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Short Rib Thoracic Dysplasia With or Without Polydactyly


Introduction

The short-rib polydactyly syndromes (SRPSs) are a genetically heterogeneous group of autosomal recessive skeletal disorders. Characteristic findings in SRPS include short horizontal ribs, shortened appendicular long bones limbs, and polydactyly. Historically, four distinct SRPS types have been recognized :

  • SRPS I (Saldino-Noonan syndrome)

  • SRPS II (Majweski syndrome)

  • SRPS III (Verma-Naumoff syndrome)

  • SRPS IV (Beemer-Langer syndrome)

Currently the SRPSs are classified as “ Ciliopathies with major skeletal involvement ” and this group of disorders also includes chondroectodermal dysplasia (Ellis–van Creveld syndrome or EVC), oral-facial-digital syndrome type 4 (Mohr-Majewski syndrome), and asphyxiating thoracic dystrophy (ATD or Jeune syndrome). While distinct radiographic and clinical features characterize the SRPS subtypes, there is significant phenotypic overlap among them due to transitional findings. SRPSs (types I–IV) are highly associated with lethality because of pulmonary hypoplasia and respiratory compromise; live-born infants usually die shortly after birth.

Disorder

Definition

SRPSs are defined by radiographic findings that include long narrow thoraces with horizontal ribs, shortened appendicular bones, often associated with hypoplastic or poorly formed bones, polydactyly, and frequently other concomitant organ system abnormalities. Similar to other Mendelian disorders that result from alterations in cilia function, multiorgan system abnormalities are common.

Prevalence and Epidemiology

Because of the rarity of this disorder, the exact incidence is unknown, though it is estimated that the frequency is 1 : 100,000 to 1 : 130,000 live births. It is well established that these disorders are autosomal recessive.

Etiology

SRPS transmission is autosomal recessive. All four SRPS types and Jeune syndrome have considerable overlap. Molecular analysis has shown both allelic and locus heterogeneity; thus mutations in the same gene can produce a wide spectrum of phenotype from immediate newborn lethality to long-term survivors.

The SRPS disorders share a narrow thorax, micromelia, polydactyly, and frequently visceral abnormalities. Jeune syndrome or ATD is very similar to SRPS type III; however, the clinical and radiographic findings are somewhat less severe.

Advances in molecular genetics have identified numerous genes responsible for SRPS including DYNC2H1 , DYNC2LI1, NEK1 , IFT140 , EVC 1, EVC2 , KIAA0586 , CEP120 , WDR19, WDR34, WDR35, WDR60, TTC21B , IFT172 , IFT80 , IFT52, IFT81, ICK, INTU, and C21ORF2 . These genes are thus candidate genes for at-risk families that can aid in prenatal diagnosis. However, cases remain that are not due to these genes, which can make molecular diagnosis challenging. However, mutations in DYNC2H1 are the most common molecular cause for the SRPS and account for about 40% of the cases. The term skeletal ciliopathies is used for these disorders because the aforementioned genes all have a profound effect on the function of the cilia.

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