Korcan DEMİR, Ece BÖBER, Damla GÖKŞEN, Gülay KARAGÜZEL, Behzat ÖZKAN, Serap TURAN, Hakan DÖNERAY, Pınar İŞGÜVEN, Atilla ÇAYIR

Endokrin Açıdan İskelet Displazileri

İskelet displazileri kemik, kıkırdak veya her iki dokunun birden etkilendiği, farklı klinik ve radyolojik bulgular ile ortaya çıkabilen karmaşık bir hastalık grubudur. Ayrı ayrı hastalıklar olarak incelendiğinde ender olmakla birlikte, iskelet displazileri toplumda 1/3000-5000 sıklığında görü- lür. Klinik, laboratuvar, radyolojik ve moleküler değerlen- dirmelere göre 40 ana gruba ayrılabilen iskelet displazile- rinde çeşitli konjenital malformasyonlar, spinal anomaliler, ekstremite kısalıkları ve orantısız boy kısalıkları görülür. Çoğu genetik nedenli olan bu hastalıklarda kemik anoma- lileri yanında hipoglisemi, hipo/hiperkalsemi, adrenal yet- mezlik, pubertal gelişim sorunları ve cinsiyet farklılaşma bozuklukları gibi endokrinolojik sorunlar da ortaya çıka- bilmektedir. İskelet displazilerin ayırıcı tanısı için detaylı öykü ve muayene, iskelet grafileri, genetik inceleme, bazı ileri laboratuvar incelemeleri ve multidisipliner yaklaşım gerekir. Bu derlemede iskelet displazilerine genel yaklaşım, eşlik edebilecek endokrinolojik anormallikler ve 2010 yılında yayınlanmış en güncel sınıflamanın sunulması amaçlanmıştır

Anahtar Kelimeler:

İskelet displazisi, boy kısalığı, hiperglisemi, kalsiyum, endokrin, adrenal yetmezlik, puberte, cinsel gelişim bozukluğu

Skeletal Dysplasias from an Endocrine Point of View

Skeletal dysplasias are complex group of diseases with diffe- rent clinical and radiologic findings involving bone, and/or cartilage. Although skeletal dysplasias are rarely seen when considered individually, general incidence in the population is 1/3000-5000. Skeletal dysplasias are classified in 40 main groups on the basis of clinical, laboratory, radiological and molecular evaluations, and congenital malformations, spi- nal abnormalities, short extremities, and disproportionate short stature are seen in sekondereletal dysplasias. In addi- tion to bone abnormalities, endocrine problems including hyperglycemia, hypo/hypercalcemia, adrenal failure, puber- tal alterations, and disorders of sexual development which are mostly due to genetic disorders may accompany skeletal dysplasias. Differential diagnosis of skeletal dysplasias requires detailed history and physical examination, skeletal X-rays, genetic analysis, some advanced laboratory met- hods, and multidisciplinary aproach. In this review, it is aimed to present a general approach to skeletal dysplasias, endocrine abnormalities that may accompany, and the most recent classification published in 2010

Keywords:

Skeletal dysplasia, short stature, hyperglycemia, calcium, endocrine, adrenal failure, puberty, disorders of sexual development,

PDF

___

Hurst JA, Firth HV, Smithson S. Skeletal dysplasias. Semin Fetal Neonatal Med 2005;10:233-41. http://dx.doi.org/10.1016/j.siny.2004.12.001
Krakow D, rimoin DL. The skeletal dysplasias. Genet Med 2010;12:327-41. http://dx.doi.org/10.1097/GIM.0b013e3181daae9b
Alanay Y, Lachman rS. A review of the principles of radio- logical assessment of skeletal dysplasias. J Clin Res Pediatr Endocrinol 2011;3:163-78. http://dx.doi.org/10.4274/jcrpe.463
Tüysüz B, Çoğulu ö. İskelet displazileri. Turkiye Klinikleri J Pediatr Sci 2005;1:93-100.
Stevenson DA, Carey JC, Byrne JL, Srisukhumbowornchai S, Feldkamp mL. Analysis of skeletal dysplasias in the Utah population. Am J Med Genet A 2012;158A:1046-54. http://dx.doi.org/10.1002/ajmg.a.35327
Barbosa-Buck CO, Orioli Im, da Graça Dutra m, Lopez- Camelo J, Castilla EE, Cavalcanti DP. Clinical epidemio- logy of skeletal dysplasias in South America. Am J Med Genet A 2012;158A:1038-45. http://dx.doi.org/10.1002/ajmg.a.35246
Warman mL, Cormier-Daire V, Hall C, Krakow D, Lachman r, Lemerrer m, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 2011;155A:943-68. http://dx.doi.org/10.1002/ajmg.a.33909
Gat-Yablonski G, Yackobovitch-Gavan m, Phillip m. Nutrition and bone growth in pediatrics. Endocrinol Metab Clin North Am 2009;38:565-86. http://dx.doi.org/10.1016/j.ecl.2009.07.001
Spranger JW, Brill PW, Poznanski AK. Introduction. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal development. 2nd ed. New York, USA: Oxford University Press, 2002: IX-XIV.
Horton WA, Hecht JT. The skeletal dysplasias-General con- siderations. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, USA: WB Saunders, 2007: 2869-2873.
Veeramani AK, Higgins P, Butler S, Donaldson m, Dougan E, Duncan r, et al. Diagnostic use of skeletal survey in sus- pected skeletal dysplasia. J Clin Res Pediatr Endocrinol 2009;1:270-4. http://dx.doi.org/10.4274/jcrpe.v1i6.270
Turan S, Bereket A, Omar A, Berber m, Ozen A, Bekiroglu N. Upper segment/lower segment ratio and armspan-height difference in healthy Turkish children. Acta Paediatr 2005;94:407-13. http://dx.doi.org/10.1111/j.1651-2227.2005.tb01909.x
Jones KL. Normal standards. In: Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, USA: Elsevier Saunders, 2006: 835-863.
ACR–SPR practice guideline for skeletal surveys in children. Accessed on February 10, 2015, at: http://www.acr.org/~/ media/ACR/Documents/PGTS/guidelines/Skeletal_Surveys. pdf
Savarirayan r, rimoin DL. Skeletal dysplasias. Adv Pediatr 2004;51:209-29.
Alanay Y, Lachman rS. A review of the principles of radio- logical assessment of skeletal dysplasias. J Clin Res Pediatr Endocrinol 2011;3:163-78. http://dx.doi.org/10.4274/jcrpe.463
Parnell SE, Phillips GS. Neonatal skeletal dysplasias. Pediatr Radiol 2012;42(Suppl 1):S150-7. http://dx.doi.org/10.1007/s00247-011-2176-2
mackenzie WG, Shah SA, Takemitsu m. The cervical spine in skeletal dysplasia. In: Benzel EC, ed. The Cervical Spine. 5th ed. Philadelphia, USA: Lippincott Williams & Wilkins, 2012: 408-8.
Baujat G, Legeai-mallet L, Finidori G, Cormier-Daire V, Le merrer m. Achondroplasia. Best Pract Res Clin Rheumatol 2008;22:3-18. http://dx.doi.org/10.1016/j.berh.2007.12.008
Krakow D, Lachman rS, rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med 2009;11:127-33. http://dx.doi.org/10.1097/GIM.0b013e3181971ccb
Schramm T, Gloning KP, minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, et al. Prenatal sonographic diagno- sis of skeletal dysplasias. Ultrasound Obstet Gynecol 2009; 34:160-70. http://dx.doi.org/10.1002/uog.6359
Ulla m, Aiello H, Cobos mP, Orioli I, García-mónaco r, Etchegaray A, et al. Prenatal diagnosis of skeletal dysplasias: contribution of three-dimensional computed tomography. Fetal Diagn Ther 2011;29:238-47. http://dx.doi.org/10.1159/000322212
Turan S. İskelet displazileri. In: Kurtoğlu S, ed. Yenidoğan Dönemi Endokrin Hastalıkları. 1st ed. İstanbul, Turkey: Nobel Tıp Kitabevleri Ltd. Şti, 2011:613-26.
rimoin DL, Cohn D, Krakow D, Wilcox W, Lachman rS, Alanay Y. The skeletal dysplasias: clinical-molecular correla- tions. Ann N Y Acad Sci 2007;1117:302-9. http://dx.doi.org/10.1196/annals.1402.072
Glazov EA, Zankl A, Donskoi m, Kenna TJ, Thomas GP, Clark Gr, et al. Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLoS Genet 2011;7:e1002027. http://dx.doi.org/10.1371/journal.pgen.1002027
min BJ, Kim N, Chung T, Kim OH, Nishimura G, Chung CY, et al. Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. Am J Hum Genet 2011;89:760-6. http://dx.doi.org/10.1016/j.ajhg.2011.10.015
Spranger JW, Brill PW, Poznanski AK. Achondroplasia. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal development. 2nd ed. New York, USA: Oxford University Press, 2002: 83-9.
Hertel NT, Eklöf O, Ivarsson S, Aronson S, Westphal O, Sipilä I, et al. Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial. Acta Paediatr 2005;94:1402-10. http://dx.doi.org/10.1080/08035250510039982
Cappa m, Ubertini G, Colabianchi D, Fiori r, Cambiaso P. Non-conventional use of growth hormone therapy. Acta Paediatr Suppl 2006;95:9-13. http://dx.doi.org/10.1080/08035320600649432
Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet 2007;370:162-72. http://dx.doi.org/10.1016/S0140-6736(07)61090-3
Schiedel F, rödl r. Lower limb lengthening in patients with disproportionate short stature with achondroplasia: a systematic review of the last 20 years. Disabil Rehabil 2012;34:982-7. http://dx.doi.org/10.3109/09638288.2011.631677
mazzanti L, Tamburrino F, Bergamaschi r, Scarano E, montanari F, Torella m, et al. Developmental syndromes: growth hormone deficiency and treatment. Endocr Dev 2009; 14:114-34. http://dx.doi.org/10.1159/000207481
Spranger JW, Brill PW, Poznanski AK. Pseudoachondro- plasia. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal develop- ment. 2nd ed. New York, USA: Oxford University Press, 2002: 147-151.
Spranger JW, Brill PW, Poznanski AK. Hypochondroplasia. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dyspla- sias: an atlas of genetic disorders of skeletal development. 2nd ed. New York, USA: Oxford University Press, 2002: 591- 593.
rothenbuhler A, Linglart A, Piquard C, Bougnères P. A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFR3 N540K-mutated hypochondroplasia. J Pediatr 2012; 160:849-53. http://dx.doi.org/10.1016/j.jpeds.2011.10.023
Spranger JW, Brill PW, Poznanski AK. Ellis-van Creveld syndrome. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal deve- lopment. 2nd ed. New York, USA: Oxford University Press, 2002: 130-5.
Versteegh FG, Buma SA, Costin G, de Jong WC, Hennekam rC; EvC Working Party. Growth hormone analysis and treatment in Ellis-van Creveld syndrome. Am J Med Genet A 2007;143A:2113-21. http://dx.doi.org/10.1002/ajmg.a.31891
Spranger JW, Brill PW, Poznanski AK. Dyschondrosteosis. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dyspla- sias: an atlas of genetic disorders of skeletal development. 2nd ed. New York, USA: Oxford University Press, 2002: 336-8.
Salmon-musial AS, rosilio m, David m, Huber C, Pichot E, Cormier-Daire V, Nicolino m. Clinical and radiological characteristics of 22 children with SHOX anomalies and fami- lial short stature suggestive of Léri-Weill Dyschondrosteosis. Horm res Paediatr 2011;76:178-85. http://dx.doi.org/10.1159/000329359
Julier C, Nicolino m. Wolcott-Rallison syndrome. Orphanet J Rare Dis. 2010; 5: 29. Doi: 10.1186/1750-1172-5-29. http://dx.doi.org/10.1186/1750-1172-5-29
Garg A. Clinical review: Lipodystrophies: genetic and acqui- red body fat disorders. J Clin Endocrinol Metab 2011;96: 3313-25. http://dx.doi.org/10.1210/jc.2011-1159
Spranger JW, Brill PW, Poznanski AK. Mandibuloacral dysplasia. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal deve- lopment. 2nd ed. New York, USA: Oxford University Press, 2002: 591-3.
Noordam C, Dhir V, mcNelis JC, Schlereth F, Hanley NA, Krone N, et al. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 2009;360:2310-8. http://dx.doi.org/10.1056/NEJMoa0810489
miyake N, Elcioglu NH, Iida A, Isguven P, Dai J, murakami N, et al. PAPSS2 mutations cause autosomal recessive brach- yolmia. J Med Genet 2012;49:533-8. http://dx.doi.org/10.1136/jmedgenet-2012-101039
Spranger JW, Brill PW, Poznanski AK. Blomstrand chond- rodysplasia. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal deve- lopment. 2nd ed. New York, USA: Oxford University Press, 2002: 28-9.
Spranger JW, Brill PW, Poznanski AK. Albright hereditary osteodystrophy. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal development. 2nd ed. New York, USA: Oxford University Press, 2002: 373-7.
mantovani G. Clinical review: Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab 2011;96: 3020-30. http://dx.doi.org/10.1210/jc.2011-1048
Spranger JW, Brill PW, Poznanski AK. Kenny-Caffey syndrome. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal deve- lopment. 2nd ed. New York, USA: Oxford University Press, 2002: 425-7.
minagawa m, Arakawa K, Takeuchi S, minamitani K, Yasuda T, Niimi H. Jansen-type metaphyseal chondrodyspla- sia: analysis of PTH/PTH-related protein receptor messenger RNA by the reverse transcriptase-polymerase chain method. Endocr J 1997;44:493-9. http://dx.doi.org/10.1507/endocrj.44.493
Unger S, Scherer G, Superti-Furga A. Campomelic dyspla- sia. In: Pagon RA, Bird TD, Dolan CR, eds. GeneReviews™ [Internet]. Seattle, USA: University of Washington, 1993-. (Accessed February 4, 2015, http://www.ncbi.nlm.nih.gov/ books/NBK1760/)
Spranger JW, Brill PW, Poznanski AK. Campomelic dysplasia. In: Spranger JW, Brill PW, Poznanski AK, eds. Bone dysplasias: an atlas of genetic disorders of skeletal deve- lopment. 2nd ed. New York, USA: Oxford University Press, 2002: 41-6.
Cragun D, Hopkin rJ. Cytochrome P450 Oxidoreductase Deficiency. In: Pagon RA, Bird TD, Dolan CR, eds. GeneReviews™ [Internet]. Seattle, USA: University of Washington, 1993-. (Accessed February 4, 2015, http://www. ncbi.nlm.nih.gov/books/NBK1419)
Vilain E, Le merrer m, Lecointre C, Desangles F, Kay mA, maroteaux P, mcCabe Er. IMAGe, a new clinical associa- tion of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. J Clin Endocrinol Metab 1999;84:4335-40. http://dx.doi.org/10.1210/jcem.84.12.6186
Arboleda VA, Lee H, Parnaik r, Fleming A, Banerjee A, Ferraz-de-Souza B, et al. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 2012;44:788-92. http://dx.doi.org/10.1038/ng.2275