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Case Report

Primary Upper Extremity Lymphedema Caused by a CELSR1 Variant

Sudduth, Christopher L.a; Smits, Patrick J.a; Cheng, Yu Shenga; Schmitz-Abe, Klausb; Agrawal, Pankajb; Greene, Arin K.a

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Journal of Vascular Anomalies: June 2022 - Volume 3 - Issue 2 - p e041
doi: 10.1097/JOVA.0000000000000041
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Primary idiopathic lymphedema has a prevalence of 1 of 100,000 persons.1 The legs are almost always affected; only 10% of patients with primary lymphedema have upper extremity disease.2 Although pathogenic germline variants in 30 genes are associated with a malformed lymphatic system causing lower extremity or generalized lymphedema, no variants have been associated with nonsyndromic, nongeneralized upper extremity disease.2 The purpose of this investigation was to identify novel causes of primary upper limb lymphedema.

Case report

A 17-year-old male presented to our lymphedema program with right upper extremity swelling since 9 months of age (Figure 1). The patient had suffered 12 episodes of cellulitis in the affected arm. At 19 years of age, he developed swelling of his right leg. He was otherwise healthy with a negative medical history. His maximum body mass index was 21 kg/m2, and he had no physical examination signs of syndromic or generalized lymphedema (e.g., distichiasis, abnormal nails, facial abnormalities, intellectual disability, intestinal lymphangiectasia, pleural effusions, ascites). His family history was significant for right lower extremity lymphedema in his mother. A diagnosis of right arm lymphedema was made by history, physical examination, and lymphoscintigraphy.3

Figure 1.:
Autosomal dominant CELSR1 variant causes nonsyndromic upper extremity lymphedema. A, Swelling of the right arm at 9 months of age. B, Persistent right arm edema at 9 years of age. C, Age 19 years with new-onset right leg swelling. D, Upper extremity lymphoscintigram at 17 years of age shows absence of radiolabeled tracer uptake into the right axillary nodes. E, Lower limb lymphoscintigram at 19 years of age illustrates absence of radiolabeled tracer uptake into the right inguinal nodes.

Genomic DNA was extracted from the blood of the patient and mother using DNeasy Blood and Tissue Kit (Qiagen, Hilden, Germany). Whole-exome sequencing (WES) was performed on the patient’s DNA (Psomagen, Rockville, MD). Libraries were made with Agilent SureSelectXT Human All Exon V5 and sequenced on Illumina NovaSeq6000 S4 to generate paired-end, 150 bp reads. A mean coverage of 290× was obtained and 99.4% of exons were covered at greater than 10×. Generated reads were aligned to the human genome reference (assembly GRCh37/hg19). Variants were called and annotated using the Codified Genomics and Variant Explorer pipelines.4 Sanger sequencing was used to confirm variants identified by WES. PCR primers were designed flanking exon 3 of the human Celsr1 gene (FP: 5′-cagggtctgcgacaggctcgttg-3′; RP: 5′-cacggaggacatcaacgtcacgatcas-3′). PCR amplification of a 405 bp fragment was done with CloneAmp polymerase (Takara) using the blood extracted DNA of patient and mother. The PCR fragments were cloned using the zero-blunt-TOPO kit (Invitrogen), and the TOPO reactions were transformed in Stellar competent bacteria (Takara). Plasmids were prepared from 10 individual colonies each for the patient and his mother and sequenced with T7 (Eton Biosciences).

In the patient’s white blood cell DNA, WES identified a frameshift deletion resulting in a premature stop codon in exon 3 of the CELSR1 gene hg19: chr22:46,835,160_46,835,166del (c.4326_4332del; p.T1443Gfs*14). The variant was absent from gnomAD and ExAC databases and deemed pathogenic (PVS1, PP4, PM2) based on ACMG Standards and Guidelines.5 A second point variant (c.A4336G; p.S1446G) also was found, which was of uncertain significance. Sanger sequencing confirmed the variants in the patient and showed that they are in cis. The same variants were also identified in the mother’s white blood cell DNA using Sanger sequencing.


Almost all of the approximately 30 known lymphedema-associated variants cause lower extremity disease.2,6-8 Variants resulting in primary upper extremity lymphedema have been found in syndromic conditions or in genes causing generalized lymphatic dysplasia: 45 XO, CCBE1, GJC2, PIEZ01.7,9-13 In this report, we show that an autosomal dominant germline frameshift deletion in CELSR1 causes nonsyndromic upper and lower extremity lymphedema without generalized lymphedema.

A role for CELSR1 in the pathogenesis of primary arm lymphedema is supported by evidence that CELSR1 variants cause autosomal dominant lower extremity disease.14-16 The lymphedema phenotypes associated with CELSR1 variants reported to date only involve the lower extremity, most commonly affect females, and exhibit incomplete or delayed penetrance in males. These CELSR1 variants are loss of function and include as follows: (1) p.E290*, (2) p.N681Mfs*16, (3) p.I1708fs*44, (4) p.W1957*, (5) c.5226 + 2T>A, (6) c.5702–1G>C, and (7) c.6739 + 1G>A.14-16 It has been hypothesized that upper and lower extremity lymphedema associated with 22q13.3 deletion syndrome (Phelan-McDermid) may result from CELSR1 inactivation because this gene is located on the same chromosome.17CELSR1 has been shown to influence the development of lymphatic valves.18


We hypothesized that primary arm lymphedema in a nonsyndromic patient without generalized lymphedema might result from a variant in a unique gene. We found, however, that a gene known for lower limb lymphedema (CELSR1) also can cause upper extremity disease.14-16 Arm involvement only comprises 10% of patients with primary lymphedema and 50% of these individuals also have the disease in their legs.2 Consequently, patients with primary arm lymphedema may represent a more severe phenotype of lower extremity disease-causing variants. The legs may be more susceptible than the arms to exhibiting edema because lymph fluid has a longer distance to travel against gravity to the venous circulation at the base of the neck. Alternatively, other modifying factors such as anatomical variation or trigger events may be responsible for upper extremity disease. CELSR1 should be included in variant screening for patients with nonsyndromic primary upper limb lymphedema.


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arm; CELSR1; primary; lymphedema; variant

Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.