Pediatric and Primary Lymphedema (PPL-WG)

The PPL Working Group, is built upon Multidisciplinary Centres of Excellence collaborating and have a long-standing expertise in the diagnosis and management of adults and children with lymphatic problems.

The PPL-WG is chaired by Dr. Robert Damstra, Dermatologist at the Expert center for lympho-vascular medicine, Nij Smellinghe hospital, Drachten, Netherlands. This WG is co-chaired by Prof. Sahar Mansour, and Prof. Peter Mortimer, Paediatric and Primary Lymphoedema Clinic, St George’s University Hospitals NHS Foundation Trust, London, UK. These chairs, and the Working Group, have a long-standing expertise in the diagnosis and management of adults and children with lymphatic problems. The PPL-WG cooperates with the Patient-WG.

The lymphatic system is arguably the most neglected bodily system, and as a result, its contribution to human health and disease is not well understood. Lymphatic impairment can be either due to an overload of the lymphatic system (high preload) or a failure / lowered transport capacity (low afterload) (primary lymphedema). Primary lymphedema is highly heterogeneous. In-depth phenotyping has led to the identification of several new conditions and genetic causes. Our group have published a classification and diagnostic algorithm (Connell et al, 2013) to assist in making an accurate diagnosis.
Accurate diagnosis and a multi-disciplinary approach to management are mandatory for this chronic condition with a high morbidity.
Secondary lymphedema is relatively common (as a complication of malignancy, surgery or infection). Many guidelines do not specifically discriminate between primary and secondary lymphedema or the dedicated treatment of children with primary lymphedema.
A dedicated approach towards primary lymphedema, and any lymphoedema in a child, needs specialized centers of expertise.
The PPL-WG will interact with all the other WGs within this ERN, especially the Vascular Anomalies WG (VASCA-WG), particularly with regard to some lymphovascular disorders, which may present with lymphedema of the extremities.

The treatment of lymphedema needs an interdisciplinary, holistic approach. As a chronic condition, the patient should be educated in self-management and awareness.

In 2001, the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) was introduced. It can be used to assess the benefits of the management and treatments for all chronic diseases. It provides an appropriate framework that allows systematic categorization of clinical observations based on an integrated bio-psycho-social model. This model focuses, not just on physical and medical aspects, but takes also social functioning, personal and environmental aspects into account. The ICF framework consists of the following components:
– Body structures and functions
– Activities and participations
– Personal and environmental factors
By using the ICF method for evaluation of the results of treatment, the focus is not just on volume of the limb but includes a more holistic approach and takes the whole patient and daily practice functioning into account. Special core set for lymphedema have been developed(4) and needs further implementation.

The International Lymphedema Framework (ILF) camp for children presents two videos:

– Highlights of the children camps, which is going to be replicated this year in Italy
– Children explaining what it means living with Lymphoedema 

Main Thematic Group: primary lymphedemas including syndromic lymphedema in children and adults, and lymphovascular disorders. Secondary lymphedema in children up to 18 years of age.

Related Rare Or Complex Disease(s):
Lymphedema (ORPHA79383)

Congenital Lymphedema
– Milroy syndrome (ORPHA79452)

Late onset lymphedema
– Meige syndrome (ORPHA90186)
– Lymphedema distichiasis syndrome (ORPHA33001)
– Emberger syndrome (ORPHA3226)

Lymphedema with systemic involvement
– Hennekam syndrome (ORPHA2136)
– PIEZO1 related lymphatic dysplasia
– Generalised lymphatic dysplasia
– Multi-systemic lymphedema with systemic involvement

Syndromes associated with lymphedema
– Noonan/CFC syndrome (RASOpathies) (ORPHA648)
– Turner syndrome (ORPHA881)
– 22q13 microdeletion (ORPHA48652)
– Microcephaly with or without Chorioretinopathy, Lymphedema and Mental Retardation (MCLMR)(ORPHA2526)

Bases for the estimated incidence and prevalence numbers: 500 Million inhabitants within European union with about 6 million newborns annually.

sub-thematic areas of expertise Rare or complex disease(s) or condition(s) or highly specialized interventions Code/ICD/ Orphacode / Group of Codes Incidence (Number of cases / year)

(in the EU)

Prevalence

 (in the EU)

PPL Lymphedema ORPHA79383 600 prevalence of primary lymphedema is unknown, but is approximately 50 000
PPL Congenital Lymphedema : Milroy syndrome ORPHA79452 unknown unknown
PPL Late onset lymphedema:

Meige syndrome

Lymphedema distichiasis syndrome, Emberger syndrome

ORPHA90186

ORPHA33001

ORPHA3226

unknown unknown
PPL Lymphedema with systemic involvement:

Hennekam syndrome

PIEZO1 related lymphatic dysplasia

Generalised lymphatic dysplasia

Multi-systemic lymphedema with systemic involvement

ORPHA2136 unknown unknown
PPL Syndromes associated with lymphedema:

Noonan/CFC syndrome (RASOpathies)

Turner syndrome

22q13 microdeletion

Microcephaly with or without Chorioretinopathy, Lymphedema and Mental Retardation (MCLMR)

ORPHA648

ORPHA881

ORPHA48652

ORPHA2526

unknown unknown

All HCP in the PPL-WG are covering this sub-thematic area of expertise.

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NETHERLANDS

Chair

Dr. Robert J. DAMSTRA
Dermatologist
Pr Raoul C Hennekam (substitute)
Paediatrician and Clinical Geneticist, Academic Medical Center
Expert center for lympho-vascular medicine
Nij Smellinghe hospital
Drachten, Netherlands

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UNITED KINGDOM

Co-chair

Pr. Sahar MANSOUR
Consultant and Honorary Professor in Clinical Genetics
Pr. Peter MORTIMER
Dermatologists
Paediatric and Primary Lymphoedema
St George’s University Hospitals
London, UK

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BELGIUM

Dr. Sarah THOMIS
Lymphovenous Center
University Hospitals Leuven
Leuven, Belgium

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FINLAND

Pr. Sinikka SUOMINEN 
Department of Plastic Surgery
Head of Breast and Lymphedema teams
Helsinki University Hospital
Helsinki, Finland

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FRANCE

Dr. Stéphane VIGNES
Primary Lymphedema Unit, CRMR Rare Vascular Diseases
Hôpital Cognacq-Jay
Paris, France

allemagne

GERMANY

Pr. Dr. Jochen Rößler
Pediatric Hematology/Oncology
Center of Pediatrics and Adolescent Medicine
University Medical Center Freiburg
Freiburg, Germany

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UNITED KINGDOM

Dr. Vaughan KEELEY
Paediatric and primary lymphoedema
Derby Teaching Hospitals NHSF Trust
Derby, UK

Centers cooperating with PPL-WG

The HCPs member applicants are having functional cooperation with other Centers:

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FRANCE

allemagne

GERMANY

Földi Clinic
European Centre for Lymphology
Merzhausen, Germany

Our PPL-WG Goals are to:

  • implement a data privacy compliant registry to collect data on Paediatric and Primary lymphedema
  • provide highly specialised healthcare for this rare and complex group of disorders
  • establish clear patient pathways
  • evaluate and implement solutions to use information and communication technology (ICT) to provide patient-centered treatment and care
  • establish clinical guidelines for the disorders within our workgroup
  • implement quality improvement programs
  • collaborative research on the diseases within our workgroup

UK:
– Fotiou E, Martin-Almedina S, Simpson MA, Lin S, Gordon K, Brice G, Atton G,
Jeffery I, Rees DC, Mignot C, Vogt J, Homfray T, Snyder MP, Rockson SG, Jeffery
S, Mortimer PS, Mansour S, Ostergaard P. Novel mutations in PIEZO1 cause an
autosomal recessive generalized lymphatic dysplasia with non-immune hydrops
fetalis. Nat Commun. 2015 Sep 3;6:8085.

– Joyce S, Gordon K, Brice G, Ostergaard P, Nagaraja R, Short J, Moore S,
Mortimer P, Mansour S. The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. Eur J Hum Genet. 2015 Aug 5.

– Atton G, Gordon K, Brice G, Keeley V, Riches K, Ostergaard P, Mortimer P,
Mansour S. The lymphatic phenotype in Turner syndrome: an evaluation of nineteen
patients and literature review. Eur J Hum Genet. 2015 Dec;23(12):1634-9.

– Hanson HL, Wilson MJ, Short JP, Chioza BA, Crosby AH, Nash RM, Marks KJ,
Mansour S. Germline CBL mutation associated with a noonan-like syndrome with
primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23. Am J Med Genet A. 2014 Jan 23.

– Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady
AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul
RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S.
Microcephaly with or without chorioretinopathy, lymphoedema, or mental
retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J
Hum Genet. 2013 Nov 27.

– Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, Mansour S,
Ostergaard P. The classification and diagnostic algorithm for primary lymphatic
dysplasia: an update from 2010 to include molecular findings. Clin Genet. 2013
Oct;84(4):303-14.

– Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG, van Impel A, Connell F,
Kalidas K, Jeffery S, Mortimer PS, Mansour S, Schulte-Merker S, Ostergaard P.
Mutation in vascular endothelial growth factor-C, a ligand for vascular
endothelial growth factor receptor-3, is associated with autosomal dominant
milroy-like primary lymphedema. Circ Res. 2013 Mar 15;112(6):956-60.

– Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A,
Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S,
Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G,
Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S,
Jeffery S. Mutations in KIF11 cause autosomal-dominant microcephaly variably
associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012 Feb 10;90(2):356-62.

– Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou
D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT,
Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S.
Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011 Sep 4;43(10):929-31.

– Ostergaard P, Simpson MA, Brice G, Mansour S, Connell FC, Onoufriadis A, Child AH, Hwang J, Kalidas K, Mortimer PS, Trembath R, Jeffery S. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J Med Genet. 2011 Feb 28. .

– Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, et al.Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V. Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases. Am J Med Genet A 152A(9):2287-2296 Sep 2010

– Connell F, Kalidas K, Ostergaard P, Brice G, Homfray T, Roberts L, Bunyan DJ, Mitton S, Mansour S, Mortimer P, Jeffery S; Lymphoedema Consortium. Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet. 2010 Feb;127(2):231-41.

– Connell F, Homfray T, Thilaganathan B, Bhide A, Jeffrey I, Hutt R, Mortimer P, Mansour S. Congenital vascular malformations: a series of five prenatally diagnosed cases. Am J Med Genet A. 2008 Oct 15;146A(20):2673-80

– Santo S, Mansour S, Thilaganathan B, Homfray T, Papageorghiou A, Calvert S, Bhide A. Prenatal diagnosis of non-immune hydrops fetalis: what do we tell the parents? Prenat Diagn. 2011 Feb;31(2):186-95.

NL/B:
– Devoogdt N, De Groef A, Hendrickx A, Damstra RJ, Christiaansen A, Geraerts I, Vergote I, Van Kampen M. Lymphoedema Functioning, Disability and Health Questionnaire for lower limb lymphoedema (Lymph-ICF-LL): reliability and validity. Physio Ther.(PTJ) 2014:94(5):705-21

NL:
– Viehoff PB, Gielink PDC, Damstra RJ, Heerkens YF, van Ravensberg CD, Neumann HAM. Functioning in lymphedema from the patient perspective using the International Classification of Functioning, Disability and Health (ICF) as a reference. Acta Oncologica 2015;54(3):411-21

– Bellini C, Hennekam RC. Clinical disorders of primary malfunctioning of the lymphatic system. Adv Anat Embryol Cell Biol 2014;214:187-204.

– Alders M, Al-Gazali L, Cordeiro I, Dallapiccola B, Garavelli L, Tuysuz B, Salehi F, Haagmans MA, Mook OR, Majoie CB, Mannens MM, Hennekam RC.
Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet 2014;35:1161-1167.

– Bellini C, Donarini G, Paladini D, Calevo MG, Bellini T, Ramenghi LA, Hennekam RC.
Etiology of non-immune hydrops fetalis: An update. Am J Med Genet 2015;167:1082-1088.

– De Wijn RS, Oduber CE, Breugem CC, Alders M, Hennekam RC, van der Horst CM.
Phenotypic variability in a family with capillary malformations caused by a mutation in the RASA1 gene. Eur J Med Genet 2012;55:191-195.

– Hopman SM, Van Rijn RR, Eng C, Bras J, Alders M, van der Horst CM, Hennekam RC, Merks JH. PTEN hamartoma tumor syndrome and Gorham-Stout phenomenon.  Am J Med Genet 2012;158A:1719-1723.

– Alders M, Mendola A, Adès L, Al Gazali L, Bellini C, Dallapiccola B, Edery P, Frank U, Hornshuh F, Huisman SA, Jagadeesh S, Kayserili H, Keng WT, Lev D, Prada CE, Sampson JR, Schmidtke J, Shashi V, van Bever Y, Van der Aa N, Verhagen JM, Verheij JB, Vikkula M, Hennekam RC. Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations. Mol Syndromol 2013;4:107-113.

D:
– Kiefer J, Koulaxouzidis G, Stark GB, Foeldi E, Torio-Padron N, Penna V. An Integrative Therapeutic Concept for Surgical Treatment of Severe Cases of Lymphedema of the Lower Extremity. Obes Surg. 2015 Nov 26. [Epub ahead of print]

– Torio-Padron N, Stark GB, Földi E, Simunovic F. Treatment of male genital lymphedema: an integrated concept. J Plast Reconstr Aesthet Surg. 2015 Feb;68(2):262-8.

– Földi E. [Therapy of lymphedema]. Hautarzt. 2012 Aug;63(8):627-33. doi: 10.1007/s00105-012-2364-5. German.

– Koulaxouzidis G, Goerke SM, Eisenhardt SU, Lampert F, Stark GB, Foeldi E, Torio-Padron N. An integrated therapy concept for reduction of postoperative complications after resection of a panniculus morbidus. Obes Surg. 2012 Apr;22(4):549-54. doi: 10.1007/s11695-011-0561-4.

– Lohrmann C, Foeldi E, Langer M. Lymphocutaneous fistulas: pre-therapeutic evaluation by magnetic resonance lymphangiography. Br J Radiol. 2011 Aug;84(1004):714-8. doi: 10.1259/bjr/14411627. Epub 2010 Dec 15.

References:
– Mortimer PS, Rockson SG. New developments in clinical aspects of lymphatic disease. J Clin Invest. 2014 Mar 3;124(3):915–21.
– International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. 2013. pp. 1–11.
– WHO. Newsletter WHO-FIC 2011 on ICF. 2011 Aug 7:1–12.
– Viehoff PB, Potijk F, Damstra RJ, Heerkens YF, van Ravensberg CD, van Berkel DM, et al. Identification of relevant ICF (International Classification of Functioning, Disability and Health) categories in lymphedema patients: A cross-sectional study. Acta Oncologica 2015 Apr 8;54(8):1218–24.