LYMPHODYSPLASIA AND KRAS MUTATION: A CASE REPORT AND LITERATURE REVIEW.

Cardio-facio-cutaneous (CFC) syndrome is a very rare and sporadic disease whose characteristics include dysmorphic facial appearance, ectodermal abnormalities, cardiac abnormalities, growth retardation and neurodevelopmental delay. This syndrome is classified as one of the RAS syndromes which are caused by altered signal transduction of the RAS/MAPK (mitogen activated protein kinase) pathway due to the mutation of genes including BRAF, MEK1/2, HRAS and KRAS. Other RAS syndromes, such as Costello syndrome and Noonan syndrome, share clinical features with CFC. Moreover, patients with the same clinical phenotype may have different molecular diagnoses. Clinical diagnosis is the starting pointfor correct classification. We describe the clinical data of one case of CFC syndrome, genetically determined by KRAS mutation, that involved chylothorax, lymphedema, sinus pericranii, craniosynostosis, and seizures. This is the second case report of the literature.

Lymphoscintigraphy patterns in newborns and children with congenital lymphatic dysplasia.

We performed lymphoscintigraphy on 31 patients (newborns and children) affected by congenital lymphatic dysplasia according to our previously published protocol. Congenital lymphatic dysplasia may present with various degrees of clinical severity, ranging from nonimmune hydrops fetalis with visceral effusions to lymphedema alone. We recommend that lymphoscintigraphy should be strongly considered in all patients with signs of lymphatic dysplasia, including those with minimal and initial signs of lymphatic impairment, in order to obtain a very early diagnosis and to start treatment. Lymphoscintigraphy is safe and useful in the diagnosis of lymphatic dysplasia in the newborn and children. Moreover, it is well tolerated by patients and well accepted by their parents.

Dynamics of pleural fluid effusion and chylothorax in the fetus and newborn: role of the lymphatic system.

Pleural fluid effusion particularly chylothorax is a relatively rare occurrence in the newborn, but when it occurs it is often life-threatening. In this article, we describe and illustrate the morphologic features of the visceral and parietal pleura including pleural lymphatics and the physiology and pathophysiology of pleural fluid balance. The role and function of the lymphatic system in controlling the volume and composition of pleural liquid are detailed and a conceptual scheme presented. Finally, the crucial role of inadequate lymphatic drainage (either functional overload from an imbalance in Starling forces or mechanical insufficiency from lymphatic dysplasia) is emphasized.

Are there lymphatic vessels in the placenta?

The role of lymphatics in placentation has been scantily studied and the true existence of placental lymphatics is under debate. Numerous blood and lymphatic-lineage molecule markers are now available and they are expressed in human placental tissue. D2-40 expression at the placental stromal level seems to indicate that network-forming, podoplanin-expressing cells may act as a reticular-lymphatic-like conductive network. This exciting area at the intersection of perinatology and lymphology needs further investigation.

Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study.

This retrospective study was carried out at eight Neonatal Intensive Care Units (NICU) Centers worldwide on 33 newborns presenting at birth with pleural, pericardial, or abdominal chylous effusions. Diagnosis of chylous effusion is based on findings of fluid with a milk-like appearance, a concentration of triglycerides in pleural effusion >1.1 mmol/l, and a total cell count >1,000 cells/ml with a predominance of >80% lymphocytes. Thirty-three newborns met the inclusion criteria and were studied. Six subjects who presented at birth with fetal effusion were treated by in-utero pleuro-amniotic shunt. Five of these patients are alive at follow-up. At birth, pleural drainage was performed in 29/33 patients and abdominal drainage was carried out in 3/33. Total parenteral nutrition (TPN) was given to 32/33 patients; 19/23 patients were fed a medium-chain triglycerides (MCT). No adverse effects were observed. Eight patients were treated with Octreotide at dosages ranging from 1 to 7 mcg/kg/hour for 8 to 35 days. All patients showed decreased chylous production. Two patients were treated by pleurodesis. Twenty-two babies are alive after at least 6 months follow-up, 9/33 are deceased, and 2 were lost to follow-up. Clinical conditions of survivors are basically good except for lung involvement [chronic lung disease (CLD) or lung lymphangiectasia] and lymphedema. All patients were using a MCT diet at follow-up with good control of chylous effusion. Visceral chylous effusions of the fetus and neonate are rare disorders, and there currently is only partial agreement on decision-making strategies. We suggest the need for an international prospective trial in an effort to establish the efficacy and effectiveness of diagnostic and therapeutic options described in this article.

Perinatal deaths and lymphatic system involvement: a diagnostic flow-chart applying immunohistochemical methods.

A diagnostic flow chart is presented for use in case of perinatal death or still birth with non-immune hydrops fetalis, visceral effusions, or increased nuchal translucency. Immunohistochemical staining with CD-31, CD-34, D2-40, and smooth muscle actin is recommended.

Congenital lymphatic dysplasia in Kabuki syndrome: first report of an unusual association.

Kabuki syndrome was first described in Japan in 1981 as a rare disorder of unknown cause. Its main features include characteristic facies, postnatal growth retardation, and mental delay. To date, there is no molecular marker for Kabuki syndrome, which is considered genetically heterogeneous and still is a clinically-based diagnosis. Here we describe the first case of a patient affected by Kabuki syndrome associated with lymphatic dysplasia. We suggest accurate evaluation of all Kabuki patients as early as possible in order to diagnose lymphedema or other clinical manifestations of lymphatic system involvement. Early identification of lymphatic system maldevelopment provides the best chance for reducing the risk of developing progressive lymphedema with associated tissue changes (fibrosis, sclerosis, and fat deposition).

The role of lymphoscintigraphy in the diagnosis of lymphedema in Turner syndrome.

Lymphedema can be present in patients affected by Turner syndrome (TS) with the dorsum of the hands and feet most commonly affected. This lymphedema results from underdevelopment of the lymphatic system before birth, and it usually decreases during childhood. The aim of our study was to evaluate the role of lymphoscintigraphy as a diagnostic tool in patients with TS to assess possible impairments in the lymphatic system. Eighteen patients with TS were karyotyped to confirm diagnosis and were evaluated by lymphoscintigraphy. Lymphatic dysfunction was demonstrated in 15/18 patients. Lymphoscintigraphic studies showed: 1) lymphatic channels, 2) collateral lymphatic channels, 3) interrupted lymphatic structures, and 4) lymph nodes of the deep lymphatic system. Our data demonstrate that lymphoscintigraphy should be mandatory not only in patients affected by Turner syndrome with signs of lymphatic dysplasia but also in those with minimal or absent signs of lymphatic impairment in order to obtain a very early diagnosis and to provide substantial information for possible medical or surgical treatment.

Selective D2-40 lymphatic endothelium immunoreactivity in developing human fetal skin appendages.

D2-40 is a novel monoclonal antibody that recognizes a 40,000 Da O-linked sialoglycoprotein podoplanin. Although its use is becoming more common, little work has been done with human foetuses. We initiated an evaluation of D2-40 antibody immunoreactivity in developing cutaneous adnexa of human fetuses at various gestational ages. Starting from a retrospective cohort of 1,098 human fetal autopsies we identified and selected a total of 48 fetuses ranging from the 12th week gestational age to term appropriate for this study. We demonstrated that the gems of the hair follicles were D2-40 negative in fetuses from the 12th to 15th week gestation, positive in fetuses between the 16th and 20th week of gestation, negative in fetuses from the 21st week gestation to term. Normal adult controls were also negative. This is the first report to demonstrate intense D2-40 immunoreactivity in the gems of hair follicles of developing human skin.

Congenital lymphatic dysplasias: genetics review and resources for the lymphologist.

Diagnosing congenital lymphatic dysplasia and counseling the parents of babies with possible genetic conditions represents a difficult task. This article attempts to provide a guide to establishing genetic tools and a reference library for use in the diagnostic work-up of congenital lymphatic diseases. The tools that are outlined herein are not meant to replace genetic counseling; their role is merely to facilitate the interaction between lymphologist and geneticist. These tools are a way of identifying lymphatic dysplasias at a very early stage.

Immunohistochemical studies in a hydroptic fetus with pulmonary lymphangiectasia and trisomy 21.

This case report presents a hydroptic trisomy 21 fetus affected by lymphatic dysplasia with no other malformations. Our studies using CD31, CD34, smooth muscle actin, desmin, and D2-40 antibodies immunohistochemistry confirm the diagnosis of severe pulmonary lymphangiectasia associated with lymphangiectasia ih the mediastinum and small bowel.

Lymphodynamics in the fetus and newborn.

Body fluid is distributed among three major fluid spaces: plasma, interstitial fluid, and intracellular fluid. The distribution of fluid in each of these compartments is dramatically different in the fetus and newborn compared to the adult. In addition, the amniotic fluid that surrounds the fetus may also be considered an extension of the extracellular space of the fetus. The purpose of this review is to discuss the complex mechanism that regulates volume in the fetus and newborn as well as the regulation of fluid distribution between the plasma and interstitial fluid, while placing special emphasis on the role the lymphatic system plays in mediating and maintaining this distribution.

Pulmonary lymphangiectasia.

Congenital pulmonary lymphangiectasia (PL) is a rare developmental disorder involving the lung and is characterized by pulmonary subpleural, interlobar, perivascular, and peribronchial lymphatic dilatation. Both frequency and etiology are unknown. PL presents at birth with severe respiratory distress, tachypnea, and cyanosis, with a very high mortality rate at or within a few hours of birth. At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated to prolonged pleural drainage. Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy present medical problems which are characteristic of chronic lung disease.

Persistence of Müllerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the Urioste syndrome.

We describe two newborn brothers with a pattern of malformation characterized by the persistence of Müllerian duct derivatives, intestinal lymphangiectasia, hypertrophied alveolar ridges, and early death. Postmortem examination showed the presence of a rudimentary uterus, fallopian tubes, the upper third of a vagina, a prostate of normal shape, a dilated colon, and generalized intestinal and pulmonary lymphangiectasia. The syndrome was first delineated by Urioste and co-workers [1993: Am J Med Genet 47:494-503]. These cases confirm the existence of a definite and distinct entity.

Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

The Genoa experience of prenatal diagnosis in NF1.

Type 1 neurofibromatosis (NF1) is an autosomal dominant disorder with an incidence of about 1 in 3500 live births. Symptoms are highly variable from a few cafè-au-lait spots and axillary freckling to plexiform neurofibromas, optic gliomas, pseudarthrosis, and malignancy. Since disease causing mutations are dispersed throughout the gene, prenatal diagnosis is usually performed in familial cases by linkage analysis and rarely by direct characterization of the mutation. We have characterized 48 families and have performed four prenatal diagnoses. In three cases, the linkage analysis was carried out using informative markers. A direct approach using the protein truncation test (PTT) and sequencing was performed in one case in which a R1947X mutation was identified. The extreme variability of the phenotypic expression of the NF1 gene makes reproductive decisions in NF1 families very difficult, as molecular diagnosis cannot predict clinical expression of the disease. The psychological management of the couple is therefore difficult. In two of the three examined families the reproductive choices were not influenced by the specific manifestations of the disease in that family.