Atelosteogenesis I

Authors: Professor David Sillence 1 and Professor Kazimierz Kozlowski Creation Date: November 2004

Scientific Editor: Professor Raoul Hennekam

1Academic Department of , The Children's Hospital at Westmead, Westmead 2145, AUSTRALIA. [email protected]

Abstract Keywords Disease name/synonyms Differential diagnosis Etiology Clinical description Diagnostic methods Epidemiology Genetic counseling Prenatal diagnosis Management including treatment Unresolved questions References

Abstract Atelosteogenesis I (AOI, incomplete formation of ) is a perinatally lethal short-limb newborn skeletal dysplasia with distinctive faces and diagnostic radiographic appearances. The patients are stillborn or die soon after birth. Prenatal sonography can detect bone dysplasia. An exact diagnosis can be established postnatally from skeletal radiographs and chondro-osseous histopathology. There is a continuum in radiographic findings between Atelosteogenesis I and Boomerang dysplasia and the two disorders are nosologically grouped. Atelosteogenesis I/Boomerang Dysplasia results from heterozygous in the gene encoding B (FLNB). All cases of this autosomal dominantly inherited disorder have been sporadic presumably resulting from a de novo in FLNB. This is a very infrequently described disorder.

Keywords Atelosteogenesis – Spondylo-humero-femoral dysplasia - Boomerang dysplasia - Atelosteogenesis I/Boomerang Dysplasia - disharmonious phalangeal maturation - FLNB gene – giant cell chondrodysplasia

pathogenetically related with a more severe Disease name/synonyms expression of skeletal anomalies. There is a Atelosteogenesis I/Boomerang Dysplasia wide range of humeral and femoral bone shapes Spondylo-humero-femoral dysplasia including round, oval, and triangular humeral Giant Cell Chondrodysplasia shapes suggesting a continuum of disorders. Atelosteogenesis III with less dysmorphic facial Differential diagnosis features and well ossified but disharmonious Boomerang dysplasia with boomerang shaped short tubular is also thought to be humeri and femora is thought to be pathogenetically related to AOI/Boomerang.

Sillence D., Kozlowski K. Atelosteogenesis I. Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-AtelosteogenesisI.pdf 1

Oto-Palato-Digital Dysplasia type II also has Piepkorn dysplasia, and presently unclassifiable similar pattern of clinical and skeletal anomalies disorders with overlapping phenotype. but shows X-linked dominant inheritance and is due to mutations in the gene encoding filamin A Epidemiology (FLNA). About a dozen cases have been reported from Atelosteogenesis type II (AOII) has similar various populations. humeral and femoral bone shapes but has distinctive and diagnostic chondro-osseous Genetic counseling histopathology. AOII results from mutations in A recurrence risk should be given which the recognises that the disorders in this group are (DTDST). sporadic but germinal cell mosaicism is possible Piepkorn dysplasia shows a similar pattern of with a (presumed) recurrence risk of about 5%. anomalies, but of all bones is more decreased, and the configurement of and Prenatal diagnosis legs is stated to be flipper-like. The cause is Prenatal sonography has a high likelihood of unknown. detecting bone dysplasia. An exact diagnosis can be made postnatally by the observation of Etiology the humeral/femoral tapering and discordant Inheritance is due to heterozygous autosomal ossification of short tubular bones. dominant mutations. All cases have been sporadic although sibling recurrence due to Management including treatment germinal cell mosaicism can possibly occur. The These disorders are perinatally lethal and long majority of cases of Boomerang dysplasia are term respiratory support is unlikely to lead to 46XY phenotypic males whereas the sex ratio in independent survival. Atelosteogenesis I cases is normal. Unresolved questions Clinical description The overlap in phenotypes between Shortening of the trunk and rhizomelic Atelosteogenesis I and Boomerang dysplasia shortening of the extremities, dysmorphic face, suggested that these two disorders are short broad hands and talipes equinovarus are pathogenetically related, and result from the major clinical abnormalities. The distinctive mutations at the same gene locus. Heterozygous face is broad with prominent forehead, FLNB mutations have been reported in AOI. In hypertelorism, saddle nose with bilateral grooves both AOI and Boomerang dysplasia, chondro- at the nasal tip and micrognathia. Non-skeletal osseous histopathology shows dysplastic malformations include cleft palate and reserve zone with giant multinucleated undescended testes. Skeletal survey shows . Atelosteogenesis III is very rare short, distally tapering humeri and femora. but there are sufficient phenotypic similarities to Alternatively humeri or femora may be absent or suggest that AO III represents an allelic disorder show one of a large number of unusual with mild phenotypic expression. This is to be geometrical shapes e.g. spherical, segment or confirmed by the finding of heterozygous FLNB shark’s tooth shapes. There may be bowing of mutations in AO III. the remaining long bones, absent fibulae, References moderate platyspondyly with coronal cleft Krakow D, Robertson SP, King LM, Morgan T, vertebrae and discordant ossification of the short Sebald ET, Bertolotto C, Wachsmann-Hogiu S, tubular bones, specifically discordant ossification Acuna D, Shapiro SS, Takafuta T, Aftimos S, Kim of distal phalanges with delay in ossification of CA, and 13 others. Mutations in the gene middle and proximal phalanges. encoding filamin B disrupt vertebral segmentation, Diagnostic methods joint formation and skeletogenesis. Nature Both anteroposterior (AP) and lateral Genetics 2004;36:405-410. radiographs of the fetal spine are valuable. Sillence D, Kozlowski K, Rogers J, Sprague P, Specific views of hands and upper and lower Cullity G, Osborn R. Atelosteogenesis: evidence limbs permit definitive characterization of each for heterogeneity. Pediatric Radiology 1987;17: entity in the AOI/Boomerang spectrum of 112-118. disorders. Disharmonious maturation of the Sillence DO, Worthington S, Dixon J, Osborn R, tubular bones of the hands is an important Kozlowski K. Atelosteogenesis syndromes. A diagnostic feature. Perinatal pathologic review with comment on their pathogenesis. examination is mandatory as the pattern of Pediatric Radiology 1997;27:388-39. chondro-osseous pathology permits definitive distinction between AOI/Boomerang, Atelosteogenesis II, Otopalatodigital syndrome,

Sillence D., Kozlowski K. Atelosteogenesis I. Orphanet encyclopedia, November 2004. http://www.orpha.net/data/patho/GB/uk-AtelosteogenesisI.pdf 2