Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Wednesday, February 29, 2012

Rare subset of diseases involving the lymphatic system

Rare subset of diseases involving the lymphatic system

Feb 2012

New Rochelle, NY, February 8, 2012—A clinically challenging and under-studied subset of diseases affecting the lymphatic system and grouped under the disease spectrum lymphangiomatosis and Gorham's disease is the focus of a special issue of Lymphatic Research and Biology, a peer-reviewed journal published by Mary Ann Liebert, Inc.. The issue is available free online at

Guest Editor, and Journal Associate Editor Francine Blei MD, MBA, St. Luke's Roosevelt Hospital, NY, has compiled a collection of articles that highlight the complex characteristics of these diseases, which can be localized, affect multiple sites, or be systemic, may be congenital or acquired, and may cause symptoms that range from mild to severe to life-threatening. The articles focus on current knowledge, ongoing research, and how these diseases differ from other lymphatic disorders.

"This disease spectrum affects a patient population that is small in number, but the effects of the disease(s) are devastating," says Stanley G. Rockson, MD, Editor-in-Chief of Lymphatic Research and Biology and Allan and Tina Neill Professor of Lymphatic Research and Medicine, Stanford University School of Medicine, CA. The collection of articles in this special issue, "highlights the current state of knowledge (and ignorance) in this paradoxically neglected area of lymphatic health and disease."


Lymphatic Research and Biology is an authoritative peer-reviewed journal published quarterly in print and online that delivers the latest developments and advances in lymphatic biology and pathology from the world's leading biomedical investigators. Topics covered include vasculogenesis and angiogenesis, genetics of lymphatic disorders, human lymphatic disease, tumor biology and metastasis, pharmacology, lymphatic imaging, and inflammation, infection, and autoimmune disease. Complete tables of content and a sample issue may be viewed online at

Mary Ann Liebert, Inc. is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Cancer Biotherapy and Radiopharmaceuticals and DNA and Cell Biology. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 70 journals, books, and newsmagazines is available at

Mary Ann Liebert, Inc. 140 Huguenot St., New Rochelle, NY 10801-5215
Phone: (914) 740-2100 (800) M-LIEBERT Fax: (914) 740-2101

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Wednesday, February 22, 2012

Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome.

Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome.

Feb 2012


Department and Clinic of Orthopaedic and Traumatologic Surgery-Division of Rehabilitation, Wroclaw Medical University, Borowska str. 213, 50-556 Wroclaw, Poland.


Lymphoedema-distichiasis syndrome (LDS, OMIM #153400) is a genetic disorder with an autosomal dominant pattern of inheritance caused by mutations in the FOXC2 gene. Affected individuals typically present with lower extremitylymphoedema and distichiasis. The most common types of mutations in FOXC2 gene include small deletions and insertions, but duplications, duplications-insertions, missense and nonsense mutations were also found. Herein, we describe three generations of a family diagnosed with LDS caused by a new mutation in the FOXC2 gene. This mutation is a frameshift due to a deletion of two nucleotides (CC) in C repeats between C586 and C591. This mutation leads to protein truncation as a result of an earlier insertion of a stop codon. To the best of our knowledge, this is the first description of this mutation in the literature and could be coupled with an atypical lymphoscintigram.


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Tuesday, February 14, 2012

A new classification system for primary lymphatic dysplasias based on phenotype.

A new classification system for primary lymphatic dysplasias based on phenotype.

May 2010


Medical Genetics Unit, Clinical Developmental Sciences, St George's University of London, Cranmer Terrace, London SW170RE, UK.


Traditional classification systems for lymphoedema are of limited use for the diagnosis of specific forms of primary lymphoedema. The understanding of primary lymphoedema has been impeded by confusing terminology and a tendency to simply divide patients into three categories based on the age of onset: lymphoedema congenita manifests at or shortly after birth, lymphoedema praecox is apparent before the age of 35 years and lymphoedema tarda manifests thereafter. The clinical presentation in the spectrum of primary lymphoedema disorders is very variable; the phenotypes of primary lymphoedema conditions vary in the age of onset, site of the oedema, inheritance patterns, associated features and genetic causes. Different inheritance patterns are recognised and there are numerous associated anomalies. Some subgroups, such as Milroy disease and Lymphoedema distichiasis, are well characterised, but others are not. A new clinical classification for primary lymphoedema has been developed as a diagnostic algorithm. Its use is demonstrated on 333 probands referred to our lymphoedema clinic. Grouping patients by accurate phenotyping facilitates molecular investigations, understanding of inheritance patterns, and the natural history of different types of primary lymphoedema. Descriptions of the diagnostic categories, some of which have not been previously clearly defined as distinct clinical entities, are illustrated by clinical cases.

Wiley Online Library

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Noonan Syndrome.

Noonan Syndrome.

Update of Aug 2011


Allanson JE, Roberts AE.

Judith E Allanson, MD
Department of Genetics
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
Amy E Roberts, MD
Cardiovascular Genetics
Children’s Hospital Boston
Boston, Massachusetts


In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.


GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.



Noonan syndrome (NS) is characterized by short stature, congenital heart defect, anddevelopmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, characteristic facies, varied coagulation defects, lymphaticdysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one third of affected individuals have mild intellectual disability.


NS is diagnosed on clinical grounds by observation of key features. Affected individuals have normal chromosome studies. Molecular genetic testing identifies a mutation in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 in 3% to 17%, and KRAS in fewer than 5%. Other genes in which mutations have been reported to cause Noonan syndrome in fewer than 1% of cases include NRAS, BRAF, and MAP2K1.


Treatment of manifestations: Cardiovascular anomalies in NS are usually treated as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. Treatment for serious bleeding is guided by knowledge of the specific factor deficiency or platelet aggregation anomaly. Growth hormone (GH) treatment increases growth velocity. Surveillance: Monitoring of anomalies found in any system, especially cardiovascular abnormalities.


NS is inherited in an autosomal dominant manner. Although many individuals with NS have a de novo mutation, an affected parent is recognized in 30%-75% of families. The risk to sibs of a proband depends on the genetic status of the parents. If a parent is affected, the risk is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%). Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.


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Sunday, February 12, 2012

Sildenafil for Severe Lymphatic Malformations

Sildenafil for Severe Lymphatic Malformations



To the Editor:

Lymphatic malformations are uncommon congenital vascular anomalies that can cause complications including obstruction of vital organs and their function, recurrent infection, and disfigurement.1 Current procedural treatments are only partially successful, and lymphatic malformations often recur. We report marked regression of lymphatic malformations in three children after treatment with oral sildenafil.

A 10-week-old girl presented with a congenital, nonpulsatile, violaceous, nodular plaque causing massive enlargement of the right chest and arm. A scan obtained with magnetic resonance imaging (MRI) revealed microcystic venolymphatic malformation with intrathoracic extension. At 5 months, congestive heart failure developed. An echocardiogram showed pulmonary hypertension without congenital anomalies. Despite initial improvement after treatment with conservative measures, the patient's cardiorespiratory condition worsened. At 9 months, cardiac catheterization confirmed the presence of idiopathic pulmonary hypertension, and sildenafil was initiated. The malformation gradually diminished, and 4 months later a thin, blue plaque and redundant tissue were seen. A subsequent MRI of the heart confirmed the presence of only minimal residual lymphatic malformation.

On the basis of this observation, a pilot study was approved by the institutional review board at Stanford University. Two children with disabling lymphatic malformations received sildenafil for 12 weeks.

In Subject 1, a 12-month-old boy, the lymphatic malformation involved the orbit and upper eyelid and obstructed visual input. Although improved eye opening was noted after 3 weeks, debulking was performed because of concerns about amblyopia. At the study's end, the child's ability to open the affected eye had increased by 25%. Tissue enlargement recurred after sildenafil was discontinued. Subject 2, a 15-month-old girl, had three large lymphatic malformations and had undergone sclerotherapy with partial improvement (Figure 1C and 1D). After administration of a 12-week course of sildenafil, the malformations had diminished by about 75%, with the malformation on her back appearing deflated, leaving sagging skin (Figure 1E). Sildenafil was stopped, and mild enlargement was noted 4 weeks later.

Neither child had significant adverse effects from treatment. Both families elected to continue administration of sildenafil after study completion.

Sildenafil selectively inhibits phosphodiesterase-5, preventing the breakdown of cyclic guanosine monophosphate.2 Inhibition of phosphodiesterase-5 decreases the contractility of vascular smooth muscle, producing vasodilation. The drug has been approved for the treatment of pulmonary hypertension in adults; it is used off-label in children with pulmonary hypertension and appears to be safe and effective.3

Lymphatic malformations are hypothesized to develop from primitive lymphatic sacs that arise from mesenchyma or embryologic endothelial networks. The contraction of thickened muscular linings may increase intramural pressure and cause cystic dilatation.4 A potential explanation for the therapeutic effect seen in this series is the relaxation of smooth muscle followed by cystic decompression. Alternatively, relaxation may allow secondary lymphatic spaces to open, or sildenafil may normalize lymphatic endothelial dysfunction.5

The observations described suggest that sildenafil represents an encouraging, propitious treatment for lymphatic malformations, used as monotherapy or with other treatments. A double-blind, placebo-controlled trial is under way.

Glenda L. Swetman, M.D.
Stanford University School of Medicine, Stanford, CA

David R. Berk, M.D.
Washington University School of Medicine, St. Louis, MO

Shreyas S. Vasanawala, M.D., Ph.D.
Jeffrey A. Feinstein, M.D., M.P.H.
Alfred T. Lane, M.D., M.A.
Stanford University School of Medicine, Stanford, California

Anna L. Bruckner, M.D.
University of Colorado School of Medicine, Aurora, CO


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Thursday, February 09, 2012

Neu-Laxova syndrome

Keywords and Terms: Neu-Laxova syndrome, microcephaly, ocular hypertelorism, craniofacial, autosomal recessive, lymphedema, edema, autopsy, Dandy-Walker Malformation, hepatomegaly, transposition of great vessels, IUGR, ichthyosis, Ultrasonography, Cerebellar hypoplasia, Cerebro-osseous-digital syndrome, lethal skeletal dysplasia, lymphatic dysplasia, limb contractures, ocular proptosis, edematous fetus.


Genetic disorder inherited as an autosomal recessive trait.

Risk Factors

Though it is believed to be genetic, researchers have attempted to isolate specific markers such as consanguinity and history of intrauterine death or stillbirth in siblings to help in the prenatal diagnosis of Neu-Laxova Syndrome.


Can be diagnosed through the use of sonography.

“The ultrasonographic may include receding forehead, hypertelorism, cataract, severe ectropion, proptosis, prominent eyes, malformed ears, flat nose, micrognathia, severe microcephaly, lissencephaly, dysgenesis of the corpus callosum, hypoplasia of the cerebellum, Dandy-Walker anomaly, choroid plexus cysts, unilateral renal agenesis, abnormal external genitalia (curved penis, cryptorchidism), hypoechoic skeletal structures, kyphosis, contractures of limbs, swelling and webbing of the knee and elbow joints, and severe edema of the hands and feet, giving the impression of absent digits, edema, polyhydramnios, intrauterine growth retardation and feeble fetal.” (1)

Differential diagnosis:

Lissencephaly, cerebrooculofacioskeletal syndrome, arthrogryposis.


Severe growth delays before birth (intrauterine growth retardation); low birth weight and length; and distinctive abnormalities of the head and facial (craniofacial) region, marked smallness of the head (microcephaly), sloping of the forehead, widely spaced eyes (ocular hypertelorism), generalized edema, Yellow subcutaneous tissue, Syndactyly of fingers, Syndactyly of toes Puffy hands, Puffy feet, Persistent embryonic eye structures, Absent eyelashes, Absent head hair, Underdeveloped genitals, Polyhydramnios, Short umbilical cord, Small placenta..

Also, permanent flexion and immobilization of multiple joints (flexion contractures); other limb malformations; and/or abnormalities of the brain,skin, genitals, kidneys, and/or heart.


Neu-Laxova is universally fatal. There is no known treatment or preventative measures that can be done.


Neu-Laxova syndrome is fatal. Affected individuals are usually stillborn or die within six months of birth.


Rare manifestations of Neu-laxova syndrome.

Feb 2012

Badakali M, Badakali A, Dombale V. Source Department of Obstetrics and Gynecology, S.N. Medical College and Research Centre, Bagalkot, India.


Keywords Neu-Laxova syndrome, growth retardation, autopsy, Dandy-Walker malformation, hepatomegaly, transposition of great vessels

Neu-Laxova syndrome is a rare lethal congenital disorder involving multiple systems. Intrauterine growth retardation, ichthyosis, microcephaly, abnormal facial findings and limb contractures are its key features. We present a stillborn female baby of 1.5 kg with characteristic features including growth retardation, microcephaly, severe ectropion, micrognathia, flattened nose, eclabion, large ears, puffy hands and feet. In addition to these features, lissencephaly, severely hypoplastic cerebrum and corpus callossum, Dandy-Walker malformation, Transposition of Great Vessels and hepatomegaly were noted at autopsy. The patient was born at 38 weeks of gestation to consanguineous (second degree) Indian parents. The mother was 26 year old second gravida with lack of prenatal followup. Therefore, the condition was diagnosed postnatally. Because of the autosomal recessive inheritence of Neu-Laxova syndrome, in countries with high rates of consanguineous marriage, serial prenatal ultrasound examinations with genetic counseling should be performed on pregnant women at high risk to offer termination of affected pregnancies.


Neu-Laxova syndrome: a prenatal diagnosis.

Oct 2011

Dhillon P, Bofill JA.


Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson. 39216, USA.


Neu-Laxova syndrome is a rare autosomal recessive congenital disorder. Prenatal diagnosis is possible via second trimester ultrasonography. Characteristic ultrasound findings include hydramnios, severe intrauterine growth restriction, craniofacial and CNS anomalies, limb contractures, skin lymphedema, skin restrictions, and akinesia. Fewer than 70 cases have been reported, and no survival beyond six months of age is known with most neonatal deaths occurring within the first few days of life. Overall, this is a lethal condition after birth secondary to severe lung hypoplasia and brain anomalies. Herein we report a recent case from our institution with prenatal diagnosis.


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