10.5826/dpc.1303a132
Introduction: Lymphedema often presents as progressive, unremitting swelling and skin changes that are extremely distressing to patients. Hereditary lymphedema (HL) constitutes a type of primary lymphedema that is passed down through generations. 
Objectives: The primary aims of this narrative review are to illustrate a framework to distinguish lymphedema from other causes of swelling and to differentiate the hereditary lymphedemas from each other. 
Results: A literature search was undertaken using relevant search terms. The articles were evaluated to generate a diagnostic algorithm to approach the swelling of an extremity using clinical and laboratory data. First, the stemmer sign should be evaluated. If it is negative, other causes should be considered. History and additional physical exam findings suggest either a primary or secondary cause of lymphedema. 
Conclusions: The hereditary lymphedemas have been classified by age of onset and then stratified by clinical criteria and genetic testing. 
text/xml
2160-9381
2752
en
Neda Nikbakht
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
lymphedema praecox
A Practical Approach to the Diagnosis of Lymphedema: a Narrative Review
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-07-31
2022-09-19
2023-07-31
2023-08-24
e2023132
Dermatol Pract Concept
Introduction: Lymphedema often presents as progressive, unremitting swelling and skin changes that are extremely distressing to patients. Hereditary lymphedema (HL) constitutes a type of primary lymphedema that is passed down through generations. 
Objectives: The primary aims of this narrative review are to illustrate a framework to distinguish lymphedema from other causes of swelling and to differentiate the hereditary lymphedemas from each other. 
Results: A literature search was undertaken using relevant search terms. The articles were evaluated to generate a diagnostic algorithm to approach the swelling of an extremity using clinical and laboratory data. First, the stemmer sign should be evaluated. If it is negative, other causes should be considered. History and additional physical exam findings suggest either a primary or secondary cause of lymphedema. 
Conclusions: The hereditary lymphedemas have been classified by age of onset and then stratified by clinical criteria and genetic testing. 
Neda Nikbakht
2023/07/31
10.5826/dpc.1303a132
e2023132
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
2160-9381
lymphedema praecox
en
e2023132
Erickson RP, Lai LW, Mustacich DJ, Bernas MJ, Kuo PH, Witte MH. Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family. Clin Genet. 2019;96(5):478-482. DOI: 10.1111/cge.13622. PMID: 31403174.
A Practical Approach to the Diagnosis of Lymphedema: a Narrative Review
https://dpcj.org/index.php/dpc/article/download/2752/2239
               A Practical Approach to the Diagnosis of
                  Lymphedema: A Narrative Review
                        Lauren Banner1, Alexa Cohen1, Viral Patel1, Neda Nikbakht1


1 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA



Key words: Lymphedema, meige syndrome, diagnosis, lymphedema praecox
Citation: Banner L, Cohen A, Patel V, Nikbakht N. A Practical Approach to the Diagnosis of Lymphedema: A Narrative Review. Dermatol
Pract Concept. 2023;13(3):e2023132. DOI: https://doi.org/10.5826/dpc.1303a132
Accepted: January 4, 2023; Published: July 2023
Copyright: ©2023 Banner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Neda Nikbakht, MD, PhD, FAAD, Assistant Professor of Dermatology
Director, Cutaneous Lymphoma Clinic, Department of Dermatology and Cutaneous Biology
Thomas Jefferson University, 233 S. 10th Street, Rm 409, Philadelphia, PA 19107 E-mail: Neda.nikbakht@jefferson.edu




  ABSTRACT             Introduction: Lymphedema often presents as progressive, unremitting swelling and skin changes
                       that are extremely distressing to patients. Hereditary lymphedema (HL) constitutes a type of primary
                       lymphedema that is passed down through generations.
                       Objectives: The primary aims of this narrative review are to illustrate a framework to distinguish
                       lymphedema from other causes of swelling and to differentiate the hereditary lymphedemas from each
                       other.
                       Results: A literature search was undertaken using relevant search terms. The articles were evaluated to
                       generate a diagnostic algorithm to approach the swelling of an extremity using clinical and laboratory
                       data. First, the stemmer sign should be evaluated. If it is negative, other causes should be considered.
                       History and additional physical exam findings suggest either a primary or secondary cause of lymph-
                       edema.
                       Conclusions: The hereditary lymphedemas have been classified by age of onset and then stratified by
                       clinical criteria and genetic testing.




Review | Dermatol Pract Concept. 2023;13(3):e2023132                                                                                1
Introduction                                                     While lymphedema tends to be a clinical diagnosis, aware-
                                                                 ness of genetic studies can provide additional information.
Lymphedema is a manifestation of lymphatic dysfunction           We present a narrative review of HL with primary aims of
presenting primarily as swelling of an extremity due to the      illustrating a framework to distinguish lymphedema from
accumulation of lymphatic fluid [1]. The diseased lymphatic      other causes of swelling and to differentiate the hereditary
system slows uptake and decreases flow of interstitial fluid     lymphedemas from one another.
resulting in buildup of lymphatic fluid [2]. As the disorder
progresses, the skin thickens and hardens [1]. The often pro-
gressive and unremitting swelling and skin changes can be
                                                                 Methods
extremely distressing to patients. Primary lymphedema refers     Literature Search
to processes that result from intrinsic damage to lymphatic
                                                                 Relevant articles were included regardless of the date pub-
structures [1]. Hereditary lymphedema (HL) constitutes a type
                                                                 lished. Using PubMed and the OMIM genetic library. En-
of primary lymphedema that is passed down through gener-
                                                                 glish language was a criterion for inclusion. The primary
ations [1]. One of the known etiologies of its pathogenesis is
                                                                 interests were the genetic basis and clinical manifestations
primarily driven by dysfunctions in the VEGFR-3 signaling
                                                                 of HL. Specific reviews and cohort studies on the diagnos-
axis, which is involved in lymphangiogenesis [2]. Secondary or
                                                                 tic workup were included if they provided useful additional
acquired lymphedema indicates an underlying pathology that
                                                                 evidence. The initial search was narrowed based on titles
damages the lymphatic tissue [1]. While secondary lymph-
                                                                 and abstracts given their relevance to research questions.
edema is more common, affecting 200 million people in the
                                                                 Cited articles within these identified manuscripts were also
world, HL has an estimated prevalence of 0.001% [1].
                                                                 considered.
    HL has been classified in various ways since it appeared
                                                                    Within the PubMed database (1935-2022), there were
in the medical literature. Until recently, lymphedema pres-
                                                                 4,465 manuscripts in the literature that pertained to the di-
ent at birth was designated Milroy disease, and adolescent
                                                                 agnosis of hereditary lymphedema. The initial search was
onset lymphedema was referred to as Meige Disease [3].
                                                                 narrowed to 1,089 results to focus on manuscripts published
Given the reported heterogeneity of these syndromes and
                                                                 in the last five years. Articles were preliminarily omitted if
new advances in analyzing genetic data, subsequent articles
                                                                 the focus was on treatment, cancer, or post-operative lymph-
characterized lymphedema by age of onset: congenital (be-
                                                                 edema. Thirty-nine relevant articles and their references were
fore age 1 year), praecox (ages 2-35 years), and tarda (after
                                                                 initially identified and reviewed to generate the backbone for
35 years) [1] and specific diseases were assigned to each of
                                                                 the diagnostic algorithm. We also searched for lymphedema
these groups. Lymphedema congenita and praecox can be ei-
                                                                 praecox which yielded 66 results of which 14 relevant ar-
ther syndromic and non-syndromic [1]. Lymphedema tarda
                                                                 ticles and their references were interrogated. In addition,
is thought to be triggered by prior infection or trauma [1].
                                                                 the OMIM database was searched for the primary hered-
It is also important to consider the complications of chronic
                                                                 itary lymphedemas: Milroy or Milroy-like lymphedema,
lymphedema such as skin changes, infections, malignancies
                                                                 hereditary lymphedema 1B, Meige lymphedema, hereditary
and psychological effects. Elephantiasis nostra verrucosa
                                                                 lymphedema type 1C, lymphedema-distichiasis syndrome,
(ENV), for example, is a severe edematous skin change
                                                                 yellow nail syndrome, primary lymphedema with myelodys-
resulting from longstanding lymphedema [4,5]. This can
                                                                 plasia or Emberger syndrome, hypotrichosis-lymphedema-
negatively impact the quality of life of patients as the limb
                                                                 telangiectasia syndrome which yielded 72 references. In
disfiguration is uncomfortable, functionally challenging, and
                                                                 total, 120 articles were considered in this work.
cosmetically unpleasant. Additionally, both congenital and
acquired lymphedema have been associated with benign vas-
cular neoplasms such as spindle cell hemangioma (SCH) and        Results
malignant angiosarcoma [6-10]. Unfortunately, there is no
curative treatment for primary lymphedema, only palliative       Diagnostic Approach to Swelling of an Extremity
strategies [11,12]. Lymphedema and its sequelae provide di-      Ruling out Other Causes of Edema
agnostic challenges, as they are rare and have several chal-     Lymphedema is often misdiagnosed due to its mimicry of
lenging differential diagnoses.                                  other conditions. A decision tool was developed by the au-
                                                                 thors to assist in diagnosing swelling in an extremity (Figure 1).

Objectives                                                       Lymphedema is more likely in patients with a positive
                                                                 Stemmer sign, which is the inability to pinch the skin on
There is a clear need for a systematic diagnostic approach       the dorsum of the second toe [13]. A study on the Stem-
that considers the current classifications of lymphedema.        mer sign showed the sensitivity to be high at 92% and the



2                                                                            Review | Dermatol Pract Concept. 2023;13(3):e2023132
                                                                                                                                                           Lipedema, Venous
                                                                                                                                                            disease, obesity,
                                                  Swelling of an                                                            Consider other
                                                                                       Stemmer sign           Negative                             Yes           CCBs,
                                                    extremity                                                                  causes
                                                                                                                                                           hypoalbuminemia,
                                                                                                                                                               myxedema
                                                                                         Positive


                                                                                       Lymphedema




                                                                                                                                                              Infection,
                                                                                                                                  History
                                                                                                                                                           malignancy, silica
                                                                                  Secondary causes                No        and physical exam      Yes
                                                                                                                                                             microparticle
                                                                                                                                 findings
                                                                                                                                                           exposure, obesity

                                                                                           Yes


                                                                                          Primary
                                                                                       lymphedema




                                                                                        Onset > 35                Yes        Lymphedema
                                                                                          years                                 tarda

                                                                                           No
                                                                                                                                                                                        Lymphedema-
                                                                                                                                                                                          Distichiasis
                                                                                        Onset 2-35
                                                                                                                                                                                          Syndrome
                                                                                          years


                                                                                  No                  Yes
                                                                                                                                                              Distichiasis
                                                                                                                                                                                                Primary
                                                                                                                                                                                            Lymphedema w/
                                                                     Congenital                             Lymphedema                                                                       Myelodysplasia
                                                                   lymphedema                                 praecox
 Congential syndromic                                                                                                                                                 AML / MDS
   lymphedema i.e.
  Noonan syndrome.
  Tuberous Sclerosis,               History                                                                                                                                                               Hereditary
   Turner syndrome,     Yes   and physical exam          Yes       Syndromic?                                Syndromic?       Yes               Features                        All 4 limbs a ected      Lymphedema
      Cholestasis                  findings                                                                                                                                                                Type 1C
     Lymphedema
                                                                       No                                        No
     syndrome etc.                                                                                                                                                  Hypotrichicosis
                                                                     Genetic                                Meige disease
                                                                     testing                                                                                                                Hypotrichosis-
                                                                                                                                                                                            Lymphedema-
                                                                                                                                                                                            Telangiectasia
                                                                                                                                                              Yellow Nails


                                                  VEGFR3             Neither                 VEGFC

                                                                                                                                                                                          Yellow Nail
                                                                    Hereditary                                                                                                            Syndrome
                                               Milroy                                      Milroy - Like
                                                                   Lymphedema
                                            Lymphedema                                    Lymphedema
                                                                          1B



Figure 1. Approach to swelling of an extremity.



specificity to be moderate at 57% for accurately detecting                                                    lymphoscintigraphy [14]. However, an ultrasound of the
lymphedema [13]. Other causes of edema such as lipedema,                                                      swollen extremity may be recommended to rule out a deep
venous disease, hypoalbuminemia, myxedema, infection,                                                         vein thrombosis [14].
and morbid obesity can also be ruled out with a thorough
history including familial conditions and laboratory results                                                  Categorization and Genetic Basis of Lymphedema
such as CBC, albumin, and TSH [1,11]. A blood smear to                                                        Once the diagnosis of lymphedema is established, the type
detect microfilaria may have utility if the patient has trav-                                                 of lymphedema should be determined. Secondary causes of
eled to an endemic area [11]. If there is no other obvious                                                    lymphedema such as infection, malignancy, podoconiosis,
cause of extremity swelling and suspicion for lymphedema                                                      and morbid obesity can be revealed via careful history and
is high even with a negative Stemmer sign, lymphoscintig-                                                     physical examination [1,11]. The hereditary lymphedemas
raphy may be considered, but it may have limited clinical                                                     can be categorized into age of onset: congenital (age < 2),
utility [1,11,14]. Other diagnostic studies include magnetic                                                  praecox (ages 2-35), and tarda (age > 35) [1]. These divi-
resonance imaging, ultrasonography, and bioimpedance                                                          sions can be further subdivided. In congenital lymphedema,
spectroscopy [11,14]. While bioimpedance spectroscopy is a                                                    there are three non-syndromic types and a multitude of syn-
non-invasive technique that has resulted in early detection of                                                dromes that are beyond the scope of this paper [1,2]. The
breast cancer related lymphedema, it is not widely available                                                  three congenital non-syndromic lymphedema syndromes
because it is considered investigational [11]. A recent study                                                 are Milroy lymphedema (HL1A), Milroy-like lymphedema
evaluated the diagnostic workup in diagnosing 49 adoles-                                                      (HL1D), and Hereditary lymphedema 1B (HL1B) [1]. Mil-
cents with lymphedema praecox with clinical exam alone,                                                       roy lymphedema is caused by either a missense or inactiva-
doppler ultrasound, MRI, lymphoscintigraphy, and X-ray                                                        tion mutation of vascular endothelial growth factor receptor
either alone or combined [14]. The diagnosis of lymphedema                                                    3 (VEGFR3) tyrosine kinase [15,16]. It may be inherited in
praecox did not change with additional imaging including                                                      an autosomal dominant (AD), autosomal recessive (AR), or



Review | Dermatol Pract Concept. 2023;13(3):e2023132                                                                                                                                                                   3
de novo fashion [15]. The onset of swelling is at birth, and     remarked on the heterogeneity of the disease with features
the lymphedema is confined to the lower extremities, which       such as distichiasis, ptosis, and yellow nails [28]. In the
contain wide caliber veins. Secondary changes include deep       last two decades, the lymphedema syndromes of pubertal
creases within toes, curved and brittle toenails, papilloma-     onset have been separated by genetic and clinical features
tosis, chronic venous ulcers, hydrocele, and cellulitis [16].    [1,12,23]. Meige disease classically presents with bilateral
HL1D has similar features to HL1A; however, the mutation         lower extremity lymphedema in the absence of other syn-
is VEGF-C rather than VEGFR [17]. HL1B is clinically simi-       dromic features [1,23]. Unilateral lymphedema may also
lar to HL1A and HL1D with a few key differences. The loca-       occur [23]. Like all lymphedemas, Meige disease may be
tion of the associated gene has been narrowed to loci 6q16.2     complicated by infections such as cellulitis or erysipelas [1].
– q22.1; however, a candidate gene FOXO3 was not impli-          The pathogenesis of the delayed onset has been proposed to
cated in the disease based on a 2008 study [18]. HL1B is dis-    be due to either a secondary infection or trauma, exposing
tinct, progressing from the onset of lymphedema at birth to      the underlying lymphatic defect, or attributed to a hormonal
papillomas and itching in childhood and early adolescence,       effect, as symptoms predominately begin occurring in pubes-
shrunken papillomas and scarring with keratinized hairless       cent or pregnant females [29].
skin in adulthood, and finally, reduction in lymphedema in           While genetic testing is not needed to distinguish the
ages 40-45 [18]. These non-syndromic congenital lymphede-        praecox syndromes, it may have a role in confirming the di-
mas are most definitively differentiated with genetic testing.   agnosis or for research purposes. LDS is typically inherited
    There are six currently identified conditions that con-      in an AD or de novo manner with variable penetrance and
stitute lymphedema praecox. Of the six, only Meige dis-          is due to a loss of function (LOF) mutation in FOXC2 [20-
ease is non-syndromic. Hereditary lymphedema type IC             22]. HL1C is an AD missense mutation in GJC2 [19]. HLTS
(HLIC), lymphedema-distichiasis syndrome (LDS), yellow           is an AD or AR LOF mutation in SOX18 [24,25]. YNS is
nail syndrome (YNS), primary lymphedema with myelodys-           sporadically inherited; however, the mutation is unknown.22
plasia (Emberger syndrome), and hypotrichosis-lymphedema-        Emberger syndrome is either an AD or de novo LOF muta-
telangiectasia syndrome are the five syndromes which can         tion in GATA2 [26,31].The gene FOXC2 has been ruled out
be differentiated by their distinct features [1]. The presence   as the cause of Meige disease [23].
of edema in all four limbs suggests HLIC [19]; ptosis and            While no gene has been explicitly determined as the cause
secondary eyelash formation leading to corneal abrasions         of Meige disease, CELSR1 was proposed to be implicated in
are seen in LDS [20,21]; and yellow nails and respiratory        hereditary lymphedema [32-34]. A 2016 case report found
tract symptoms indicates YNS [22]. The triad of yellow nails,    that a rare early inactivating mutation in CELSR1 caused
respiratory symptoms, and lymphedema is only present in          non-syndromic hereditary lymphedema in seven individuals
27-60% of patients, and the complete triad of YNS may not        spanning three consecutive generations [32]. Another study
be present at once, increasing the diagnostic difficulty [22].   analyzed 95 probands for the CELSR1 gene [33].Ten pa-
The color of the nails in YNS is yellow/green with increased     tients had a loss of function mutation. Four patients had
curvature, onycholysis, shedding, cross-ridging, and loss of     progressive or relapsing lymphedema with no other symp-
lunulae and cuticles [23]. The nails grow thicker but less       toms reported [33]. One patient’s presentation was consis-
rapid longitudinally [22]. This is distinct from the yellow      tent with Noonan syndrome [33]. The remaining five had
discoloration seen in many lymphedema syndromes. As any          no phenotypic of lymphedema. In all but one case, the age of
form of lymphedema may have yellow nails as a nonspecific        onset was prior to 35 years [33]. Based on the two studies,
feature, the specific appearance of the yellow nails must be     the inheritance pattern appears to be autosomal dominant
observed to definitively diagnose YNS [23]. Another lymph-       with incomplete penetrance and variable expressivity [32,
edema praecox syndrome is Hypotrichosis-lymphedema-              33]. In the second study, five out of six females with the
telangiectasia syndrome (HLTS). It is associated with vascu-     CELSR1 gene developed lymphedema, but only one out of
lar malformations including aortic dilation, cutaneous telan-    four males developed lymphedema and did so later in life
giectasias, and defects in hair follicle development; however,   [33]. A third manuscript supported the female driven pene-
lymphedema is not always present [24,25]. Finally, Emberger      trance of the gene. All females with the variant had lymph-
syndrome is the presence of myelodysplasia with or without       edema, and all males with the variant served as carriers with
congenital deafness in patients with lymphedema [26].            none developing lymphedema [34]. This inheritance pattern
    Non-syndromic Meige disease (Hereditary lymphedema           is consistent with the higher predominance of lymphedema
type II), the most common form of primary lymphedema,            praecox in females [23]. Further studies are needed to pro-
was first written about in 1898 [27]. Subsequent reports         vide a convincing link between this gene and Meige disease
of the disease defined it as pubertal onset lymphedema and       specifically.




4                                                                            Review | Dermatol Pract Concept. 2023;13(3):e2023132
           Table 1. Pathogenesis, genetic basis, and clinical features of lymphedema [1,2, 15-30]
                                       Genetic basis                    Key features                   Category         Pathogenesis
 Milroy Lymphedema                    FLT4                Non-syndromic                             Congenital          Primary
 (Hereditary Lymphedema               (VEGFR3)                                                      Lymphedema
 Type 1A)
 Hereditary Lymphedema                Unknown             Non-syndromic.
 Type 1B                                                  Disease occurs in four stages
 Milroy-like Lymphedema               VEGFC               Non-syndromic
 (Hereditary Lymphedema
 Type 1D)
 Congenital lymphedema                Varies              Specific to syndrome
 syndromes
 Meige disease (Hereditary            Unknown             Non-syndromic                             Lymphedema
 Lymphedema Type II)                                                                                Praecox
 Lymphedema Distichiasis              FOXC2               Ptosis, secondary eyelash formation
 Syndrome                                                 and corneal abrasions
 Primary Lymphedema with              GATA2               Myelodysplasia, congenital deafness
 Myelodysplasia (Emberger                                 may be present
 Syndrome)
 Hereditary Lymphedema                GJC2                Lymphedema in 4 limbs
 Type 1C
 Hypotrichosis-Lymphedema-            SOX18               Vascular malformations including
 Telangiectasia                                           aortic dilation and cutaneous
                                                          telangiectasias, hypotrichosis
 Yellow Nail Syndrome                 Unknown             Triad of yellow/green nails,
                                                          respiratory symptoms, and
                                                          lymphedema
 Lymphedema Tarda                     N/A
 Obesity                              N/A                                                           Secondary
 Infection                            N/A
 Malignancy                           N/A
 Microparticles                       N/A
N/A = Not applicable.


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                                                                          5. Sisto K, Khachemoune A. Elephantiasis nostras verrucosa:
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                                                                             dothelioma: a clinicopathological and immunohistochemical
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