Atypical breakpoint in a t(6;17) translocation case of acampomelic campomelic dysplasia

2014-05-10 15:38:27

European Journal of Medical Genetics; 2014 May 1; DOI: 10.1016/j.ejmg.2014.04.018

Lauren C. Walters-Sen, Devon Lamb Thrush, Scott E. Hickey, Sayaka Hashimoto, Shalini Reshmi, Julie M. Gastier-Foster, Robert E. Pyatt, Caroline Astbury


Campomelic dysplasia (CD) is a skeletal dysplasia characterized by Pierre Robin sequence (PRS), shortened and bowed long bones, airway instability, and the potential for sex reversal. A subtype of CD, acampomelic CD (ACD), is seen in approximately 10% of cases and preserves long bone straightness. Both syndromes are caused by alterations in SOX9, with translocations and missense mutations being overrepresented in ACD cases. We report a term infant with PRS, severe cervical spine abnormalities, eleven rib pairs, hypoplastic scapulae, and female genitalia. Chromosome analysis identified a 46,XY,t(6;17)(q25;q24) karyotype. FISH analysis with a series of BAC probes localized the translocation breakpoints to 6q27 and a region at 17q24.3 in the range of 459-379 kb upstream of SOX9. Therefore, this case extends the region classified as the proximal breakpoint cluster. In addition, the comorbidity of acampomelia, complete sex reversal, and severe spinal anomalies in our patient underscores the variability in the level of malformation in the CD/ACD family of disorders.


Campomelic dysplasia (CD) is an autosomal dominant skeletal dysplasia characterized by a variety of clinical features. Skeletal abnormalities include eleven pairs of ribs; hypoplasia of several elements, including the scapulae, iliac wings, and thoracic vertebral pedicles; scoliosis or kyphosis, with particular
emphasis on the cervical spine; and the campomelia, or bowing, of the long bones for which the disorder is named. Other salient findings include Pierre Robin Sequence (PRS) with cleft palate, midface hypoplasia, and laryngotracheomalacia. Approximately 10% of cases lack the characteristic limb bowing and are classified as acampomelic campomelic dysplasia (ACD). In addition, both CD and ACD can present with ambiguous genitalia or complete sex reversal, which is seen in approximately 75% of 46,XY cases.

Both CD and ACD are caused by alterations in the SOX9 gene. The majority of cases (approximately 90%) are due to coding region or splice-site mutations. Partial or whole-gene deletions are detected in approximately 5% of cases, and the remaining 5% are identified cytogenetically due to de novo interstitial deletions or reciprocal translocations involving the long arm of chromosome 17. Missense mutations in the SOX9 coding region and chromosomal rearrangements in the vicinity of the SOX9 locus are overrepresented in ACD cases. In addition, there appears to be a correlation between the distance of the rearrangement breakpoint from the SOX9 locus and the severity of the disease phenotype; milder phenotypes, including ACD, are associated with rearrangements farther upstream from SOX9. To date, twenty-five cases of CD/ACD due to balanced translocations upstream of SOX9 have been reported. Breakpoints for twenty of these cases have been clustered into two distinct regions, classified as proximal and distal, 50-375 kb and 585-932 kb upstream of SOX9, respectively. In addition, a third breakpoint cluster, approximately 1.02e1.20 Mb upstream of SOX9, has been identified that segregates with isolated PRS.

We report a patient with limited skeletal findings, including acampomelia, and complete sex reversal due to a translocation between the long arms of chromosomes 6 and 17. Fluorescence in situ hybridization (FISH) localized the chromosome 17 breakpoint to a region approximately 459-379 kb upstream of SOX9. Our patient provides another example of the phenotypic variability seen in SOX9-related disorders and extends the centromeric boundary of the proximal breakpoint cluster.

To Access Article, Click Here