Generic selectors
Exact matches only
Search in title
Search in content
Search in posts
Search in pages
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstract
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Addendum
Announcement
Art & Psychiatry
Article
Articles
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Commentary
Conference Oration
Conference Summary
Continuing Medical Education
Correspondence
Corrigendum
Cosmetic Dermatology
Cosmetology
Current Best Evidence
Current View
Derma Quest
Dermato Surgery
Dermatopathology
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
e-IJDVL
Editor Speaks
Editorial
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Errata
Erratum
Focus
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
General
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
History
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL AWARDS 2015
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
In Memorium
Inaugural Address
Index
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
LETTER TO THE EDITOR - LETTERS IN RESPONSE TO PUBLISHED ARTICLES
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Medicolegal Window
Messages
Miscellaneous Letter
Musings
Net Case
Net case report
Net Image
Net Letter
Net Quiz
Net Study
New Preparations
News
News & Views
Obituary
Observation Letter
Observation Letters
Oration
Original Article
ORIGINAL CONTRIBUTION
Original Contributions
Pattern of Skin Diseases
Pearls
Pediatric Dermatology
Pediatric Rounds
Perspective
Presedential Address
Presidential Address
Presidents Remarks
Quiz
Recommendations
Regret
Report
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Retraction
Review
Review Article
Review Articles
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Special Article
Specialty Interface
Studies
Study Letter
Supplement-Photoprotection
Supplement-Psoriasis
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
SYMPOSIUM - VITILIGO
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Tables
Technology
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
View Point
Viewpoint
What’s new in Dermatology
View/Download PDF
CROSSMARK LOGO Buy Reprints
PDF

Translate this page into:

Case Letter
87 (
2
); 240-244
doi:
10.25259/IJDVL_287_19

Hennekam lymphangiectasia syndrome: A rare case of primary lymphedema

Department of Dermatology and STD, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
Corresponding author: Dr. Sarita Sanke, Department of Dermatology and STD, Lady Hardinge Medical College and Associated Hospitals, New Delhi - 110 001, India. sankesarita@gmail.com
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Sanke S, Garg T, Manickavasagam S, Chander R. Hennekam lymphangiectasia syndrome: A rare case of primary lymphedema. Indian J Dermatol Venereol Leprol 2021;87:240-4.

Sir,

Hennekam syndrome is an autosomal recessive disorder resulting from malformation of the lymphatic system. This syndrome was first described by the Dutch physician Hennekam in 1989.1 It is a very rare syndrome and fewer than 50 cases have been reported in the medical literature.2 The characteristic signs of Hennekam syndrome are lymphangiectasia, lymphedema, facial anomalies and mental retardation.3

A 13-year-old boy from Uttar Pradesh, born out of consanguineous parentage, presented with edema of the external genitalia and both of his legs of 8-years duration. The edema had a fluctuating course (some days the right leg was more edematous, while in the other days the edema was more in the left leg, [Figure 1]). However, there was no diurnal variation. It was not associated with pain or tenderness. There was no history of prior radiation exposure, trauma or surgeries. There was no similar history in his family members. He had a past history of recurrent respiratory tract infections, since 6 months of age and history of recurrent diarrhea since he was 1 year old, which occurred approximately once in 2 weeks. He was evaluated and treated for lymphatic filariasis multiple times with no significant improvement.

Figure 1:: Edema of legs

On examination, the patient had pallor and an antalgic gait. The facial features noted were synophrys, flat midface, bushy eyebrows [Figure 2a], Bitot spots of the eye [Figure 2b], smooth philtrum and thin upper lip. There was generalized dry, xerotic skin with multiple excoriation marks and atrophic scars on the body [Figure 2c]. Generalized hypertrichosis was also noted. Pitting pedal edema was present on both his lower limbs, extending just above the ankle joint.His external genitalia showed gross enlargement of scrotum and penis giving the appearance of “Saxophone penis”[Figure 3]. The great toenails showed Beau’s line, brownish discoloration and onychorrhexis [Figure 4]. There was malocclusion of the teeth with caries on oral examination. On investigations, he had anemia with hemoglobin of 8.1 g/dL, and raised erythrocyte sedimentation rate of 68 mm/hr. Serum immunoglobulins (IgG and IgM) were low. Enzyme-linked immunosorbent assay for Human immunodeficiency virus (HIV) was nonreactive. The rest of the investigations including chest roentgenogram, electrocardiogram and echocardiogram were normal. Peripheral smear after diethylcarbamazine provocation and microfilarial antigen test were, both negative. (Circulating filarial antigen detection test is now regarded as the “gold standard” for diagnosing Wuchereria bancrofti infections. Enzyme-linked immunosorbent assay methodology yields semi-quantitative results and has high sensitivity and specificity.) Ultrasound of the abdomen revealed massive splenomegaly, while that of the scrotum showed thickening of scrotal skin with connective tissue proliferation. Upper gastrointestinal endoscopy showed features of duodenitis and few discrete pale-white areas on the duodenal mucosa. Biopsy of the same showed mild duodenal inflammation with few lymphangiectasias. Lymphoscintigraphy of the legs showed dermal backflow in the left lower calf region on the left leg. On the right leg, there was no tracer movement and non-visualization of inguinal and femoral lymph nodes [Figure 5]. These features were suggestive of primary lymphedema. Ophthalmology referral was taken which showed glaucomatous cupping of both eyes. Psychiatry opinion was sought and the child was found to have moderate mental retardation with an intelligence quotient of 48.

Figure 2a:: Bushy eyebrows with synophrys, thin upper lip, smooth philtrum
Figure 2b:: Bitot’s spots (Yellow arrow) with dry xerotic skin on the face (Blue arrow)
Figure 2c:: Atrophic scars on the body (yellow arrows)
Figure 3:: Gross edema of the penis and scrotum (saxophone penis)
Figure 4:: The great toe nails showed Beau’s line, brownish discoloration and onychorhexis
Figure 5:: Lymphoscintigraphy of the legs showed dermal backflow at the left lower calf region on the left leg. On the right leg, there was no tracer movement and non-visualization of inguinal and femoral lymph nodes

Based on the above features, a provisional diagnosis of lymphatic filariasis and syndromic primary lymphedema were kept. Lymphatic filariasis was ruled out on the basis of the negative diethylcarbamazine provocation test and microfilaria antigen test. The syndromes of primary lymphedema that were thought of included Noonan syndrome, lymphedema distichiasis syndrome, Emberger syndrome and Hennekam syndrome. Table 1 enumerates all these possibilities with their differentiating points.

Table 1:: Differential diagnosis of bilateral limb edema in a child Noonan syndrome
Noonan syndrome Lymphedema-distichiasis syndrome Emberger syndrome Hennekam syndrome
Upper torso lymphedema associated with
typical facies
Sparse eyebrows
Webbed neck
Rocker bottom feet
Cognitive delay
Congenital heart defects like pulmonary stenosis, hypertrophic obstructive cardiomyopathy
PTPN11 mutations
Asymmetric lymphedema of the legs (late childhood/adolescent onset)*
Distichiasis
Varicose veins
Congenital heart disease
Ptosis
FOXC2 mutations
Childhood onset*
Unilateral or bilateral lower limb* +/− genital lymphedema*
Myelodysplasia
Hypotelorism, slender fingers, neck webbing,
Multiple warts
Erythroid transcription factor (GATA mutations)
Asymmetrical lymphedema of limbs and genitalia*
Lymphangiectasias*
Mental retardation*
Typical facies*
Growth Retardation*
Renal anomalies
Glaucoma*
Hearing defects
Dental anomalies*
Hypertrichosis*
Anemia*
Hypogammaglobulinemia
Limb anomalies
Blood vessel anomalies
Central Nervous System anomalies
Unlikely Unlikely Unlikely Multiple coinciding features
Features present in our patient. PTPN11-Tyrosine-protein phosphatase non-receptor type 11. FOXC2 - Forkhead Box C2

CNS: central nervous system. GATA: Erythroid transcription factor

In view of the characteristic facial features, intestinal lymphangiectasias, borderline mental retardation and lymphoscintigraphy findings, a final diagnosis of Hennekam lymphangiectasias syndrome was made. Our patient was referred to a gastroenterologist and was advised to take low fat and protein-rich diet, along with supplements of vitamin A and vitamin D. Limb elevation and manual lymph drainage from distal to proximal leg, along with compression therapy (elastic crepe bandaging) was advised. For the xerosis, he was given emollients and antihistamines. However, the patient was lost to follow-up after a few weeks.

Hennekam syndrome is primarily a developmental disorder of the lymphatics with an autosomal recessive mode of inheritance. The etiology remains unknown, but the clinical features suggest that the syndrome results from abnormal development of the vascular and lymphatic systems, that disrupts critical events in craniofacial morphogenesis.1 Mutations of collagen and calcium-binding domain 1(CCBE 1)4 and FAT atypical cadherin 4 (FAT4)5 have been known to cause the disease. Mutational analysis in our patients was not done, due to the scarcity of resources. CCBE1 gene mutations that cause Hennekam syndrome, result in a change of the shape of the protein, thereby hampering its function in the formation of the lymphatic vessel epithelium. The resulting malformation of lymphatic vessels leads to lymphangiectasia and lymphedema. This malformation can affect any lymphatic vessel in any organ of the body. FAT4 gene mutations result in a FAT4 protein with decreased function which impairs the normal development of the lymphatic system, but the mechanism is unknown. The genotype registry includes various studies like sequence analysis of the entire coding region Hennekam lymphangiectasia-lymphedema syndrome type 1, complete CCBE1 gene sequencing, lymphedema sequencing panel with copy number variation detection, FAT4 mutation analysis, etc., The syndrome is characterized by a wide clinical spectrum with the association of lymphedema, intestinal lymphangiectasia, intellectual deficit and facial dysmorphism, being the most commonly encountered features. Altered lymphatic development before birth (intrauterine) may change the balance of fluids and impair normal development, contributing to dysmorphic facial features and poor brain development. Facial anomalies seen are the flat face, upper lip and nasal bridge, hypertelorism, epicanthal folds, synophrys, bushy eyebrows, craniosynostosis, atresia of the ear canal, smallmouth, retrognathia, oligodontia and conical crowns. The dermatological anomalies described are severe lymphedema of the limbs, face and genitalia, infection of oozing lymphatics (erysipelas) and alopecia areata. Glaucoma is also noted in some of the cases.

The most characteristic anomaly reported in the gastrointestinal tract is intestinal lymphangiectasia. Tortuous, dilated mucosal and submucosal lymphatic vessels, due to increased lymphatic pressure are the hallmark of primary intestinal lymphangiectasia.6 These intestinal lymphangiectasias could be the cause of recurrent diarrhea in our patients. The congenital pulmonary lymphangiectasis is a rare developmental disorder of the pulmonary lymphatic vessels which is associated with Hennekam Syndrome. Urogenital anomalies described are genital lymphedema, duplicated ureter, hydroureteronephrosis, chyluria (rupture of renal lymphangiectasis lacteals) and cystitis due to vesicoureteral reflux.7 However, our patient did not have any renal involvement. Treatment is symptomatic.3 Many patients are treated with total parenteral nutrition, a medium-chain triglyceride-rich diet and albumin infusions. Fat-soluble vitamins and electrolyte supplements, together with a high-protein diet have been reported to be beneficial. The lymphedema may be severely disabling and require repeated surgical intervention. The prognosis is variable and few patients have been described with very severe manifestations leading to an early death.2 To conclude, all cases of lymphedema in a child are not necessarily due to filariasis. A dermatologist needs to work up the case thoroughly to exclude all the syndromes with primary lymphedema.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. , , , , , , et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet. 1989;34:593-600.
    [CrossRef] [PubMed] [Google Scholar]
  2. , , . Hennekam lymphangiectasia syndrome. Int J Res Med Sci. 2015;3:516-9.
    [CrossRef] [Google Scholar]
  3. , , , , , , et al. Lymphedema lymphangiectasia mental retardation (Hennekam) syndrome: A review. Am J Med Genet. 2002;112:412-21.
    [CrossRef] [PubMed] [Google Scholar]
  4. , , , , , , et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 2009;41:1272-4.
    [CrossRef] [PubMed] [Google Scholar]
  5. , , , , , , et al. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Mal dergem syndrome. Hum Genet. 2014;133:1161-7.
    [CrossRef] [PubMed] [Google Scholar]
  6. , , , , , . Hennekam lymphangiectasia In: Text Book of Gastroenterology (5th ed). US: Wiley Blackwell; . p. 1101-2.
    [Google Scholar]
  7. , , , , . Cutaneous manifestations and massive genital involvement in Hennekam syndrome. Pediatr Dermatol. 2006;23:239-42.
    [CrossRef] [PubMed] [Google Scholar]

Fulltext Views
974

PDF downloads
421
View/Download PDF
Download Citations
BibTeX
RIS
Show Sections