Developmental Disorders of the Lymphatics

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Thursday, April 06, 2006

Congenital Intestinal Lymphatic Hypoplasia Presenting as Non-Immune Hydrops In Utero, and Subsequent Neonatal Protein-Losing Enteropathy

Journal of Pediatric Gastroenterology and Nutrition: Volume 35(5) November 2002 pp 691-694

Stormon, M.O.*; Mitchell, J.D.*‡; Smoleniec, J.S.§; Tobias, V.†; Day, A.S.*‡

Departments of Gastroenterology and †SEALS, Sydney Children's Hospital; ‡School of Women's and Children's Health, University of New South Wales, and §Feto Maternal Medicine, Liverpool Hospital, Sydney, Australia
Correspondence to Dr. Andrew S. Day, Department of Gastroenterology, Sydney Children's Hospital, High Street, Randwick, NSW, 2031, Australia (e-mail:

Intestinal lymphangiectasia and other abnormalities of lymphatic drainage from the gastrointestinal tract result in protein-losing enteropathy. Recently, hypoplasia of intestinal lymphatics has been described as an additional cause of protein-losing enteropathy presenting in infancy. We report the case of a child, with features consistent with intestinal lymphatic hypoplasia, in whom non-immune hydrops, requiring repeated intervention, was detected at 18 weeks' gestation and who developed protein-losing enteropathy post-natally.

Case Report

Antenatal History

This was the 26-year-old mother's second pregnancy, having 2 years earlier delivered a healthy female infant at term. The parents were unrelated. A routine antenatal ultrasound scan at 18 weeks' gestation suggested the presence of ascites. Repeat ultrasound performed by the Fetal Medicine Unit (FMU) at Liverpool Hospital, NSW, Australia, confirmed moderate fetal ascites, and also demonstrated bilateral pleural effusions and peripheral edema, thereby defining a diagnosis of fetal hydrops. Subsequent investigations included detailed fetal anatomy, fetal echocardiography, and cordocentesis. An in utero karyotype analysis showed normal male (46 XY). Since no cause had been identified, a diagnosis of idiopathic non-immune hydrops was made.

The consensus at this stage was that the prognosis was likely poor. Consequently, the parents were counseled extensively. The mother, who felt the fetal activity was more than in her previous pregnancy, declined termination and the parents requested that everything possible be done for the fetus.

Because of the risk of pulmonary hypoplasia secondary to bilateral pleural effusions, repeated pleural aspirations were commenced at 22 weeks. Although pleurocentesis was initially required every few days to maintain lung expansion, the frequency steadily decreased over subsequent weeks with the final aspiration performed at 36 weeks gestation. In total, the right pleural effusion was drained 12 times and the left on four occasions. In addition, paracentesis was undertaken twice, at 23 and 24 weeks gestation. Despite these repeated interventions, all measured parameters of fetal well being and growth, especially of the thorax, remained normal throughout the pregnancy.

Postnatal History

At 38 weeks' gestation emergency caesarian section was performed because of the development of fetal distress. After delivery, bag and mask resuscitation was required briefly. APGAR scores were six and nine at one and five minutes respectively.

On initial examination the infant weighed 3410 g and had mild generalized edema. Serum albumin on the first day of life was measured at 28 g/L (normal range 32-48 g/L). Although a right pleural effusion was demonstrated on chest radiograph, there was no respiratory distress. He remained well over the first week of life, established feeding with no further concerns, and was discharged home on day seven.

At seven weeks of age the child was admitted to Sydney Children's Hospital, Sydney, Australia, for repair of bilateral inguinal hernias which had been first noted during week two. On examination at admission he weighed 3.85 kg and had gross generalized edema. Inspiratory stridor was noted.

Initial laboratory investigations demonstrated hypoalbuminaemia (21 g/L), and hypo-gammaglobulinaemia (IgA 0.1 g/l; IgM 0.3 g/l; IgG 0.6 g/l). There was a trace of protein on urinalysis and a markedly increased stool α-1-antitrypsin level of 31.1 g/kg (normal <1.5>

Gross ascites was demonstrated on abdominal ultrasound. Portal venous flow was normal. Echocardiography revealed a small secundum atrial septal defect. There was no evidence of malrotation on a barium contrast study; however, nodular thickening of the small bowel mucosa was evident.

To determine the cause of the protein-losing enteropathy, multiple small intestinal biopsies were undertaken. Initially Crosby capsule biopsies were undertaken at 8 and 10 weeks of age. Subsequently, duodenal biopsies were obtained endoscopically at 10 weeks, 15 weeks, and 8 months of age. The duodenal mucosa was uniformly milky white on each occasion that it was visualized. Duodenal fluid trypsin and enterokinase levels were adequate.

Laparotomy was performed in conjunction with endoscopy at 15 weeks of age to define the extent of bowel involved. The serosal surface of the small intestine was milky white and fatty in appearance from the proximal duodenum up to 20 cm from the ileo-cecal valve. There were no dilated lacteals or fat-laden lymph nodes visible in the small bowel mesentery. A partial malrotation was noted with a high fixed right-sided caecum in close proximity to the duodenal-jejunal flexure, but there was no evidence of intermittent volvulus. Full-thickness biopsies were taken from the duodenal-jejunal flexure and terminal ileum. Following these biopsies milky-white fluid exuded from the luminal surface. In addition, cecopexy and appendicectomy were performed.

Dietary changes were initiated within days of the initial admission. However, despite the administration of medium-chain triglyceride (MCT)-based formulae, semi-elemental formulae, or periods of bowel rest with total parenteral nutrition, marked albumin and immunoglobulin losses continued. The hypoalbuminemia was managed with intravenous infusions of 20% albumin initially given daily. Albumin requirements decreased progressively over the following months. By six months of age the frequency of infusions was reduced to an interval of ten to fourteen days. Regular gammaglobulin infusions were administered to maintain IgG levels in an attempt to reduce the occurrence of intercurrent respiratory infections.

The distribution of edema seen after the serum albumin had initially normalized was often somewhat asymmetric. The occiput was particularly affected, even when sitting and later when ambulant. Moderate to marked edema, fluctuating with the albumin level, persisted through the first few years of life. Recently, however, edema has been present only at lower serum albumin levels and is now predominantly pedal. In addition to peripheral edema, pleural effusions and ascites were present in the first months of life. Pleural effusions were managed conservatively. However, paracentesis was required on one occasion to manage ascites, following the development of respiratory compromise. The ascitic fluid was an exudate that was grossly lipemic (cholesterol 3.1 mmol/l and triglyceride 13.5 mmol/l) with total protein of 36g/l (albumin 28g/l). Stridor, secondary to laryngeal edema, has been present intermittently since initial presentation. At times of increased respiratory distress both nebulized adrenalin and oral steroids proved efficacious. Anterior cricoid split was required on one occasion to manage moderately severe stridor associated with respiratory distress.

Over time a number of further diagnostic possibilities were considered. Carbohydrate deficient glycoprotein syndrome was excluded by normal transferrin electrophoresis pattern. Clinical assessment by a geneticist at 13 months of age delineated mild dysmorphic features not present in either of his parents. These included short upturned nose, long philtrum with full lips, broad nasal bridge with mild epicanthic folds, sparse hair, a very broad forehead and horizontal eyebrows with some flaring. The pattern of these features was not felt to be diagnostic.

Various therapeutic modalities have been tried over time. These modalities include systemic corticosteroids, a six-month trial of subcutaneous octreotide (somatostatin), treatment with pancreatic enzyme supplements (pancrease), and spironolactone. While receiving octreotide and steroids, fecal α-1-anti trypsin levels decreased slightly and albumin requirements decreased transiently.

Now aged five and a half years, he has remained very well for over two years. Albumin and immunoglobulin requirements have continued to decrease and infusions have been administered every six to eight weeks recently. He has made normal developmental progress and is growing at the 10th centile for weight and height.


Examination of all mucosal biopsies by light microscopy showed essentially normal small bowel mucosa with villi of normal height in most areas. Occasional areas of mild partial villous atrophy were present in jejunal biopsies along with mild accompanying inflammatory infiltrate within the lamina propria. There was, in addition, focal vacuolation of the surface epithelium. Modified oil red O staining of frozen tissue sections of mucosal biopsies showed prominent fat in the epithelium and lamina propria. This was especially marked in biopsies obtained after returning the infant to a cow's milk-based formula for a 24-hour period. No lymphatic vessels were visible in the many sections examined.

Light microscopy of the full-thickness specimens showed preservation of villous architecture with markedly edematous villi. No lymphatic vessels could be identified with certainty in any of the sections. In contrast, lymphatics were easily identifiable in full-thickness biopsy sections obtained from normal controls. This difference was especially noticeable when comparing the appendix of the case with that of controls (Fig. 1). Electron microscopy of the intestinal full-thickness was reviewed by Dr. C.W. Chow (Royal Children's Hospital, Melbourne, Victoria, Australia) who confirmed the absence of lymphatic channels utilizing previously described criteria (1).


This child was initially thought to have intestinal lymphangiectasia as the cause of his severe protein-losing enteropathy. However, several features suggested an alternative diagnosis, including in utero hydrops, absence of lymphopenia, lack of response to the high MCT diet, and failure to identify dilated or ectatic lymphatics on multiple small bowel biopsies. Indeed, lymphatic spaces were noted to be inconspicuous and difficult to identify suggesting lymphatic hypoplasia as a possible etiology. This might explain the absence of lymphopenia, which is typically seen in lymphangiectasia, and is thought to be due to gut losses of lymph from ruptured lymphatics. Given that lymphatics could not be identified in our case, absence of lymphopenia is perhaps not surprising.

Hardikar et al. (1) report two siblings presenting with neonatal protein-losing enteropathy most likely due to intestinal lymphatic hypoplasia. The authors noted difficulties in making this diagnosis. In particular, the authors highlighted the problems associated with diagnosing the absence of a normal structure as opposed to defining the presence of an abnormal feature. Similar obstacles in identifying lymphatic spaces were encountered in the current case, despite reference to the features suggested by Hardikar and others (1,2).
Lymphangiography or lymphoscintigraphy may have been potentially useful methods to confirm hypoplasia of lymphatic spaces. These tests were not attempted in this child because of the technical difficulties associated with performing such a procedure in a small child and the risks of exposure to a relatively large dose of radiation occurring at a localized site if lymphatic hypoplasia caused failure of removal of the radiolabel. There was also concern that the outcome of such a study would be unlikely to alter the management.

The endoscopic features of a milky white duodenal mucosa, in conjunction with the macroscopic appearance of the serosal surface seen at laparotomy, and the absence of either dilated lacteals or fat-laden lymph nodes in the small bowel mesentery, are consistent with the findings in previously reported cases of histologically proven lymphangiectasia (3-5). Other causes of fat-filled enterocytes include Anderson disease (chylomicron retention disease) (6) and abetalipoproteinemia (7). These have been excluded, the former by the presence of fat within the lamina propria and a normal serum cholesterol and the latter by normal apolipoprotein levels. Other lymphoedema syndromes such as Nanne-Milroy syndrome (8) and Noonan syndrome (9) were considered but clinical findings were inconsistent. The similarity to the autosomal recessive Hennekam syndrome (10), which has features of lymphoedema, intestinal lymphangiectasia, characteristic facial anomalies and mental retardation, also was raised. The absence of limb abnormalities, mental retardation, lymphocytopenia, and evidence of lymphangiectasia made this diagnosis unlikely. A further syndrome considered was carbohydrate deficient glycoprotein syndrome (CDGS). Niehues et al. (11) include protein-losing enteropathy in their initial description of CDGS Type 1b, which also may feature thrombosis and life-threatening bleeding but does not involve neurologic manifestations. In addition, de Koning et al. (12) have shown that CDGS may present with non-immune hydrops fetalis. Transferrin electrophoresis testing has, however, excluded this as a diagnosis in the current case.

The histologic findings in mucosal biopsies, of prominent fat in the epithelium and lamina propria on modified oil red staining, is suggestive of the histologic picture seen in lymphangiectasia. However, lymphatics were not seen during histologic analysis. The absence of these structures was confirmed by histologic assessment of full-thickness biopsies, and electron microscopy of the mucosa. The characteristics of small bowel biopsies mean that lesions may be missed if disease is focal rather than generalized. However, in the current case, representative samples were taken from duodenal-jejunal flexure and the terminal ileum, which were both abnormal macroscopically. In fact, almost the entire small bowel was milky white at laparotomy, suggesting generalized changes. Despite the prominence of fat in the epithelium and lamina propria, serum lipid (cholesterol and triglyceride) levels were normal. The mucosal biopsy findings of partial villous atrophy, lamina propria inflammatory infiltrate, and focal vacuolation of the surface epithelium were mild, and the significance of these findings is uncertain.

A number of therapies were utilized over time in attempts to decrease enteric protein loss in the current case. Octreotide, for instance, has been demonstrated to reduce enteral losses of protein in both Menetrier disease (13) and lymphangiectasia (14), via mechanisms that include reduction of lymph fluid excretion through the action of octreotide on vascular somatostatin receptors (14). Dietary changes are also generally efficacious in lymphangiectasia (15). The relatively poor response in our patient to a diet low in long-chain triglycerides suggests a more severe hypoplasia, or even absence, of lymphatics. This is in contrast to the report from Hardikar et al. (1) in which both patients responded to this diet. The intrauterine involvement (with predominance of pleural fluid accumulation), more severe postnatal protein losses and the unusual distribution of edema over the first year may result from a more widespread lymphatic abnormality than purely intestinal in the current case. It would seem likely that the current case more clearly illustrates the features of congenital lymphatic hypoplasia.

In conclusion, this case illustrates clinical findings consistent with congenital lymphatic hypoplasia. Thus far a satisfactory treatment has not been found for this child and he remains albumin dependent, although this requirement has decreased over time. Given the in utero presentation and the initial requirements for aggressive management, the outcome of this child has been much better than expected and includes age-appropriate developmental progress. Early and severe symptomatic hydrops may lead to demise of the infant. Consequently, it is conceivable that the incidence of this condition may be more than previously reported and warrants consideration in cases with similar features.


Our thanks to Dr CW Chow, Royal Children's Hospital, Melbourne, Australia, for his electron microscopy assessment of mucosal biopsies.


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Intestinal lymphatic hypoplasia; Protein-losing enteropathy; Infant