Peripheral edema of variable degree, usually symmetrical, from moderate (lower limb edema) to severe, including the face and external genitalia, is the main clinical feature, which accounts for 95% of PIL clinical manifestations [⁴]. Moderate serous effusions (pleural effusion, pericarditis, chylous ascites) are common, and life-threatening anasarca may occur rarely throughout the course of the disease [¹,⁵]. The edema is pitting because the oncotic pressure is low due to hypoalbuminemia resulting from exsudative enteropathy. PIL may be suspected at birth or during pregnancy based on ultrasonography images, which can detect fetal ascites or lower limb lymphedema [⁶].

In children, PIL is generally diagnosed before 3 years of age [⁵,⁷,⁸] and may be complicated by fatigue, abdominal pain, nausea, vomiting and weight loss, inability to gain weight and growth retardation [⁵]. Malabsorption may cause fat-soluble vitamin deficiencies and hypocalcemia leading to convulsions [⁵].

-Lymphedema is a rare disorder which is usually not associated with another disease, but it may be associated with intestinal lymphangiectasia. Clinical features of lymphedema are specific (Figure 1). Lymphedema is less pitting than edema due to hypoproteinemia, and is localized to the lower limbs (foot, ankle, calf, rarely thigh) and predominantly bilateral. Upper limb with hand and forearm involvement, lymphedema of breast and external genitalia (with skin thickening) may also be present [⁹]. In most patients with lymphedema, edema as a consequence of hypoproprotidemia has also been observed. The two types of edema are not always easily distinguished. Stemmer's sign is an important element to confirm the diagnosis and differentiate lymphedema from edema: i.e., it is impossible to lift and wrinkle the dorsal skin on the second toe because of skin-thickening as the result of fibrosis.

- Moderate or discontinuous diarrhea is the main digestive symptom [¹⁰].

- An abdominal mass was found in the epigastrium and right upper quadrant of a 12-year-old girl. Ultrasonography failed to confirm an abdominal mass but the mass was attributed to small bowel edema [¹¹].

- A malabsorption syndrome may be encountered in the elderly [¹²].

-Mechanical ileus of the small intestine caused by localized edema leading to intestinal wall-thickening and lumen diminution. It may be visualized as a segmental mass requiring resection (histological findings: dilation of submucosal lymphatics, extensive pseudocysts in the jejunal wall, intramural lymph edema, secondary bleeding, tight stenosis of the jejunal lumen) [¹³].

-Chylous reflux into the skin of the right flank resembles lymphangioma circumscriptum with multiple dome-shaped vesicles filled with milky-white fluid, which is discharged into the surrounding skin [¹⁴].

- Chyle can also backflow into the skin of the lower limb, perineum or external genitalia [¹⁵].

- An association with celiac disease has been reported in children [¹⁶].

-Iron deficiency with anemia occurs secondary to chronic blood loss resulting from non-specific multiple ulcers in the small intestine [¹⁷].

-Necrolytic migratory erythema can be seen [¹⁸].

-Recurrent hemolytic uremic syndrome has been described [¹⁹].

-Osteomalacia resulting from vitamin D deficiency was reported in a 63-year-old woman [²⁰].

- It remains open to debate whether recurrent gastrointestinal bleeding is indeed a manifestation of PIL [²¹].

First described in 1964 by Samman and White, the yellow nail syndrome is a very rare condition which may be associated with PIL. Dystrophic yellow nails with ridging and loss of lunula on the hands are associated with lymphedema and pleural effusions [²²].

Five syndromes are associated with intestinal lymphangiectasia: von Recklinghausen, Turner (X0) or Noonan, Klippel-Trenaunay and Hennekam [²³]. In general, these syndromes are easily distinguishable by the presence of facial abnormalities (Turner, Noonan, Hennekam), mental retardation (Hennekam, Noonan), seizures (Hennekam), severe limb and/or face lymphedema (Hennekam), neurofibromas and other tumors (von Recklinghausen), and hemihypertophy of the limbs associated with vascular malformations (Klippel-Trenaunay).

Although various methods have been proposed to investigate PIL, none of them can replace histological examination of biopsies to confirm the diagnosis.

PIL patients have immunological abnormalities involving both the B-cell and T-cell lineages of the immune system. The B-cell defect is characterized by low immunoglobulin levels (IgG, IgA and IgM) and poor antibody responses [^38-40]. The T-cell defect is characterized by lymphocytopenia, prolonged skin-allograft rejection and impaired in vitro proliferative responses to various stimulants (anti-CD3, anti-CD28) [⁴¹]. Furthermore, PIL patient's peripheral blood samples contain extremely low counts of CD4⁺ T cells, especially na?ve, CD45RA⁺ CD62L⁺, while CD45RO⁺ memory cells, are only moderately below normal. CD45RA⁺ and CD45RO⁺ CD8⁺ T cells are moderately below normal [⁴¹].

It is not clear whether the occurrence of malignancy, especially lymphomas, is fortuitous or related to PIL. Indeed, only a few lymphomas associated with PIL have been reported. Among 50 PIL patients reviewed, 3 had malignant lymphomas, that arose 3 to 25 years after the initial diagnosis [⁶⁰]. The interval from PIL diagnosis to lymphoma diagnosis was even 39 and 40 years in a study [⁶¹]. Some lymphomas were confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum), i.e. in PIL involved sites, while in other patients they were extra-intestinal (retroperitoneum, mediastinum, bone) [^60-63]. In the well-described histological and immunological studies, only B-cell lymphomas (large cells, small cells, centroblastic, immunoblasts) were encountered [⁶¹]. Chemotherapy achieved regression of the exsudative enteropathy in only two of those previous cases [⁶²,⁶³].

Lymphoma may be related to PIL as a consequence of several mechanisms: (1) long-standing protein-losing enteropathy may be resolved after treatment (chemotherapy and/or radiotherapy) [^62-64]; (2) lymphoma may cause secondary intestinal lymphangiectasia, (3) lymphoma in PIL could be associated with an immune deficiency. Indeed, a primary deficiency of B cells and/or helper T cells has been proposed in PIL, in combination with a secondary immune deficiency resulting from the loss of immunoglobulins and lymphocytes [³⁹,⁴⁰]. But no clear evidence of depressed intestinal immunity was found in PIL patients compared to those with other primary immunodeficiencies and having gut infections, like giardiasis.

PIL patients were reported to have diffuse and multiple cutaneous warts in association with lymphoma [⁶⁵,⁶⁶]. Widespread viral warts may be associated with a primary immune deficiency in PIL or secondary to lymphoma.

Although PIL patients have moderate-to-severe hypogammaglobulinemia and lymphopenia, their risk of pyogenic bacterial infection is not significantly elevated and opportunistic infections are uncommon. Only one case of a severe infection with group G streptococcal empyema was reported [⁶⁷] and another had cryptococcal meningitis [⁶⁸].

It is an uncommon disorder characterized by the replacement of hematopoietic cells and adipocytes by amorphous extracellular material composed of acid mucopolysaccharides. The only reported case of a gelatinous transformation of the bone marrow in a PIL patient was attributed to the malnutrition resulting from malabsorption [⁶⁹].

Low-fat diet associated with supplementary medium-chain triglycerides (MCT) is the cornerstone of PIL medical management [⁷⁰]. It is likely that the absence of fat in the diet prevents engorgement of the intestinal lymphatics with chyle, thereby preventing their rupture with its ensuing protein and T-cell loss. MCT are directly absorbed into the portal venous circulation and thus provide nutrient fat but avoid lacteal engorgement. After a few weeks, this treatment may lead to reversal of clinical and biochemical signs (albuminemia, immunoglobulin levels and lymphocyte counts) [⁷¹]. In patients not responding to a low-fat diet, enteral nutritional therapy (elemental, semi-elemental and polymeric diets) may be required. In a few very severe cases, total parenteral nutrition is warranted [⁷²]. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. Long-term PIL monitoring essentially concerns its predominant clinical manifestation (edema). Laboratory analyses (albuminemia, lymphocyte counts, immunoglobulin levels) are required when lower limb edema becomes more pronounced.

In the literature, other treatments have been proposed to treat PIL. They can be used after or in combination with a low-fat diet associated with MCT supplementation. Their efficacy is variable and insufficiently evaluated.