II/III be treated pharmacologically?a