Lymphatic Dysplasia Research Articles

Etiology and Outcome of Hydrops Fetalis: Report of 62 Cases

We aimed to define the etiologic and prognostic factors in live-born infants with hydrops fetalis (HF) in our tertiary neonatal intensive care unit over a 10-year period. Medical records of newborn infants with HF during 2002-2011 were reviewed retrospectively. Demographic data, prenatal interventions, clinical and laboratory findings, outcomes, and the results of postmortem examinations were analyzed. During the study period, 62 newborn infants with HF were identified from 16,200 live-born deliveries and the incidence of HF was 3.8/1000 live births in our hospital. Twenty-eight infants (45.2%) had immune HF, whereas 34 (54.8%) had nonimmune HF. An etiologic factor could be identified in 24 (70.5%) infants with nonimmune HF. Lymphatic dysplasias comprised the majority (23.5%) of the infants with nonimmune HF. Mortality rate was 50%. The presence of two or more serous cavity effusions and gestational age were independently associated with the risk of mortality. Despite the improvements in neonatal care, mortality rate in infants with HF is still high. Gestational age and the extent of serous cavity determine the risk of mortality. Timely and advanced prenatal or postnatal new therapeutic strategies may alter this fatal outcome in appropriate patients.

CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops

BackgroundLymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS.MethodsConsanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes.ResultsBoth siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known ‘cholestasis genes’ did not demonstrate homozygosity in the LCS patient.ConclusionsMutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.

The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings

Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010, we introduced a new classification and diagnostic pathway as a clinical and research tool. This algorithm has been used to delineate specific primary lymphoedema phenotypes, facilitating the discovery of new causative genes. This article reviews the latest molecular findings and provides an updated version of the classification and diagnostic pathway based on this new knowledge.

Postnatal phenotype according to prenatal ultrasound features of Noonan syndrome: a retrospective study of 28 cases

Noonan syndrome is a frequent genetic disorder with autosomal dominant transmission. Classically, it combines postnatal growth restriction with dysmorphic and malformation syndromes that vary widely in expressivity. Lymphatic dysplasia induced during the embryonic stage might interfere with tissue migration. Our hypothesis is that the earlier the edema, the more severe postnatal phenotype. This retrospective study analyzed data from all 32 cases of Noonan syndrome diagnosed in the Medical Genetics Department of Hautepierre Hospital in Strasbourg, France, between 1995 and 2011. The postnatal evolution of Noonan syndrome was compared according to the presence of at least one prenatal ultrasound feature of lymphatic dysplasia. The most frequent prenatal ultrasound features found were increased nuchal translucency, cystic hygroma and polyhydramnios; their global prevalence was 46.4%. The presence of these features was not significantly associated with the postnatal phenotype of Noonan syndrome. The results of our study indicate that prenatal ultrasound features of lymphatic dysplasia do not predict an unfavorable postnatal prognosis for Noonan syndrome.

Primary Congenital Lymphedema Complicated by Hydrops Fetalis: A Case Report and Review of the Literature

Introduction. Primary congenital lymphedema is a rare disorder associated with insufficient development of lymphatic vessels. Usually most patients present with lower extremity edema seen sonographically. Rarely primary congenital lymphedema may be associated with severe lymphatic dysfunction resulting in hydrops fetalis. Case. A 27-year-old primigravida with a family history of leg swelling throughout multiple generations was diagnosed early in the third trimester with hydrops fetalis. Delivery was undertaken at 32 weeks for nonreassuring fetal status and the infant expired at approximately 45 minutes of life. Primary congenital lymphedema was confirmed via molecular testing of the vascular endothelial growth factor receptor-3 gene. Discussion. The diagnosis of PCL is suspected prenatally when ultrasound findings coincide with a positive family history of chronic lower limb lymphedema. Isolated PCL is rarely associated with significant complications. Rarely, however, widespread lymphatic dysplasia may occur, possibly resulting in nonimmune hydrops fetalis.

Noonan Syndrome Presenting as Lymphoedema Precox

Noonan Syndrome is an autosomal dominant disorder characterized by short stature, typical facial features and congenital heart defects. Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, bleeding tendency and lymphatic dysplasia. We are reporting a 13 year old boy of Noonan syndrome presenting with lymphoedema of lower limb and genitalia. DOI: http://dx.doi.org/10.3329/jom.v13i2.12771 J Medicine 2012; 13 : 243-245

Three-dimensional HDlive rendering image of cystic hygroma

Three-dimensional (3D) HDlive rendering images with both adjustable lighting and new skin-like colors give the normal embryo and fetus, fetal anomalies, and intrauterine abnormalities a natural and anatomically realistic appearance [1–4]. Cystic hygroma is characterized by septated fluid-filled sacculations of the bilateral neck and nuchal region that result from lymphatic dysplasia [5]. We present our experience of cystic hygroma reconstructed employing the three-dimensional (3D) HDlive rendering mode. A total of three cystic hygromas at 11-17 weeks’ gestation were studied employing transvaginal or transabdominal 3D sonography with the HDlive rendering mode (VOLUSON E8, General Electric Medical Systems, Zipf, Austria). Using a curved array transabdominal transducer (4–8.5 MHz) or mechanical transvaginal transducer (4.5–11.9 MHz), the sweep took less than a few seconds at an angle of 70 –85 . The data set was stored on a 700-MB CD-R and could be retrieved for further analysis [3, 4]. All volume data for each fetus were examined, and optimal images were selected for further analysis. Three-dimensional reconstruction was carried out using the HDlive rendering algorithm. The light source was adjusted until the structures of interest were visualized for the examiner to create favorable lighting and shadowing effects [4]. The 3D HDlive rendering mode provided new realistic sensations for the diagnosis of cystic hygroma (Figs. 1, 23). There have been three reports on conventional 3D sonographic diagnosis of cystic hygroma [5–7]. However, conventional 3D surface rendering images are not realistic. In the present report, the 3D HDlive rendering mode provided extraordinarily natural and realistic imaging of cystic hygroma, with greater detail and clarity than are possible with conventional 3D sonography. In particular, the 3D HDlive rendering mode provides new realistic sensations for the diagnosis of cystic hygroma in utero, and it seems to be almost impossible to differentiate between gross specimens and 3D HDlive rendering images, because nearphotographic images were obtained by employing the 3D HDlive rendering mode.

Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome

Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well-studied. This cross-sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16-68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full PTPN11 sequencing; 37% were PTPN11 positive, 23% were SOS1 positive, and 3% were BRAF positive. Mean adult height in both men and women was at the 3rd-10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi-organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. Larger studies characterizing the clinical conditions found in NS adults are needed to provide potential genotype-phenotype correlations that may aid in clinical management.

Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations

The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.

정신지체와 주의력결핍 과잉행동장애를 보이는 Noonan 증후군 1예

Noonan syndrome is characterized by short stature, typical facial dysmorphology, and congenital heart defects. The main facial features of Noonan syndrome are hypertelorism with down-slanting palpebral fissures, ptosis, and low-set posteriorly-rotated ears with a thickened helix. The cardiovascular defects most commonly associated with this condition are pulmonary stenosis and hypertrophic cardiomyopathy. Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency, and lymphatic dysplasias. The patient is a 10-year-old boy. He had experienced repeated febrile convulsions. He had typical facial features, a short stature, chest deformity, cryptorchidism, vesicoureteral reflux, and mental retardation. His language and motor development were delayed. When he went to school, it was difficult for him to pay attention, follow directions, and organize tasks. He also displayed behavior such as squirming, leaving his seat in class, and running around inappropriately. Clinical observation is important for the diagnosis, so we report a patient who was diagnosed with Noonan syndrome, mental retardation, and attention-deficit hyperactivity disorder.

Pathologie lymphatique thoracique primitive de l’adulte

Primary thoracic lymphatic diseases are both infrequent and probably under diagnosed. Current classification distinguishes lymphangioma (solitary tumor), lymphangiectasies (dilatation), lymphangiomatosis (proliferation) and lymphatic dysplasia syndrome (dysplasia). Classifications' efforts and radiologic progress may lead to an improvement in the management of these patients.

CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non‐immune hydrops fetalis

<i>CCBE1</i> mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non‐immune hydrops fetalis

Use of somatostatin analogues to treat chylothorax in a child with Generalised Lymphatic Dysplasia

Generalised Lymphatic Dysplasia is a rare condition that may be associated with significant chylothoraces. The management of such effusions is often challenging. We present the case of a 15-year-old girl with bilateral chylothoraces and lymphoedema of her limbs. A clinical diagnosis of Generalised Lymphatic Dysplasia was made and long-term treatment with somatostatin analogues (somatostatin initially followed by monthly octreotide) was initiated. Over 12 months there was symptomatic benefit with some objective improvement in lung function and no adverse effects. After a year of treatment there was some reaccumulation of fluid, however this did not require any intervention. This is the first paediatric report of the use of somatostatin analogues to manage chylothorax in Generalised Lymphatic Dysplasia and we conclude that they represent a potentially useful treatment modality. Experience is only anecdotal however and further studies are required to establish an evidence base with regard to efficacy and safety.

Lymphatic and venous malformation or “lymphangiohemangioma“ of the anterior mediastinum: case report and literature review

Lymphatic and venous malformations (LVM) are tumor-like lesions combining dysplastic lymphatic and venous vessel structures. They are rarely found in the mediastinum. We present a case of mediastinal LVM, with review of the literature. An asymptomatic 60-yearold man presented for evaluation of an anterior mediastinal mass. On chest computed tomography (CT), the mass demonstrated contrast enhancement and its 7-mm vein draining directly into the left brachiocephalic vein. The tumor was resected completely using video-assisted thoracoscopic surgery. The surgical specimen revealed combined features of venous and lymphatic dysplasia, and was diagnosed it as LVM, so-called mediastinal lymphangiohemangioma. Management plans based on precise imaging studies using magnetic resonance imaging and multi-detector-row CT phlebography could be helpful in guiding both preoperative diagnosis and subsequent treatment decisions for mediastinal LVM.

Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel

Lymphedema is a manifestation of lymphatic system insufficiency. It arises from primary lymphatic dysplasia or secondary obliteration after lymph node dissection or irradiation. Although improvement of swelling can be achieved by comprehensive non-operative therapy, treatment of this condition requires lifelong care and good compliance. Recently molecular-based treatments using VEGF-C have been investigated by several researchers. We designed the present study to determine whether the therapeutic efficacy of implanted human adipose-derived stem cells (hADSCs) could be improved by applying a gelatin hydrogel containing VEGF-C (VEGF-C hydrogel) to the site of tissue injury in a lymphedema mouse model. Four weeks after the operation, we evaluated edema and determined lymphatic vessel density at various post-operative time points. Mice treated with hADSCs and VEGF-C hydrogel showed a significantly decreased dermal edema depth compared to the groups of mice that received hADSCs only or VEGF-C hydrogel only. Immunohistochemical analysis also revealed that the hADSC/VEGF-C hydrogel group showed significantly greater lymphatic vessel regeneration than all the other groups. hADSCs were detected in the implantation sites of all mice in the hADSC/VEGF-C group, and exhibited a lymphatic endothelial differentiation phenotype as determined by co-staining PKH-labeled hADSCs for the lymphatic marker LYVE-1. Our results suggest that co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis.

Nonimmune Hydrops Fetalis in the Stillborn

To the Editor, I read with interest the excellent article by Taweevisit and Thorner that was recently published online [1]. The article describes a series of 78 stillborn fetuses with hydrops fetalis (HF) from the Central Region of Thailand. The purposes of the study were to analyze the etiology of HF by performing autopsy investigations and to identify the various causes of nonimmune HF (NIHF) occurring in Thailand. All cases were diagnosed as NIHF. The authors established that the most common cause of NIHF in their series was homozygous alphathalassemia, compatible with the geographic origin of the series. Among other results, the authors state that 9 cases (11.5%) had no identifiable etiology and that 2 cases (2.6%) presented a phenotype indicating a chromosomal or genetic disorder. A systematic review of the etiology of NIHF was recently published [2]. All 5437 reviewed cases were categorized using 14 classification groups. Among these 14 groups, the chromosomal group comprised chromosomal abnormalities and the syndromic group included syndromes defined as clusters of structural malformations, while the idiopathic group comprised undiagnosed cases. The link between a cause and the mechanism that may trigger generalized edema of the fetus is not always clear. Although most of the 14 NIHF categories were assigned to a defined pathophysiological pathway that led to congestive heart failure, obstructed lymphatic flow, low-plasma colloid osmotic pressure, or, lastly, a combination of the above, it was not possible to reliably classify patients who had previously been assigned to the chromosomal or syndromic disorders groups. In this systematic review, the authors concluded that a definitive pathophysiological mechanism could not be identified in 33.6% of cases, including chromosomal (13.4%), syndromic (4.4%), and idiopathic (15.8%) groups. Although chromosomal or syndromic entities make up a great deal of reported causes of NIHF, I feel that these disorders are not NIHF causes per se. In an attempt to reduce the unacceptably high number of ‘‘nondiagnosed’’ (or only apparently diagnosed) cases, autopsy examination is strongly recommended. The usefulness of immunohistochemical staining techniques in the etiologic diagnosis of NIHF was recently described [3]. Seventy-nine fetuses with a diagnosis of NIHF (out of a total of 1098 fetuses) were studied using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40). This study demonstrated that applying a standard autopsy protocol, very similar indeed to Taweevisit and Thorner’s methods, allowed for the identification of an etiologic diagnosis in only 42 of 79 cases. Adding immunohistochemical methods and reevaluating all cases, a specific pathogenetic mechanism leading to NIHF was able to be identified in an additional 17 fetuses (59/79). The difference was statistically significant (chi-square test; P 5 0.005). This study underlined that a pathogenetic mechanism of NIHF (ie, lymph-vessel dysfunction linked to congenital dysplasia), although rarely recognized and only speculated, in fact should seriously be taken into consideration. Although immunohistochemical staining methods to detect lymphatic dysplasia are widely available, they are not usually included in the standard protocol for fetal autopsy studies. The article [3] concluded that specific immunohistochemical techniques should be mandatory in the autopsies for fetuses with NIHF.

Immunohistochemistry in non‐immune hydrops fetalis: A single center experience in 79 fetuses

The objective of our study was to evaluate the usefulness of immunohistochemical (IHC) staining techniques in the etiological diagnosis of non-immune hydrops fetalis (NIHF). The records of all 1,098 autopsies performed between January 1987 and May 2008, by the Division of Fetal Pathology of the University of Genoa, were reviewed and all 79 fetuses diagnosed with NIHF were re-evaluated. Additional IHC staining using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40) were performed. Results were compared to results from the literature. Our results showed that in 67/79 cases, evaluation by standard autopsy protocol led to an etiologic diagnosis. Furthermore, we were able to identify the pathogenetic mechanisms that eventually caused NIHF in 42/79 cases. Adding IHC staining to all evaluations identified the pathogenetic mechanism in a further 17 cases (total 59/79 cases). Lymphatic dysplasia was diagnosed by standard autopsy protocol in 1/79 (1.3%), while adding IHC staining resulted in 18/79 (22.8%) cases being diagnosed (P = 0.0001). The present rate of 22.8% of lymphatic dysplasia in non-immune hydrops fetalis is significantly higher than reported in the literature (36/818 or 4.4%; P = 0.01). In conclusion, specific IHC staining techniques aimed at detecting lymphatic dysplasia are needed and should be mandatory in autopsies of fetuses with non-immune hydrops fetalis.

A new classification system for primary lymphatic dysplasias based on phenotype

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.

Cholelithiasis in a neonate with chylous ascites

A case of a neonate with congenital chylous ascites resulting from primary lymphatic dysplasia is described. The baby also presented with a sludge ball in the gallbladder that eventually progressed to gallstones. The association of chylous ascites with cholelithiasis in this neonate is discussed.

Noonan Sendromlu Bir Olguda Oktreotid ve Orta Zincirli Yağ Asitleri Kullanılarak Şilotoraksın Başarılı Tedavisi

Noonan syndrome (NS), is an autosomal dominant disorder commonly seen in childhood and is characterized by short stature, congenital heart defects and facial abnormalities (especially in adults) along with thoracic deformity. Lymphatic dysplasia can be seen with this syndrome causing chylothorax by development of fistulas between thoracic duct and pleural space or it can directly occur by malformation of thoracic lymphatic vessels. Hence, chylothorax can also be seen. Herein, we present a case with this syndrome and chylothorax secondary to possible lymphatic dysplasia. We achieved a great success with ocreotide and medium chain trigliserides in the management of chylothorax and hence suggest this therapy to other clinicians.