Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1.

Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6atm1d/+. We show that Kdm6atm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6atm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a-/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a+/+ controls. RNA-seq showed that Kdm6a-/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d-/- and Kdm6a-/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice.

Kabuki syndrome 1 (KS1) is a Mendelian disorder of the epigenetic machinery caused by mutations in the gene encoding KMT2D, which methylates lysine 4 on histone H3 (H3K4). KS1 is characterized by intellectual disability, postnatal growth retardation, and distinct craniofacial dysmorphisms. A mouse model (Kmt2d+/ßGeo) exhibits features of the human disorder and has provided insight into other phenotypes; however, the mechanistic basis of skeletal abnormalities and growth retardation remains elusive. Using high-resolution micro-CT, we show that Kmt2d+/ßGeo mice have shortened long bones and ventral bowing of skulls. In vivo expansion of growth plates within skulls and long bones suggests disrupted endochondral ossification as a common disease mechanism. Stable chondrocyte cell lines harboring inactivating mutations in Kmt2d exhibit precocious differentiation, further supporting this mechanism. A known inducer of chondrogenesis, SOX9, and its targets show markedly increased expression in Kmt2d-/- chondrocytes. By transcriptome profiling, we identify Shox2 as a putative KMT2D target. We propose that decreased KMT2D-mediated H3K4me3 at Shox2 releases Sox9 inhibition and thereby leads to enhanced chondrogenesis, providing a potentially novel and plausible explanation for precocious chondrocyte differentiation. Our findings provide insight into the pathogenesis of growth retardation in KS1 and suggest therapeutic approaches for this and related disorders.

The cisterna chyli: enhancement on delayed phase MR images after intravenous administration of gadolinium chelate.

PURPOSE: To retrospectively evaluate cisterna chyli (CC) enhancement on magnetic resonance (MR) images obtained after intravenous administration of a gadolinium-based contrast agent. MATERIALS AND METHODS: This retrospective HIPAA-compliant study of 1.5-T MR imaging findings was institutional review board approved; informed patient consent was waived. All MR examinations involved the acquisition of heavily T2-weighted single-shot fast spin-echo (SSFSE) images and three-dimensional (3D) gradient-echo images obtained before and during the arterial, venous, and 3-5-minute delayed phases after intravenous bolus injection of gadopentetate dimeglumine. Included were the data of 59 patients (37 men, 22 women; mean age, 59 years) who had a CC 4 mm or greater in transverse diameter, which was identified as a tubular structure with fluid signal intensity (SI) on SSFSE images. The SI of the CC relative to the spinal canal (SC) was noted and was measured on 3D gradient-echo images obtained during all phases. The Student t test was performed for statistical evaluations. RESULTS: Mean CC-SC SI ratios on nonenhanced, arterial phase, venous phase, and delayed phase images were 0.92, 0.98, 0.99, and 2.13, respectively. The CC had low SI on all 3D gradient-echo images obtained during the nonenhanced, arterial, and venous phases and high SI, similar to the azygos vein SI, on all delayed phase images. The CC-SC SI ratio during the delayed phase was significantly higher than that during the other phases (P<.001). CONCLUSION: The CC has minimal or no enhancement on arterial phase and venous phase images but intense enhancement--similar to the enhancement of veins--on delayed phase images. Comparison of delayed phase images with SSFSE and venous phase images may help to distinguish the CC seen on delayed phase images from lymph nodes, the azygos vein, or esophageal varices.

Adenomyosis:common and uncommon manifestations on sonography and magnetic resonance imaging.

OBJECTIVE: The purpose of this presentation is to show the imaging findings of the common and uncommon variants of adenomyosis as seen on sonography and magnetic resonance imaging (MRI). METHODS: A 3-year database search was performed to identify women who had pelvic sonography and pelvic MRI within a 6-month interval. Images of these cases were retrospectively reviewed. RESULTS: Eighty women were identified. Adenomyosis was diagnosed on MRI, which was used as the reference standard, in 45 of these women. The correct diagnosis was made on sonography in 73% of the cases. CONCLUSIONS: Awareness of the spectrum of imaging features of adenomyosis is important to use sonography effectively for diagnosing this entity and to help avoid misdiagnosis.