Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic

Abstract

Background

Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life.

Methods

Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected.

Results

Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P = .007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P = .001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema.

Conclusions

Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed.

Keywords

lymphedema primary lymphedema pediatric lymphedema genetic of lymphedema syndromic lymphedema isolated lymphedema

Bullets

Pediatric lymphedema is usually primary affecting 1/6000 children.

It may be isolated or associated with internal lymphatic effusions or intestinal lymphangiectasia, other vascular anomalies, and/or a genetic syndrome.

Imaging studies including ultrasound doppler, MRI and lymphoscintigraphy and a multidisciplinary team are optimal.

Compressive garments are essential to therapy.

Complications include cellulitis, paronychia, functional and financial burden, and pain.

Introduction

Lymphedema is the accumulation of protein-rich liquid in the soft tissues of the skin, due to the dysfunction of the lymphatic system, leading to adipose deposition and progressive fibrosis. Lymphedema can be primary, if the defect is from the lymphatic system itself or secondary if it follows an extra-lymphatic pathology (like tumor, infection, obesity, thrombophlebitis) or a surgical procedure.

Primary lymphedema is more frequent in children than adults, and occurs in approximately 1/6000 in the UK,¹ but the literature is sparse. Pediatric lymphedema is a chronic disease with a heavy burden on the child’s quality of life (functional and social impairment).² It affects most often the lower extremities, but also upper extremities, face, and genitalia.

The diagnosis of lymphedema in children is often delayed and must exclude secondary causes. The differential diagnosis of lymphedema includes overgrowth syndrome, edema (which can be due to renal and cardiovascular insufficiency, hypoalbuminemia, venous insufficiency, or inactivity), lipedema, myxedema, and other vascular anomalies. Clinical signs include edema (pitting or non-pitting), loss of the usual sharp definition of the joints, the Stemmer sign, hyperkeratosis, papillomatosis, pigmentary changes, scaling between the digits and nail dystrophy. Evaluation of children with edema of the extremities necessitates also a complete blood count, renal and hepatic functions, thyroid, protein and albumin and, if pertinent, filariasis serology. Useful imaging includes Magnetic Resonance Imaging (MRI), US-doppler and lymphoscintigraphy. Genetic testing is an important part of the diagnostic process.

Twenty-nine genetic mutations have been described so far,³ in isolated primary or syndromic lymphedema. The St George’s Classification of lymphedema distinguish 5 subgroups of primary lymphedema: lymphedema associated with genetic syndromes, lymphedema associated with systemic or internal lymphatic problems, lymphedema associated with vascular anomalies or segmental overgrowth (where the lymphedema is not the predominant problem) and isolated congenital (occurring before 1 year of age) or non-congenital lymphedema.¹

Pediatric lymphedema benefits from evaluation and treatment by a multidisciplinary team (dermatologist, radiologist, nuclear medicine physician, pediatrician, geneticist, physiotherapist, specialized nurse, social worker, and psychologist). Treatment is mainly conservative, with complete decongestive therapy (CDT) consisting of manual lymphatic drainage accompanied by bandaging, compression garments, exercise, and self-care.⁴ Active monitoring is essential to prevent complications such as worsening of the lymphedema, irreversible cutaneous changes and infections.⁵

Considering the paucity of studies of pediatric lymphedema,^6

-9 the purpose of this study is to further describe the differential diagnosis, epidemiology, clinical signs, and symptoms, genetic features, investigation, and response to treatment.

Methods

Medical records of patients below 18 years of age referred to the specialized lymphedema clinic in the Sainte-Justine University Hospital Center (UHC), Montreal, Quebec, Canada were reviewed. Demographic data, sex, age at presentation and at diagnosis, location of the lymphedema, genetic testing, symptoms, complications, investigations, and treatment were collected. All available clinical pictures were reviewed.

Age of onset was classified as follows: congenital lymphedema was defined as lymphedema present at birth or occurring in the first year of life, childhood lymphedema appeared between 1 and 8 years in girls and between 1 and 9 years in boys, and adolescent lymphedema appeared from 9 to 18 years in girls and from 10 to 18 years in boys. “Syndromic lymphedema” gathers the 3 firsts subgroups of the St George’s classification¹ (associated with other genetic syndromes, with systemic or internal lymphatic problems or with vascular anomalies or segmental overgrowth). Outcome was reported following the clinical evaluation of the patient’s record. Functional impairment refers to the patient or the caregivers complaining of inability to perform normal daily activities (walking, sports, social activities), according to the age of the patient.

Data were analyzed using descriptive statistics and proportions were compared using the chi-square test. Age of apparition was compared using the Mann-Whitney U test. Two-tailed values of P < .05 were considered significant. Statistics were performed with the SPSS software package (Release 26.0.0.1; SPSS, Inc., Chicago, Ill.). Approval for the study was obtain from the ethics and scientific committees of the Sainte-Justine UHC.

Results

In total, 180 patients were referred between 1996 and 2021, and lymphedema was confirmed in 151/180 (83.9%).

The mean delay between onset of symptoms (noticed by the patient or parents) and diagnosis of lymphedema was 15.42 months (SD = 24.991, range from 0 to 132 months). 123/151 (81.5%) patients were followed at the lymphedema clinic, and for those, the average follow-up time was 3.76 years (standard deviation (SD) = 4.3320, range 0-17 years).

137/151 (90.7%) children had primary lymphedema. Among them, 88/137 (64.2%) were female. 29/137 (21.2%) had syndromic lymphedema, whereas 108/137 (78.9%) were isolated lymphedema. Median age of appearance of primary lymphedema was 7.00 (SD = 5.907) years, and the mean was 8.00; the mean of 3.98 years in boys, range 0-17 compares to 7.72 years in girls, range 0-17, which is significantly younger (P < .001). Supplemental Table 1 shows the primary lymphedema patients characteristics and clinical features. The most frequent cutaneous changes were accentuation of skin folds at the base of the toes (63 of 113, 55.8%), interdigital desquamation (30/119, 25.2%) and xerosis (30/116, 25.9%). Stemmer sign (inability to pinch the skin of the dorsum of the second toe) was positive in 65/83 (78.3%) and pitting in 64/103 (62.1%). There was no sex predominance among cases of primary congenital lymphedema, though these cases made up a larger majority of the overall male cases (25/49, 51.0%) than overall female cases (24/88 27.3%, P = 0,007). Among the lymphedema cases arising by age 1 year, 33/44 (75.0%) were present at birth, and of those, over one third 12/33 (36.4%) had an antenatal diagnosis of a lymphatic anomaly (lymphedema of the extremities (n = 5), pleural effusion (n = 4, 1 isolated, 2 with ascites, 1 with hydrops), hydrops (n = 2) and one lymphatic malformation(n = 1)). Primary lymphedema onset during adolescence was more frequent in girls (47/88 (53.4%) versus 12/48 (25.0%) boys, P = .001). Lower limbs were by far the most impacted (121/137 (88.3%) patients having at least one lower limb affected). Ten boys and one girl had lymphedema of the genitals, and all of these had associated lymphedema of at least 1 lower limb. Seven patients had lymphedema involving other parts of the body (face (n = 5), thorax (n = 1), hemibody (n = 1)), associated with lymphedema of upper or lower limbs or both. 60/137 (43.8%) patients had genetic testing performed. Table 1 summarizes the genetic mutations and chromosomal abnormalities. All genetic testing was performed on blood samples, and the only patients who had tissue sampling were those who were negative on blood analysis but mosaic for PIK3CA mutation in the skin. Seven/137 (5.1%) patients had extensive/central lymphatic malformations, and 24/137 (17.5%) patients had a polymalformative syndrome: anomaly of the chromosome 22 in six, , PIK3CA-related Overgrowth Syndrome (PROS) (n = 3,), Turner syndrome (n = 3), Noonan syndrome (n = 2), Emberger syndrome with GATA2 deficiency (n = 2), Tuberous Sclerosis Complex (TSC) (n = 2), Hennekam syndrome (n = 1), Hypotrichosis-Lymphedema-Telangiectasia syndrome (n = 1), acrodysostosis (n = 1), cutis laxa (n = 1), duplication of 3q29 (n = 1), association of lymphedema and hepatic steatosis linked to Apolipoprotein B (APOB) mutation (n = 1)).

Table 1

Genetic Mutations and Chromosomal Abnormalities.

Genetic mutation	N
SOX18	1 (pathogenic)
FLT4^a/^b	9 (4 pathogenic, 5 VUS
PIEZO1^a	6 (VUS)
GJC2^a	1 (VUS)
GJA1^c	1 (VUS)
GATA2	2 (pathogenic)
FAT4	5 (4 VUS, 1 unknown)
ADAMTS3^c	1 (pathogenic)
SOS1	1 (VUS)
RIT1	1 (pathogenic)
CCBE1^b	1(VUS)
PIK3CA	2 (pathogenic)
Chromosome 22 anomalies	6(pathogenic)
Phelan-McDermid	(2)
DiGeorges	(2)
Duplication 22q13.31 (situated in CELSR1)	(1)
Ring chromosome 22 (site unknown)	(1)
TSC	2(pathogenic)
45,X	3
Duplication of 3q29	1(pathogenic)
Other mutations^d	5 (3 pathogenic, 2 VUS)

^aOne patient had 3 concomitant VUS in FLT4, PIEZO1 and GJC2, with isolated lymphedema arising in adolescence. One hrad 2 VUS concomitant in FLT4 and PIEZO1, with isolated congenital lymphedema.

^bOne patient had a pathogenic variant in FLT4 concomitant with a VUS in CCBE1. This patient had an isolated lymphedema.

^cOne patient had a pathogenic variant in ADAMTS3 concomitant with a VUS in GJA1.

^dMutation of a gene non previously described with lymphedema: 1 patients with nephrotic syndrome and a mutation of NPHS2, 1 patient with a variant PTEN of unknown significance and a variant PARD3 of unknown significance, 1 patient with a pathogenic mutation of APOB that also had 2 VUS in FAT4, 1 patient with a mutation of PDE4D (acrodysostosis).

14 patients had secondary lymphedema (graft-versus-host disease (GVHD, n = 1), stiff skin syndrome (n = 1), thrombophlebitis (n = 3), trauma (n = 4), surgery (n = 3), radiotherapy (n = 1) and filariasis (n = 1)). Of note, the patient with GVHD developed lymphedema complicated by hypoalbuminemia and eosinophilia and died rapidly from worsening sclerotic GVHD complicated by ulcerations.

Lymphoscintigraphy was performed in 80/151 (53.0%) of patients (both primary and secondary lymphedema), at a median age of 11.00 years (SD = 5.33). Lymphoscintigraphy demonstrated additional lymphatic malformations in two cases. Additional lymphatic or venous anomalies were found in 14 patients by ultrasound—doppler or MRI. 76/151 (50.3%) patients had an ultrasound-doppler examination, usually to exclude deep vein thrombosis. Among the 64 patients who had an MRI, edema of the subcutaneous fat tissue was visible in 46 (71.9%). Lymph-MRI was reserved for evaluation of those cases suspecting an internal lymphatic anomaly such as pleural effusions, ascites, or intestinal lymphangiectasia.

Twenty-six/151 (17.2%) patients experienced at least one episode of cellulitis. 8/151 (5.3%) patients had recurrent cellulitis (more than 3 episodes), all with primary lymphedema. 29/151 (19.2%) of the patients were treated for tinea pedis. 34/151 (22.5%) of the patients complained about pain, and 27/151 (17.9%) about functional impairment.

Most patients (110/151, 72.8%) used compression garments (flat knit). Manual lymphatic drainage (MLD), reported in 44/151 patients (29.5%), was performed either by a physiotherapist or by trained parents and could be combined with multilayer bandages briefly until the compression garment was available.

5/151 patients (2 PROS, 1 patient with TSC and 2 patients with extensive lymphatic malformations and intestinal lymphangiectasia) were treated by sirolimus, and in all of them, the lymphedema began before the introduction of the medication. The patient with TSC who had both lymphatic and venous aplasia of the lower limbs observed improvement of the lymphedema after the introduction of sirolimus, 2 were about to change the medication for alpelisib at the time of publication, and 2 discontinued the medication because the lack of improvement.

In the 101 patients for whom we had detailed information, lymphedema was stable in 51/101 (50.5%), 23/101 (22.8%) improved, and 22/101 (21.8%) experienced a worsening at some point. 5/101 (5.0%) had complete resolution of symptoms and were able to stop wearing compressive stockings (all isolated lymphedema, 4 primary and one secondary post-traumatic lymphedema: 3 adolescent onset, one congenital, one childhood).

Twenty-nine patients were referred to the specialized lymphedema clinic but had another diagnosis (Supplemental Table 2).

Comparisons are drawn between other pediatric lymphedema series (Table 2).^1,6

-9

Table 2

Comparative Pediatric Lymphedema Case Series.

	Smeltzer et al (1985)	Schook et al (2011)	Todd et al(2014)	Vidal et al (2016)	Watt et al(2017)	Our series (2022)
Selected cases	Primary lymphedema in children and adolescents (0, 20 years)	Primary lymphedema in pediatric patients (0, 21 years)	Pediatric lymphedema (0, 18 years-	Pediatric primary lymphedema (0, 18 years)	Pediatric lymphedema (0, 18 years)	Pediatric lymphedema (0, 18 years)
Total number of patients	125	142	455	155	86	151
Primary/secondary lymphedema	125/0	138/4	NR	155/0	80/6	136/15
Female/male	97/28	81/57^a	265/190	109/46	53/34	97/54
Mean age at onset	12.5	NR	NR	NR	NR	6.81
Apparition during the first year/childhood/adolescence	NR	68/13/57^a	268/NR/NR	NR	46/15/16	50/30/68
LL/UL/genitals	NR	121/22/25^a	346/55/36	151/14/9	81/8/13	132/40/13
Pain	NR	NR	NR	NR	19	34
Infections/Recurrent infections	39/NR	26/10^a	57/23	21/6	22/NR	26/8
Lymphoscintigraphy confirms diagnosis/processed	9/20	NR/33^a	110	56/64	40/48	66/80
US processes	NR	64^a	50	NR	42	76
MRI processed	N/A	66^a	126^b	NR	26	64
Compressive therapy	99	104^a	NR	NR	81	110
Manual lymphatic drainage	NR	NR	NR	60	80	44
Patients with associated syndromes	13	16^a	38	12	16	34
Antenatal diagnosis of an enlarged limb or lymphatic anomaly	NR	3^a	NR	21	6	12
Stabilization or improvement of lymphedema	NR	40 (on 95 patients)	NR	113	NR	79

Abbreviations: . LL = Lower limb, MRI = Magnetic resonance imaging; NR = Not reported, UL = upper limb, US = ultrasound.

^aAmong primary lymphedema only.

^bMRI / CT scan / Duplex).

Discussion

In children, lymphedema is far more frequently primary than secondary, as seen in our cohort, and in other previously published studies. The frequency of secondary lymphedema in our cohort was 9.3% as compared to the literature (2.8%, 7%).^6,9

We showed an overall female predominance 64.2% in primary lymphedema as previously described.^6,8,9 Similarly, in male patients, congenital lymphedema is more frequent (51.0%), wherein female patients, onset during adolescence is more frequent (54.3%).⁶ This is probably explained by epigenetic factors, such as hormonal influence.

The diagnosis of lymphedema is mainly clinical, and the Stemmer sign (Figure 1) is the specific sign which is 92% sensitive and 57% specific for lymphedema¹⁰ (positive in 65/83 (78.3%) in this study), and is only present if the lymphedema affects the distal extremity (toes, fingers). In pediatric lymphedema, typical cutaneous signs of lymphedema were discrete, however accentuation of skin folds at the base of the toes (Figure 2) has been seen in up to 2/3 of cases with lymphedema of the lower limb and loss of clear definition of the ankle or wrist joint was frequent (Figure 3). Fibrosis, hyperkeratosis and papillomatosis were rarely seen.¹¹

In our experience as in the literature, lymphoscintigraphy is an ideal imaging technique to evaluate the lymphatic flow and confirm the diagnosis of lymphedema,^12

-16 although near-infrared fluorescent (NIRF) image-guided lymphatic mapping is being used now particularly in conjunction with surgery. The major disadvantages in the former are pain at the injection site and followed by 1-4 hours during which the child must cooperate to walk or perform arm exercises.¹⁷ Lymphoscintigraphy was performed in 80 cases and details of our findings will be given in a future publication.

MRI and US-doppler are very important to reveal associated vascular anomalies: They uncovered complex lymphatic anomalies in 6 of our patients, and overgrowth syndromes including 3 cases of PROS. Chest X-ray and MRI may demonstrate pleural or pericardial effusions or ascites, and GI capsule endoscopy can identify intestinal lymphangiectasia.

The rate of confirmed diagnosis of lymphedema among referred patients in the lymphedema clinic is similar to what has previously been described in most tertiary referral centers (83.9%)¹⁸ although one group had a low 58.4% lymphedema diagnosis.⁶ The differential diagnosis includes peripheral edema from immobility, thyroid anomalies, renal insufficiency, vascular tumors or malformations, overgrowth syndromes, lipedema,¹⁹ obesity and neoplasia.²⁰

Although uncommon in children, secondary lymphedema must be eliminated and a careful history of trauma preceding the occurrence of lymphedema must be taken, along with information about susceptible medication, history of cancer and/or radiotherapy and surgery. In the experience of the authors, when peripheral edema arises in a patient with GVHD in combination with eosinophilia, it is a harbinger of acute deterioration and sclerotic GVHD.²¹

Most with lymphedema have sporadic Inheritance.^5,8,9,22 Genetic testing is worthwhile as it may translate to therapeutic options. Mutations in several genes have been identified in isolated or syndromic forms of lymphedema (Table 3).^{23

-32} In our opinion the terms “Milroy disease” and “Meige syndrome” should no longer be used, and we should rather focus on accurate genetic diagnosis.

Table 3

Principal Mutated Genes Described in Isolated or Syndromic Forms of Lymphedema.

FLT4²⁶	Milroy disease, isolated familial congenital lymphedema
VEGFC²⁶	Milroy-like disease
FOXC2²⁶	Lymphedema-distichiasis
GJA1²⁶	Oculodentodigital dysplasia/lymphedema
PTPN14²⁶	Choanal atresia/lymphedema
SOX18²⁶	Hypotrichosis, lymphedema, telangiectasia
HGF²⁶	(lymphedema-lymphangiectasia
GJC2²⁶	familial late onset lower limb lymphedema (formerly called Meige syndrome)
GATA2²⁶	Emberger syndrome
FAT4^26 -28	Hennekam syndrome
CCBE1^26 -28	Hennekam syndrome
ADAMTS3^26 -28	Hennekam syndrome
NEMO²⁶	Hypomorphic mutation causing the syndrome osteopetrosis, and lymphedema, ectodermal dysplasia anhydrotic with immunodeficiency, osteopetrosis, and lymphedema, OLEDAID
KIF11²⁶	Lymphedema, microcephaly with or without chorio-retinopathy, or mental retardation
CELSR1²⁹
ANGPT2³⁰
EPBH4³¹
ITAG9²⁶
RELN³²
PIEZO1^33,34	Biallelic mutations of PIEZO1 have been identified as causative for lymphatic dysplasia/congenital lymphedema with hydrops fetalis^a.

^aSix of our patients had a monoallelic variant of uncertain significance (VUS) of PIEZO1, 2 of them with congenital lymphedema and antenatal pleural effusion and ascites. Two others had also other VUS (on FAT4, GJC2 and FLT4).

Lymphedema is also a feature of several polymalformative syndromes, as seen in our series. Mutation of the RAS signaling pathway can also lead to lymphedema in some patients, described with RASA1 (CM-AVM/Lymphedema), PTPN11, SOS1 and RIT1, HRAS, KRAS³³ and RAF1 mutations.³⁴ Lymphedema has been reported in Noonan syndrome (mutation of PTPN11, SOS1 or RIT1), with an onset ranging from infancy to adulthood.³⁴ Our 2 cases of Noonan had onset of their lymphedema during infancy, and lymphorrhea from the scrotum has been a major limitation for one. Primary congenital lymphedema has been described in 13 cases of TSC.³⁵ Both of our patients with TSC had a lymphedema present at birth. Lymphedema is also linked with chromosome 22 anomalies; it has been described in 25% of Phelan-McDermid syndromes,³⁶ and rarely in DiGeorge syndrome.³⁶ CELSR1 is also on chromosome 22, and mutations associated with lymphedema has been described.^26,37 25% of patients with Turner syndrome experience lymphedema of the extremities, and it is usually an early sign, along with the webbed neck, that should raise the possibility of a 45X karyotype. In Turner syndrome, lymphedema may resolve spontaneously before the age of 2, but may relapse at a later age.³⁸ Two of our 3 cases had marked improvement of lymphedema whereas one showed deterioration at the age of 5 years. In the literature, one patient with terminal duplication of 3q presented multiple anomalies including developmental delay (greater in the expressive language field), facial dysmorphism and lymphedema of the dorsal foot.³⁹ Our patient with a 3q29 duplication had lymphedema, autism spectrum disorder but no frank facial dysmorphism. To our knowledge, no other case describing the association between cutis laxa and lymphedema has been published. Association between PROS and lymphedema has not been previously described, although lymphedema was a minor finding in our 3 PROS patients.

Cellulitis, especially when recurrent, is the most dangerous complication of lymphedema. Recent studies of pediatric lymphedema have reported cellulitis rates similar to ours: 17.2%^1,6,8 with 29.7% recurrence rate, whereas 72.1% of adults report a history of cellulitis.⁴⁰ This compares to a recent study of 128 children with primary lymphedema reporting 29.7% of cellulitis and 55.3%% recurrence.⁴¹ It is commonly agreed that fungal infections are more prevalent in the lymphedema population, but no previous study described the prevalence of interdigital desquamation as in 21.2% in our cohort. This desquamation reflects a perturbed skin barrier which may add to the risk of cellulitis. However true tinea pedis was confirmed in 6 of the 14 tested (42.9%) and only 6/151 (4,0%) overall.

The outcome of lymphedema seems to be better in children than in adults, as we found that more than 70% of our patients had no deterioration of their lymphedema. This has also been confirmed in other studies.⁶ No patient had angiosarcoma in our cohort, which has been described in 5 young girls, and 19 adults overall in congenital primary lymphedema⁴² ; angiosarcoma remains an unusual but aggressive complication affecting adults with secondary lymphedema.⁴³

Functional impairment and pain in pediatric lymphedema have been underestimated. In our cohort, about one out of four patients experienced pain, and one fifth had functional impairment, the latter close to what Watt et al. described in their cohort.⁹ Even this could be underestimated, as children can have difficulties to express their pain, and are often coping with functional impairment using unconscious compensation strategies.

Mammalian target of rapamycin (mTOR) inhibitors is now used in lymphatic malformations with reduction in the size of the lesions, as well as symptoms and improvement of the quality of life.³ One of our 2 patients with TSC necessitated everolimus for the control of the renal angiomyolipoma, but there was concern about the possibility of increasing the lymphedema.^44,45 Nevertheless, the medication was introduced, leading to the control of the angiomyolipom and the epilepsy, and the lymphedema remained stable. Our other patient had enlarging subependymal giant cell astrocytoma for which he was treated with sirolimus, with remarkable improvement of the striking lymphedema which had been complicated by recurrent cellulitis; the basis was due to lymphatic and venous hypoplasia of the left lower limb. This patient had already been described.⁴⁶ Another patient with TSC and lymphedema improved under everolimus has been described.⁴⁷ We had no cases of secondary lymphedema due to mTOR inhibitors, despite being a tertiary pediatric center, with at least 100 patients using mTOR inhibitors. Lymphedema seems to be an extremely rare secondary effect of mTOR inhibitors.

The treatment of lymphedema is laborious. In 1985, Smeltzer et al. ⁷ described that “the stockings are expensive, and they are hot and uncomfortable to wear,” with some improvement in esthetics over time. There is no quality evidence regarding the efficacy of treatment (CDT) in pediatric lymphedema.⁴ Nevertheless, there is a consensus for using the combination of compression therapy (CT), maintaining a low to moderate Body Mass Index, and exercise. Most of our patients (72.8%) wore flat knit compressive garments and most patients find it comfortable and socially acceptable. Compliance with CT is usually best at a younger age whereas adolescents may not adhere to daily use of compressive stockings. About one third of patients performed MLD. The advantages of CT and MLD can be inferred from the studies in the adult population.^48,49 In pediatric patients, treatment must be weighed with inconvenience, comfort, feasibility in the familial daily life, and the desire to be « normal ».²

Limitations

Our study has the inherent limits of a retrospective study in a single institution. We do not have experience with lymphatic pumps in any of our patients, nor surgical procedures such as lymphaticovenous anastomoses.

Conclusion

The diagnosis of pediatric lymphedema is primarily clinical. In our cohort, approximately 1 in 5 patients referred had another diagnosis.. Delay in diagnosis is common. Lymphoscintigraphy is useful to confirm the diagnosis. Evaluation and follow-up in a multidisciplinary center with a vascular anomalies team is essential. Looking for associated complex vascular anomalies and/or overgrowth syndromes is important.

Primary lymphedema accounted for 90.7% of our cohort, and a pertinent genetic anomaly was found in 63.3% of our patients when investigated.

Pain and functional impairment have been underestimated in pediatric lymphedema and may affect one fourth to one fifth of children respectively. Cellulitis was a significant cause of morbidity in 17.2% of our cohort with recurrence in a third of patients. In the experience of the author, there is a huge emotional and financial burden on the parents and children facing this lifelong chronic disease. Prospective studies are needed to assess the effect of CDT and MLD in children as well as future therapeutic avenues.

Supplemental Material

Table S1 - Supplemental material for Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic

Supplemental material, Table S1, for Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic by Caroline Colmant, Sophie Turpin, Raymond Lambert, Nicole Wong, Sandra Ondrejchak, Chantal Lapointe, Julie Powell, Josée Dubois and Catherine McCuaig in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Table S2 - Supplemental material for Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic

Supplemental material, Table S2, for Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic by Caroline Colmant, Sophie Turpin, Raymond Lambert, Nicole Wong, Sandra Ondrejchak, Chantal Lapointe, Julie Powell, Josée Dubois and Catherine McCuaig in Journal of Cutaneous Medicine and Surgery

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Caroline Colmant

Sophie Turpin

Supplemental Material

Supplemental material for this article is available online.

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