Spondyloepimetaphyseal Dysplasia, Krakow Type

A number sign (#) is used with this entry because of evidence that the Krakow type of spondyloepimetaphyseal dysplasia (SEMDK) is caused by homozygous mutation in the SIK3 gene (614776) on chromosome 11q23.

Description

Krakow-type spondyloepimetaphyseal dysplasia is characterized by severe skeletal dysplasia, severe immunodeficiency, and developmental delay (Csukasi et al., 2018).

Clinical Features

Csukasi et al. (2018) reported 2 sibs (R07-429A and R07-429B) from a consanguineous family with spondyloepimetaphyseal dysplasia characterized by rhizomelia and mesomelia with significant anterior bowing of all limbs. Neither sib ever walked, and both were wheelchair bound, unable to bear weight on the lower extremities. Radiographic features included widened/flared metaphyses with irregular ossifications, moth-eaten long bones, fragmentation of the proximal metacarpals, rounded vertebral bodies, and a distinctive transverse gap in the tibiae. The sibs had significant developmental delay with abnormalities on brain MRI, as well as a severe unclassified immunodeficiency, and normal PTH levels with mild hypercalcemia. One sib showed a more severe phenotype, particularly of the immune system, and died of an Epstein-Barr virus-induced small-muscle cancer at 10 years of age. Her sib was alive at 14 years of age. The authors noted similarities between this skeletal dysplasia and metaphyseal chondrodysplasia of the Jansen type (MCDJ; 156400), but stated that the sibs exhibited unique features that did not match any of the currently classified skeletal disorders.

Molecular Genetics

In 2 sibs with SEMD, immunodeficiency, and developmental delay, who were negative for mutation in the PTH1R gene (168468), Csukasi et al. (2018) performed exome sequencing and identified homozygosity for a missense mutation in the SIK3 gene (R129C; 614776.0001) that segregated with disease in the consanguineous family.

Pathogenesis

Csukasi et al. (2018) analyzed cells from patients with SEMDK and controls and demonstrated that SIK3 is an essential positive regulator of mTOR (601231) signaling that functions by triggering DEPTOR (DEPDC6; 612974) degradation in response to PTH (168450)/PTHRP (168470) signaling during skeletogenesis. The authors also studied chondrocytes from patients with MCDJ, who exhibit skeletal features similar to those seen in SEMDK, and observed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 (see 601231) activity, indicating a common mechanism of disease for the 2 disorders.