Ureteropelvic junction obstruction with primary lymphoedema associated with CELSR1 variants.

BACKGROUND: Primary lymphoedema (PL) is a chronic, debilitating disease caused by developmental and functional defects of the lymphatic system. It is marked by an accumulation of interstitial fluid, fat and tissue fibrosis. There is no cure. More than 50 genes and genetic loci have been linked to PL. We sought to study systematically cell polarity signalling protein Cadherin Epidermal Growth Factor Laminin G Seven-pass G-type Receptor 1 (CELSR1) variants linked to PL. METHODS: We investigated 742 index patients from our PL cohort using exome sequencing. RESULTS: We identified nine variants predicted to cause CELSR1 loss of function. Four of them were tested for nonsense-mediated mRNA decay, but none was observed. Most of the truncated CELSR1 proteins would lack the transmembrane domain, if produced. The affected individuals had puberty/late-onset PL on lower extremities. The variants had a statistically significant difference in penetrance between female patients (87%) and male patients (20%). Eight variant carriers had a kidney anomaly, mostly in the form of ureteropelvic junction obstruction, which has not been associated with CELSR1 before. CELSR1 is located in the 22q13.3 deletion locus of the Phelan-McDermid syndrome. As variable renal defects are often seen in patients with the Phelan-McDermid syndrome, CELSR1 may be the long-sought gene for the renal defects. CONCLUSION: PL associated with a renal anomaly suggests a CELSR1-related cause.

Skin Layer Thickness and Shear Wave Elastography Changes Induced by Intensive Decongestive Treatment of Lower Limb Lymphedema.

Background: A detailed quantitative evaluation would be beneficial for management of patients with limb lymphedema. Methods and Results: In 47 patients with lower limb lymphedema at International Society of Lymphology clinical stage 2A (18 limbs), 2B (41 limbs), and 3 (13 limbs), we measured the limb circumference and thickness of epidermis, dermis, and subcutis layers with B-mode ultrasonography and subcutis elastic modulus with ultrafast shear wave velocity (ultrasound elastography) at 5 anatomical levels (M1 to M5) before and after a 3- to 5-day intensive decongestive therapy (IDT) session. Limb circumference and thickness of the epidermis, dermis, and subcutis were greater in the 72 limbs with lymphedema than in the 22 unaffected limbs before and after IDT. The affected limb volume was 10,980 [8458-13,960] mL before and 9607 [7720-11,830] mL after IDT (p < 0.0001). The IDT-induced change in subcutis thickness was -9 [-25 to 13]% (NS), -11 [-26 to 3]% (p = 0.001), -18 [-40 to -1]% (p < 0.0001), -15 [-35 to 3]% (p = 0.0003), and -25 [-45 to -4]% (p < 0.0001) and significantly correlated with the change in elastic modulus, which was 13 [-21 to 90]% (p = 0.004), 33 [-27 to 115]% (p = 0.0002), 40[-13 to 169]% (p < 0.0001), 9 [-36 to 157]% (p = 0.024), and -13 [-40 to 97]% (NS), respectively, at the M1, M2, M3, M4, and M5 levels. Intraobserver reproducibility was satisfactory for skin thickness and fairly good for elastography, but interobserver reproducibility was poor or unacceptable. Conclusions: IDT reduced the circumference and subcutis thickness of lower limbs with lymphedema and increased their elastic modulus, implying greater tissue stiffness probably due to fluid evacuation. Although subcutis thickness measurement proved to be reliable, technological and methodological improvements are required before ultrasonographic elastography can be used in clinical practice.