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14.1 Introduction

Lymphedema is a chronic, often progressive swelling of subcutaneous tissue due to failure of the lymphatic system to drain fluid from the interstitial spaces, causing fluid accumulation. Clinically a distinction is made between “primary” and “secondary” lymphedema (Rockson and Rivera 2008). Primary lymphedema is defined as lymphedema caused by dysplasia of the lymph vessels. It is usually congenital and genetically determined. It can be either isolated, so without manifestations in other tissues or outside the lymph vessels, or be part of a disorder that shows other signs and/or symptoms as well (syndrome). The distinction between isolated forms of lymphedema and those that are part of a more generalized entity is not strict as it also depends on the detail of the studies in affected individuals to search for other characteristics next to lymphedema. For instance the presence of an additional row of eyelashes (distichiasis) can be easily missed if not specifically searched for. Primary lymphedema usually affects the extremities as a result of abnormal regional lymph drainage, although visceral drainage showing in lymphangiectasias of for instance gut or lung can also be impaired. Secondary lymphedema is acquired, typically as consequence of an infection, trauma, or malignancy, and will not be discussed any further in this chapter.

Primary lymphedema in children can cause considerable diagnostic difficulties to clinicians and distress to parents. It is essential to obtain a rapid diagnosis and to implement correct treatment at the earliest opportunity. It is estimated that many physicians and surgeons will see less than ten cases of lymphedema in a year (Tiwari et al. 2006). It is therefore imperative that patients are referred at an early stage to a clinic with wide experience and expertise in diagnostics and treatment. Primary lymphedema can also show in lymphangiectasia of internal organs. When affecting the intestines it produces a protein-losing enteropathy and severe malabsorption of lipids and other nutrients (Braamskamp et al. 2010) Congenital pulmonary lymphangiectasia is a rare developmental disorder involving the lung and characterized by pulmonary subpleural, interlobar, perivascular, and peribronchial lymphatic dilatation, complicated by chylous pleural effusion (Bellini et al. 2006). Lymphangiectasias can also occur in other internal organs such as the pericardium, kidneys, and thyroid gland (Van Balkom et al. 2002). Lymphedema should be discerned from lipedema. This is a poorly understood condition characterized by swelling and enlargement of the lower limbs due to abnormal deposition of subcutaneous fat. Lymphatic system involvement seems likely but is actually debated (Child et al. 2010).

The increased knowledge regarding the etiology and pathogenesis of inherited disorders involving the lymphatic system has offered further insight in lymph vessel formation in general. Developments in lymphatic biology and various pathways and mechanisms through which the lymphatic system contributes to the pathogenesis of disorders have been reviewed elsewhere extensively (Tammela and Alitalo 2010; Alitalo 2011; Martinez-Corral and Makinen 2013) and are out of the scope of the present chapter.

14.2 Epidemiology

According to World Health Organization, lymphedema has a worldwide incidence of 300 million cases (~1 in every 20 individuals). Almost half of lymphedemas are of primary origin, due to congenital lymphatic dysplasia and subsequent poor functioning of lymph nodes and/or lymphatic vessels. Some 70 million are of parasitic origin (especially Filaria Bancrofti); 50 million are postsurgery cases, often following breast cancer surgery. The remaining 30 million cases are likely caused by functional problems related to water overload on lymphatic circulation (http://www.chirurgiadeilinfatici.it/en/lymphatic-diseases/lymphedema/epidemiology). The exact prevalence of primary lymphedema is unknown. Within the USA, it has been estimated to be 1.15 per 100,000 children (Smeltzer et al. 1985). A population prevalence of 1.33 per 1,000 for all ages has been reported, but it is probably an underestimation of the true burden of disease (Moffatt et al. 2003). A female preponderance (M:F = 1:3) is documented, although in part this may represent ascertainment bias.

14.3 Classifications

Primary lymphedema is chronic edema, in which fluid accumulates due to abnormal structure or functions of the lymphatic system (Mortimer 1995). In most cases, edema will be present from birth, but in some cases the lymphedema develops at a later age despite the lymphatic dysplasia being present congenitally. Possibly an increased need of lymphatic functioning due to increased body size and weight or other factors such as hormones or external influences plays a role. Primary isolated lymphatic dysplasias constitute a spectrum of disorders that may manifest by a variety of clinical presentations: lymphedema, chylous effusions, lymphangiomatous malformations with cystic masses and localized gigantism, intestinal lymphangiectasia with malabsorption, lung lymphangiectasia, and lymphangiectasias of other internal organs and glands. Clinical classification of the various types of primary isolated lymphedema has historically been into three groups: lymphedema congenita, lymphedema praecox, and lymphedema tarda. Such classification based purely on the age of onset of the lymphedema does not take into account many other aspects of lymphedema and hinders a refined, detailed classification of phenotypes.

Anomalies of the lymphatic system should be considered as part of vascular anomalies. Mulliken and Glowacki (1982) proposed a classification system for vascular anomalies based on the clinical manifestations and endothelial cell characteristics into two main groups, i.e., hemangiomas and vascular malformations. This classification was adopted by the International Society for the Study of Vascular Anomalies (ISSVA) and with some subsequent modifications widely accepted. At present the two main types of vascular anomalies are vascular tumors (the most common type being hemangioma) and vascular malformations (Enjolras and Mulliken 1997) (Table 14.1). The term malformation that is used in this and other publications to indicate this is mostly wrong as the anomalies are in fact no malformations but dysplasias, although exceptions exist (Hennekam et al. 2013). However, to avoid confusion, we have chosen to use here the terminology used by the ISSVA and will discuss the right terminology with the ISSVA. Vascular malformations include slow-flow malformations which contain the lymphatic malformations (LM). The ISSVA uses a similar classification, splitting the congenital lymphatic dysplasias in truncular (T) or extratruncular (ET), depending on endothelial cells characteristics and the embryonic stage at which the defect was produced. The ET-LMs are embryonic remnants, which have occurred during early stages of vasculogenesis. The immature mesenchymal tissue (in fact dysplastic tissue), of which these malformations are formed, maintains a proliferative capacity. In the case stimuli occur such as pregnancy, hormonal stimulation, trauma, or surgery, ET-LMs can be stimulated and develop into (micro- and/or macro-) cystic lesions: lymphangioma. The T-LMs develop later during embryogenesis. The vascular tissue is mature and no longer has proliferative capacity. Primary lymphedema is linked with such malformations (Lee et al. 2005).

Table 14.1 Main characteristics of primary isolated lymphatic malfunctioning
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The Hamburg classification (7th international ISSVA workshop on vascular anomalies, Hamburg, 1988) distinguishes congenital vascular malformations (CVMs) in truncular (T) and extratruncular (ET) forms (Belov 1993; Lee et al. 2005). The Hamburg classification includes a further group of mixed venous malformations (VMs), identified as hemolymphatic malformation (HLM), making the classification of lymphatic malformations (LM) difficult and confusing. The majority of LM lesion exists as an “independent” form of the CVM, either as primary lymphedema representing “truncular” LM lesion or as cystic, cavernous, or capillary lymphangioma representing “extratruncular” LM lesion. Extratruncular LM lesion and truncular LM lesion co-occur together infrequently. In our opinion the Hamburg classification causes considerable problems. It is often extremely difficult to determine whether a finding is truncular or extratruncular as in fact this asks for detailed embryological studies in animal models and in fact also in humans, and the subdivision as is made now is build only for a small part on solid embryological grounds. The various terms used in the classification are often not sufficiently carefully chosen as malformations and dysplasias are insufficiently discerned from one another while this distinction has significant consequences in patient care. Lastly, the subdivision of the various forms of lymphatic malfunctioning is in our opinion not helpful in diagnostics or in providing optimal care to patients, and these issues should be the main determinants in any classification of disorders. A new classification of lymphatic malfunctioning is urgently needed.

Clinically, lymph reflux (backflow of lymph) may occur localized or at systemic level. The backflow of chyle from intestine is characteristic of intestinal lymphangiectasia. Intestinal lymphangiectasia results in protein-losing gastro-enteropathy, but it can also affect the abdominal lymphatics or the thoracic duct; if the latter occurs, a chylothorax may develop. The primitive backflow at the level of pleural and pulmonary lymphatics results in pulmonary lymphangiectasia. Lymphangiectasia presents as dilated lymphatics and is usually associated with lymphedema. The pressure in the dilated lymphatics is increased, causing leakage of lymph into surrounding tissues. Lymphangiomatosis is characterized by well-differentiated lymphatic capillaries which are dilated forming cysts and are not always associated with lymphedema. This collection of dilated lymphatics is typically isolated from the remainder of the lymphatic system, which can be completely normal. These are thought to arise from inappropriate connection of the embryonic lymph sacs with the lymphatic system during embryogenesis. The lymphangioma may be uni- or multilocular and macro- or microcystic and may occur in any part of the body. The most common site is the neck (cystic hygroma). Lymphangiomatosis is the widespread, multifocal occurrence of lymphangioma, which can grow aggressively. Lymphangiomatosis can be difficult to diagnose.

In general, LM may coexist with a wide spectrum of CVM and thus be part of complex disorders, affecting the entire circulation system: arteries, veins, lymphatics, and capillaries. This occurrence can be demonstrated in Klippel-Trenaunay syndrome, in which LM may coexist with venous and capillary malformation, or in Parkes Weber syndrome, in which LM presents in association with AV malformation. Indeed, in the entity that goes along with the most widespread lymphatic dysplasia, Hennekam syndrome, the co-occurrence of anomalies of other parts of the vascular system has been described (Van Balkom et al. 2002; Alders et al. 2013). Table 14.1 summarizes the main characteristics of the LMs.

14.4 Isolated Types

Primary congenital lymphedema (Milroy syndrome) is an autosomal dominant disorder of the peripheral lymphatics characterized by lower limb lymphedema, typically affecting the dorsum of the feet. It is usually bilateral and present at birth or evident soon thereafter. Milroy syndrome can also present as lymphedema of the upper limbs, or in markedly affected individuals, the lymphedema can start at the lower limbs and become present at the upper limbs later in life. In such individuals also the external genitalia may become affected, and the differentiation with more marked lymphedema as can be present in Hennekam syndrome may be difficult. Indeed molecularly proven cases with chylothorax and hydrops fetalis have been described (Daniel-Spiegel et al. 2005). Usually the lymphedema in Milroy syndrome becomes gradually more marked during life although rarely it can improve during life as well. The severity of lymphedema shows a marked variability, also intrafamilial, and careful evaluation of family members is regularly needed to establish whom in the family is affected or not. Milroy syndrome can be caused by mutations in FLT4 and GJC2 and may also be caused by VEGFC mutations.

Primary lymphedema at an older age (Meige syndrome) is an autosomal dominant disorder characterized by peripheral lymphedema predominantly in the lower limbs with onset around puberty. It is thought that the lymphatic system normally functions at ~10 % capacity (Connell et al. 2009). It is assumed to be caused by underdevelopment of the lymphatic vessels, which is however still sufficient in the first years of life but becomes functionally insufficient with increased body size and due to other such as puberty. Upper limb and facial involvement can also present. The lymphedema, which occurs in Meige syndrome, is clinically indistinguishable from that found in the lymphedema-distichiasis syndrome. Indeed there have been publications reporting on FOXC2 mutations in Meige syndrome, but likely this was a family with lymphedema-distichiasis syndrome. Until now no causative gene for Meige syndrome has been reported. It should be noted there is also an adult-onset segmental dystonia that is termed Meige syndrome (OMIM #128100).

Primary intestinal lymphangiectasia (Vignes and Bellanger 2008) is a disorder with unknown prevalence but which seems to occur only infrequently. It is characterized by hypoproteinemia, edema, and lymphocytopenia, resulting from loss of lymph fluid into the gastrointestinal tract due to intestinal lymphatic vessels dilatation, thus resulting in protein-losing gastro-enteropathy. The loss of lymph fluid can be confirmed by the elevated 24-h clearance of alpha-1-antitrypsin in stools. Bilateral lower limb edema and diarrhea are typical clinical signs that are secondary to the gastro-enteropathy. Lymphocytopenia, hypogammaglobulinemia, hypocalcemia, trace metal deficiency due to malabsorption, and chylous pleural effusions and chylous ascites may occur as secondary consequences in long-standing lymphangiectasia. Primary limb lymphedema may be present as well which can be difficult to distinguish from edema. If this occurs, more generalized lymphatic dysplasia such as occurs in Hennekam syndrome must be considered.

Primary pulmonary lymphangiectasia (Bellini et al. 2006) is an infrequently described developmental disorder involving the lung and characterized by pulmonary subpleural, interlobar, perivascular, and peribronchial lymphatic dilatation. The prevalence is unknown. Pulmonary lymphangiectasias typically present at birth with severe respiratory distress, tachypnea, and cyanosis, with a very high mortality rate at birth or within a few hours of birth. Most reported cases are sporadic and the etiology remains unexplained. Patients affected by PL who survive infancy present medical problems which are characteristic of chronic lung disease. Pulmonary lymphangiectasias also develop at a later age (often puberty of adolescence) in more generalized lymphatic dysplasias such as Hennekam syndrome. Also in such individuals the course is typically unpredictable but eventually fatal.

Chylothorax is defined as an accumulation of chyle in the pleural space. Chylothorax should be considered as a common endpoint for a variety of pathological processes including intrinsic abnormalities of the lymphatic system or disruption of the thoracic duct via trauma, surgery, malignancy, or cardiovascular disease. Congenital defects of the thoracic duct, either isolated or associated with generalized lymphatic vessel dysplasia, are the most frequent cause of congenital chylothorax. Congenital chylothorax is a rare cause of respiratory distress in the newborn but is the most common form of pleural effusion in the neonatal period. Reported incidence ranges from 1:1,000 to 1:15,000 pregnancies (Dubin et al. 2000). The actual incidence in man is probably higher, as intrauterine fetal death as well as stillbirth might well be underestimated. Although familial occurrence has been reported the exact pattern inheritance is not yet known. There is a 2:1 male to female predominance. Both X-linked and autosomal recessive inheritance have been suggested (Straats et al. 1980) and in our opinion it is likely genetically heterogeneous. It has been suggested that congenital pulmonary lymphangiectasia is a constant pathological finding in congenital chylothorax and that this may imply a common pathogenesis for these disorders (Bellini et al., 2006; Bellini et al., in press).

The course of congenital chylothorax varies widely and the prognosis is unpredictable. Overall mortality for congenital chylothorax has been reported as high as 50 %. The presence of hydrops fetalis has significant prognostic implications (Dubin et al. 2000). In cases of chylothorax complicated by hydrops fetalis, a decrease in survival from 100 to 52 % has been reported. Still, nonimmune hydrops caused by chylothorax carries a better prognosis than nonimmune hydrops in general. The frequency of spontaneous resolution, which may occur either before or after birth, is still unknown. Lymphangiomatosis and lymphangiectasia are the two main anomalies of lymphatic development that cause chylothorax (Fox et al. 1998).

14.5 Syndrome Types

We performed a literature search to obtain an overview of syndromic forms of primary lymphatic malfunctioning. We used the online edition of Mendelian Inheritance in Man and the Winter-Baraitser Dysmorphology Database (WBDD), using as search terms lymphedema, lymphangiectasia, and chylothorax. OMIM is the comprehensive compendium of human genes and genetically determined phenotypes. OMIM contains information on all known Mendelian disorders and over 12,000 genes (http://www.ncbi.nlm.nih.gov/omim). The Winter–Baraitser Dysmorphology Database currently contains information on ~6,000 entities characterized by one or more morphologic abnormalities. It includes Mendelian disorders, chromosomal imbalances, sporadic conditions, and those caused by environmental agents (http://www.lmdatabases.com/).

The thus retrieved entries are summarized in Table 14.2, which contains the main characteristics of each entity such as chromosomal locus, gene involved, pattern of inheritance, and major clinical manifestations. It is impossible to discuss each entity listed in detail. Therefore we will only provide short descriptions of three entities that we consider paradigmatic of the various form of lymphatic maldevelopment.

Table 14.2 Main characteristics of primary lymphatic malfunctioning as part of a syndrome
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Lymphedema-distichiasis syndrome is a single gene disorder caused by FOXC2 (forkhead transcription factor) mutations (Sutkowska et al. 2012). Distichiasis (from Greek “distikhos,” meaning two rows) is a congenital anomalous growth of eyelashes from the meibomian glands of the eyelid, causing the presence of a double row of eyelashes. It has been suggested that the lymphatic vessel malfunction may be linked to lymphatic valvular insufficiency which causes marked lymphatic reflux (Brice et al. 2002). The severity of lymphedema varies among families and among affected individuals of a single family and is linked to the grade of lymph reflux. “Yellow nail syndrome” has been published as a separate entity characterized by lymphedema and yellow, dystrophic, thick, and slowly growing nails. However, it has become likely that the thickening and yellow discoloration of the nails is not a distinctive sign and can occur in several marked forms of distal limb lymphedema, and most patients with “yellow nail syndrome” may in fact have had lymphedema-distichiasis syndrome (Rezaie et al. 2008).

Hennekam syndrome is a form of very marked lymphatic dysplasia, in which lymph vessels in all body areas are affected (Van Balkom et al. 2002; Alders et al. 2013) and which is caused by mutation in CCBE1 (Alders et al. 2009). These are also already affected prenatally, and the facial manifestations are thought to be explainable this way. According to the original description (Hennekam et al. 1989) the main characteristics are lymphedema, intestinal lymphangiectasia, intellectual disability (which can be markedly different, also within a single sibship, varying from moderate to severe intellectual disability to completely normal development), and facial signs. The lymphedema has always been congenital, sometimes markedly asymmetric, and after initial decrease in the first years of life has become often gradually progressive with age. Lymphangiectasias are not limited to the intestines but can also be found in the lungs, pleura, pericardium, thyroid gland, and kidneys.

Noonan syndrome is a well-known and frequent entity that is mainly characterized by short stature, unusual face, webbing of the neck, a combined pectus carinatum and excavatum, pulmonic stenosis and later on an increased chance to develop a cardiomyopathy, and a host of further major and minor anomalies. Congenital lymphedema of the distal upper and lower limbs is often but not always present. Some infants and children develop more marked lymphatic malfunctioning including intestinal lymphangiectasias and chylothorax. Within families the variability of the lymphatic system involvement can vary very widely. Indeed even newborns with fatal hydrops have been born to an affected parent with only limited manifestations of the syndrome. Noonan syndrome can be caused by a series of genes that all act in the same MAPK pathway and is one of the entities that form the rasopathies (Rauen 2013).

14.6 Molecular Findings

In isolated and syndromic primary lymphedema various patterns of inheritance can be recognized. The etiology and pathogenesis of the group of disorders is only partially understood (Table 14.2), but research in this field has improved significantly in recent years due to advances in sequencing techniques. Mutations in VEGFR3, FOXC2, and SOX18 are known to cause Milroy disease, lymphedema-distichiasis syndrome, and hypotrichosis-telangiectasia-lymphedema syndrome, respectively (Ferrell et al. 1998; Fang et al. 2000; Irrthum et al. 2003; Brice et al. 2005) and VEGFC mutations have been found in a Milroy-like disorder (Gordon et al. 2013). CCBE1 has been reported to be mutated in a proportion of patients with Hennekam syndrome and the analysis of this gene should be studied in every patient with a Hennekam syndrome phenotype or otherwise marked lymphatic malfunctioning (Alders et al. 2009, 2013; Connell et al. 2010), irrespective of the cognitive functioning of affected individuals or the presence or absence of other abnormalities. Chromosome imbalances often result in multiple organ defects and the lymphatic system can be part of this as well, although this is not common, except for Turner syndrome. The number of genes known to cause isolated primary lymphatic malfunctioning is still relatively small compared to the number of genes known to cause similar vascular malfunctioning, and we may expect several other genes to be recognized as being involved in lymphangiogenesis or lymphatic functioning. Indeed sequencing of a series of biologically plausible candidate genes such as PROX1, EMILLIN1, LCP2, LYVE1, NRP2, PDPN, and SYK has been suggested as these may be involved in primary lymphedema families.

14.7 Diagnostic Work-Up

The approach to establish the diagnosis in the often complex and sometimes confusing lymphatic disorders can cause difficulties. We suggest a general scheme to provide help in the diagnostic process that can be generally applied in disorders that go along with lymphatic malfunctioning. In all patients a detailed family history of at least two generations and including information to the existence of a possible consanguinity between the parents should be obtained. The examination of a fetus with a suspected lymphatic dysplasia may comprise amniotic fluid examination and chorionic villi study, in particular searching for inherited metabolic disease, lysosomal storage diseases (LSD) included. The examination of a deceased fetus may include autopsy, including babygram, photo-documentation, immunohistochemical studies, and also a skin biopsy (both for DNA collection and to have access to cultivated cells), samples of other tissues, examination of the placenta, and obtaining and evaluation of fetal urine for metabolic disorders.

Lymphedema in an infant or child is usually diagnosed clinically, but in case of doubt lymphoscintigraphy is the main instrument to establish the diagnosis of lymphedema and to visualize peripheral lymphatic vessels. Lymphoscintigraphy relies on one of the essential functions of the lymphatic system, i.e., to transport lymph. Thus, it can demonstrate each defect in lymphatic functions, as delayed lymphatic drainage, asymmetric or absent visualization of regional lymph nodes, dermal backflow, and interrupted lymphatic structures (Keeley 2006). It can study both superficial and deep lymphatic circulation. Lymphoscintigraphy has been demonstrated to be safe and effective in newborns and in children (Bellini et al. 2008). The diagnostic approach in an individual with visceral lymphangiectasia is usually complex. Lymphoscintigraphy may be helpful and is often combined with computerized tomography scanning and interstitial magnetic resonance imaging. These combined methods of studying lymphatic anomalies are nor widely available however. Additional laboratory exams are usually indicated if lymphangiectasias are present. Determining fecal excretion of alpha-1-antitrypsin helps in diagnosing a protein-losing syndrome and points to intestinal lymphangiectasias. If visceral effusions are present, such as chylothorax, chylopericardium, and chylous ascites, the abnormal fluids should be obtained and examined to evaluate the triglyceride level (pointing to lymph if >110 mg/dL [= 1.1 mmol/L]), presence of chylomicrons (Sudan III staining), determining the absolute cell count (pointing to lymph if >1,000 cs/mcL, with a lymphocyte fraction of >75–90 %), and the cholesterol level (abnormal if 60 mg/dL or above) (Bellini et al. 2012).

Recognizing congenital lymphatic disorders and diagnosing reliably lymphatic malfunctioning are still challenging. It still starts with clinical recognition, but likely other tools that are patient-friendly such as molecular genetics and other biomarkers can be developed in the near future.