DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20150184

A case report of recurrent achondroplasia in fetuses of normal parents

Anbumani TL, Anthony Ammal S, Thamarai Selvi A

Abstract


Achondroplasia, a skeletal dysplasia has an incidence of 1 in 15000 to 1 in 30000 live births. It is inherited in an autosomal dominant manner. The occurrence of recurrent achondroplasia in babies born to normal parents is rare. The present case report is one such type. A female fetus of 27 weeks gestational age was brought to the Department of Anatomy, Karpaga Vinayaga Institute of Medical Sciences, Maduranthagam. There was frontal bossing of forehead, rhizomelic type of limb shortening with limitation of elbow extension in the fetus. The mother of the fetus, who is 26 years old, gave history of recurrence of such condition. Her first pregnancy was a twin pregnancy, conceived by natural methods, where one of the twins was a male baby who also had achondroplasia and died 2 hours after delivery. The other twin is a girl and the child has delayed developmental milestones. Her second pregnancy was uneventful. The present fetus under study is from her third pregnancy. Her marriage is of second degree consanguineous type. The age of her husband is 36 years old. Germinal mosaicism has been attributed for the causation of recurrent achondroplasia in children, whose parents are normal. 80% of achondroplasia is due to a new mutation. Only 20% of achondroplasia is inherited. Increased paternal age is a risk factor for new mutations to occur. The other investigations of the case and the genetic analysis are described further in the article.


Keywords


Achondroplasia, Autosomal dominant, Germinal mosaicism, FGFR-3

Full Text:

PDF

References


Stoll C, Dott B, Roth MP, Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet. 1989;35:88-92.

Velinov M, Slaugenhaupt SA, Stoilov I, Scott CI Jr, Gusella JF, Tsipouras, P. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genet. 1994;6:318-21.

Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet. 1995;56:368-73.

Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16:1446-65.

Shiang R, Thomson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994;78:335-42.

Hecht JT, Bodensteiner JB, Butler IJ. Neurologic manifestations of achondroplasia. Handb Clin Neurol. 2014;119:551-63.

Shinde DN, Elmer DP, Calabrese P, Boulanger J, Arnheim N, Tiemann-Boege I. New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. Hum Mol Genet. 2013 Oct;22(20):4117-26.

Horton WA. Molecular pathogenesis of achondroplasia. Growth Genet Horm. 2006;22:49-54.

Mettler G, Fraser FC. Recurrence risk for sibs of children with “sporadic” achondroplasia. Am J Med Genet. 2000;90:250-1.

Natacci F, Baffico M, Cavallari U, , Bedeschi MF, Mura I, Paffoni A, et al. Germline mosaicism in achondroplasia detected in sperm DNA of the father of three affected sibs. Am J Med Genet A. 2008 Mar;146A(6):784-6.

Pauli RM, Conroy MM, Langer LO, McLone DG, Naidich T, Francosi R, et al. Homozygous achondroplasiawith survival beyond infancy. Am J Med Genet. 1983;16:459-73.

Risch N, Reich EW, Wishnick MM, McCarthy JG. Spontaneous mutation and parental age in humans. Am J Hum Genet. 1987;41:218-48.

Fryns JP, Kleczkowska A, Verresen H, Van den Berghe H. Germinal mosaicism in achondroplasia. A family with 3 affected siblings of normal parents. Clin Genet. 1985;24:156-8.

Opitz JM. Unstable premutation in achondroplasia. Penetranceversus phenotrance. Am J Med Genet. 1984;19:251-4.

Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, et al. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998;63:711-6.

Clermont Y. Renewal of spermatogonia in man. Am J Anat. 1966;118:509-24.

Saltvedt S, Almström H, Kublickas M, Valentin L, Grunewald C. Detection of malformations in chromosomally normal fetuses by routine ultrasound at 12 or 18 weeks of gestation - a randomised controlled trial in 39572 pregnancies. BJOG. 2006;113:664-74.

Mettler G, Fraser FC. Recurrence risk for sibs of children with “sporadic” achondroplasia. Am J Med Genet. 2000;90:250-1.

Aviezer D, Golembo M, Yayon A. Fibroblast growth factor receptor-3 as a therapeutic target for achondroplasia - genetic short limb dwarfism. Curr Drug Targets. 2003;4:353-65.

Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, et al. Overexpression of CNP in chondrocytes, rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004;10:80-6.