Original article 83
Variable clinical presentation in primary lymphoedema: report of two cases Abdullah Ozyurta, Eylem Sevincb, Ali Baykana, Duran Arslanb, Mustafa Arguna, Ozge Pamukcua and Kazim Uzuma Lymphoedema is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system. Lymphoedema may be primary or secondary and can be inherited. Primary lymphoedema (primary lymphatic dysplasia) is a chronic oedema caused by a developmental abnormality of the lymphatic system. Primary lymphoedema most commonly affects the lower limbs, but other body parts can also be affected. It can be associated with some specific syndromes (i.e. Hennekam syndrome) and genetic disorders. In this article, we report on two patients with congenital multisegmental lymphoedema and Hennekam syndrome, both primary
c 2014 lymphoedemas. Clin Dysmorphol 23:83–87 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
tests. Faecal excretion of a1 antitrypsin was positive. Bilateral pleural effusions were observed on chest radiography and massive ascites was visualized on abdominal ultrasonography. Analysis of the ascitic fluid showed that it was chylous ascites (Fig. 1a), with triglyceride 928 mg/dl (serum level of 104 mg/dl), albumin 1.1 g/l (serum level of 1.9 g/l) and glucose 231 mg/dl (serum level of 83 mg/dl). The cell count of the fluid was 1.1/mm3 white blood cell, of which 90% were lymphocytes. Simultaneous examination of the blood indicated 5.6/mm3 white blood cells, of which 60% were lymphocytes.
Primary lymphoedema arises because of abnormal development of the lymphatic system and is generally present at birth, although symptoms may not become apparent until later in life. Primary lymphoedema is rare, affecting B1.15/100 000 of the population younger than 20 years of age (Smeltzer et al., 1985). In most cases, the lymphoedema affects the lower limbs, but it can also affect upper limbs. Connell and colleagues proposed a classification system of the primary lymphatic dysplasias that is based on phenotype rather than age of onset. In Connell’s classification, phenotypes are divided into five categories (syndromic, systemic or visceral involvement, disturbed growth/cutaneous manifestations, congenital and age). Primary lymphoedema is a recognized feature of many syndromes, the more common conditions with primer lymphoedema are Turner, Noonan and Hennekam syndromes (Connell et al., 2013).
Clinical report Case 1
A 2-month-old boy who had been born at 36 weeks’ gestation, with a birth weight of 2800 g, was admitted to the neonatal ICU with respiratory difficulties. In the early postnatal period, he had generalized oedema and at that time serum total protein and serum albumin were very low. There was no hepatosplenomegaly. The cardiac examination and echocardiography were normal. Laboratory examinations indicated hypoproteinaemia (range between 3.1 and 5.2 g/l) and hypoalbuminaemia (range between 1.5 and 2.8 g/l). Investigations showed a normal complete blood count, renal function and liver function c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827
Clinical Dysmorphology 2014, 23:83–87 Keywords: ascites, Hennekam syndrome, octreotide, primary lymphoedema a
Division of Pediatric Cardiology and bDivision of Pediatric Gastroenterology, Erciyes University Faculty of Medicine, Kayseri, Turkey Correspondence to Abdullah Ozyurt, MD, Division of Pediatric Cardiology, Erciyes University Faculty of Medicine, Kayseri 38039, Turkey Tel: + 90 352 207 6666 x25036; fax: + 90 352 437 5825; e-mail: [email protected] Received 22 June 2013 Accepted 11 February 2014
The generalized lymphoedema resolved after periodical intravenous infusions of albumin, but ascites persisted. After resolution of the hydrops fetalis, distinctive facial features became apparent. These included a prominent forehead, hypertelorism, epicanthic folds, a broad and depressed nasal bridge, a bulbous nasal tip, small mouth, long philtrum, micrognathia and a high-arched palate (Fig. 1b and c). An upper gastrointestinal endoscopy study indicated widespread whitish patches with a snowflake appearance in the second and third parts of the duodenum. Histopathological examination of a biopsy specimen from the duodenum showed marked oedema in the lamina propria. Hennekam syndrome was diagnosed on the basis of the clinical and dysmorphic features together with the biochemical and endoscopic findings. Subcutaneous octreotide treatment and a medium-chain triglyceride-based formula, together with a low-fat, highprotein diet and fat-soluble vitamin supplements were administered. There was no need for albumin replacement as the albumin levels remained at 2–2.5 g/dl without albumin infusion. Currently, the patient is DOI: 10.1097/MCD.0000000000000036
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
84
Clinical Dysmorphology 2014, Vol 23 No 3
Fig. 1
Paracentesis fluid appearance typical of intestinal lymphangiectasia. (a) Facial phenotype typical for Hennekam syndrome: prominent forehead, hypertelorism, epicanthic folds, broad and depressed nasal bridge, a bulbous nasal tip, small mouth, long philtrum, micrognathia and high-arched palate, abdominal distention because of ascites (b and c).
1 year old and during this follow-up period, there has been no diarrhoea nor dyspneic attacks. Development is age appropriate.
Case 2
This 13-year-old girl was admitted to the emergency room with chest pain. A massive pericardial effusion with diastolic collapse of the right atrium was observed on echocardiography. Voltage suppression was evident on the ECG (Fig. 2a). Analysis of the pericardial fluid showed that it was noninfectious pericarditis. From the patient’s medical history, polyhydramnios had been noted during pregnancy. Dysmorphic facial features and lymphoedema of the hands, feet, lower legs and genitalia had been noted at birth. Initially, the lymphoedema in her left side of the body had been considered to be because of allergy, but this had not responded to multiple ointments. She had noninfectious diarrhoea attacks lasting 1 or 2 days and resolving spontaneously.
On examination, she had dysmorphic features comprising a small mouth, thin lips, low-set ears and long philtrum. The patient did not allow us to a take a photograph of her face. There was oedema especially on the left side of both lower extremities and the left side of the upper limb (Fig. 2b). She had normal intellectual development. Laboratory investigations indicated lymphopenia (1300/mm3), hypoproteinaemia (4.9 g/dl), hypoalbuminaemia (1.5 g/dl) and normal faecal a1 antitrypsin levels. Renal function was normal; there was no proteinuria. Bone age was 11 years old. Bone mineral density was found to be reduced on dual-energy X-ray absorptiometry. Abdominal ultrasound and cranial MRI were normal. Full-body radionuclide lymphoscintigraphy showed abnormal drainage, especially in the lower limbs and the left upper limb, particularly in the axilla (Fig. 3). Gastroduodenoscopy showed a snowflake appearance of the duodenum (Fig. 4). Small intestinal biopsy confirmed the diagnosis of intestinal lymphangiectasia. The patient’s clinical history, laboratory and imaging findings
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Primary lymphoedema Ozyurt et al. 85
Fig. 2
protein diet and fat-soluble vitamin supplements were administered to patient. Following this treatment, the oedema of the extremities resolved and the diarrhoea attacks stopped. During follow-up, the serum albumin level was elevated to the normal range and therefore albumin replacement was discontinued. The pericardial effusion has not recurred during the 1-year follow-up.
Discussion
Normal sinus rhythm and mild right axis deviation and diffuse QRS voltage suppression were observed in 12-lead standard ECG. (a) Oedema in all extremities except for the right side upper limb can be seen (b).
Fig. 3
Snowflake appearance consistent with duodenal intestinal lymphangiectasia was observed in gastroduodenoscopy of the second patient.
suggested a diagnosis of congenital multisegmental lymphatic dysplasia. In addition to subcutaneous octreotide treatment, a medium-chain triglyceride-based formula, a low-fat, high-
These two patients have different clinical presentations of primary congenital lymphatic dysplasia. Hennekam syndrome is a rare autosomal recessive syndrome originally described by Hennekam et al. (1989). Since the first report, 33 patients have been described. Generalized maldevelopment of the lymphatic system is characteristic of the syndrome, preferentially affecting the intestine, limbs and genitalia, but it can also affect the pleura, pericardium, thyroid gland, kidneys and the eye (Van Balkom et al., 2002; Bellini et al., 2003). Intestinal lymphangiectasia has been present in most, but not all patients. As documented by intestinal biopsy, this is characterized by dilatation of the intestinal mucosal lymphatic channels in the lamina propria. The snowflake appearance on gastroduodenoscopy, as found in our patients, is the macroscopic finding of intestinal lymphangiectasia (Al-Gazali et al., 2003). The facial features of Hennekam syndrome typically include a flat mid-face, a flat and broad nasal bridge, and hypertelorism. Other characteristics are a broad forehead, bilateral epicanthic folds, low-set and dysplastic ears with a narrow meatus, smooth philtrum and a small mouth with gingival hypertrophy. Additional features that have been demonstrated in some reported patients are a high palate, atretic ear canals, preauricular tags and craniosynostosis. There can be facial asymmetry. The variability of the phenotype has been stressed recently and it was suggested that the syndrome is possibly not homogeneous and that phenocopies may exist (Angle and Hersh, 1997; Van Balkom et al., 2002; Al-Gazali et al., 2003). Multisegmental lymphatic dysplasia with systemic involvement is characterized by a segmental pattern of lymphoedema affecting different body parts, together with systemic involvement. It may be associated with hemifacial swelling and conjunctival oedema on the affected side. More than one limb may be affected, but they may be contralateral. Intelligence is normal and there are no associated structural abnormalities (Connell et al., 2013). Our second case did not have typical facial features, but growth retardation, intestinal, pericardial and limb lymphangiectasia were present. Congenital lymphoedema can be caused by mutations in the lymphatic specific growth factor VEGFR3 (vascular endothelial growth factor receptor 3), and mutations in Gap junction gamma-2 (GJC2). Mutations in collagen and calcium-binding EGF-domain 1 (CCBE1) on
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
86
Clinical Dysmorphology 2014, Vol 23 No 3
Fig. 4
Because of abnormal drainage in both lower and upper left-sided extremities (especially the axillary region), pathological uptake is observed on radionuclide lymphoscintigraphy.
chromosome 18q21 have been identified as causal in Hennekam syndrome (Alders et al., 2009; Connell et al., 2013). We could not carry out molecular studies in our patients because of funding issues. In primary lymphatic dysplasias, the major symptoms are caused by protein loss, which results in peripheral oedema, ascites and hypogammaglobulinaemia. In addition, there can be loss of lymphocytes, causing lymphopenia, loss of fat-soluble substances such as vitamin A, D and E and loss of electrolytes (calcium, potassium, magnesium and zinc) (Yasunaga et al., 1993; Van Balkom et al., 2002). The calcium levels were normal in both of our patients, but bone mineral density was decreased, which could have been because of vitamin D malabsorption in patient 2. Patient 1, with presumed Hennekam syndrome, has intellectual impairment, but the second patient has normal intelligence. Hyperactivity and seizures may occur in association with primary lymphatic dysplasia, but some patients have normal psychomotor development (Huppke et al., 2000). In most cases, lymphoedema is present in the distal limbs (31/33) and face (23/32). The involvement of the limbs can be asymmetrical. Lymphoedema is usually apparent at birth or in early infancy and may be static for a prolonged period of time, but can also be progressive.
Pleural lymph vessel anomalies have been reported in 8/30 cases, pericardial lymph vessel anomalies in 8/27 and ascites 17/31. One boy with a massive pericardial effusion was reported (Ni ¸sli et al., 2008). Generalized lymphangiectasia involving the pleural/pulmonary lymph vessels was reported in another case with nonimmune hydrops (Bellini et al., 2003). Although there are a limited number of reports advising the use of octreotide in intestinal lymphangiectasia, octreotide treatment may be useful for such cases (Fedeli et al., 2011). Both of our patients’ symptoms improved with octreotide therapy. Conclusion
In addition to 33 cases presented in the literature, these two cases are presented to draw attention to the rare presentation of congenital lymphatic dysplasia. Massive pericardial effusion and nonimmune hydrops were rare clinical presentations in our cases. Radionuclide scintigraphy and gastroduodenal endoscopy may help in the diagnosis of primary congenital lymphoedema when the face is not typical for Hennekam syndrome.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Primary lymphoedema Ozyurt et al. 87
References Al-Gazali LI, Hertecant J, Ahmed R, Khan NA, Padmanabhan R (2003). Further delineation of Hennekam syndrome. Clin Dysmorphol 12:227–232. Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, et al. (2009). Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41:1272–1274. Angle B, Hersh JH (1997). Expansion of the phenotype in Hennekam syndrome: a case with new manifestations. Am J Med Genet 71:211–214. Bellini C, Mazzella N, Arioni C, Campone F, Massocco D, Mezzano P, et al. (2003). Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax and congenital pulmonary lymphangiectasia. Am J Med Genet 120:92–96. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. (2013). The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 84:303–314. Fedeli P, Gasbarrini A, Cammarota G (2011). Spectral endoscopic imaging: the multiband system for enhancing the endoscopic surface visualization. J Clin Gastroenterol 45:6–15.
Hennekam RCM, Geerdink RA, Hamel BCJ, Hennekam FA, Kraus P, Rammeloo JA, Tillemans AA (1989). Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34:593–600. Huppke P, Christen HJ, Sattler B, Hanefeld F (2000). Two brothers with Hennekam syndrome and cerebral abnormalities. Clin Dysmorphol 9: 21–24. Nisli ¸ K, Oner N, Kayserili H, Ertug˘rul T (2008). A case of Hennekam syndrome presenting with massive pericardial effusion. Turk Kardiyol Dern Ars 36: 325–328. Smeltzer DM, Stickler GB, Schirger A (1985). Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206–218. Van Balkom IDC, Alders M, Allanson J, Bellini C, Frank U, De Jong G, et al. (2002). Lymphedema–lymphangiectasia–mental retardation (Hennekam) syndrome: a review. Am J Med Genet 112:412–421. Yasunaga M, Yamanaka C, Mayumi M, Momoi T, Mikawa H (1993). Protein losing gastroenteropathy with facial anomaly and growth retardation; a mild case of Hennekam syndrome. Am J Med Genet 45:477–480.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Variable clinical presentation in primary lymphoedema: report of two cases Abdullah Ozyurta, Eylem Sevincb, Ali Baykana, Duran Arslanb, Mustafa Arguna, Ozge Pamukcua and Kazim Uzuma Lymphoedema is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system. Lymphoedema may be primary or secondary and can be inherited. Primary lymphoedema (primary lymphatic dysplasia) is a chronic oedema caused by a developmental abnormality of the lymphatic system. Primary lymphoedema most commonly affects the lower limbs, but other body parts can also be affected. It can be associated with some specific syndromes (i.e. Hennekam syndrome) and genetic disorders. In this article, we report on two patients with congenital multisegmental lymphoedema and Hennekam syndrome, both primary
c 2014 lymphoedemas. Clin Dysmorphol 23:83–87 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
tests. Faecal excretion of a1 antitrypsin was positive. Bilateral pleural effusions were observed on chest radiography and massive ascites was visualized on abdominal ultrasonography. Analysis of the ascitic fluid showed that it was chylous ascites (Fig. 1a), with triglyceride 928 mg/dl (serum level of 104 mg/dl), albumin 1.1 g/l (serum level of 1.9 g/l) and glucose 231 mg/dl (serum level of 83 mg/dl). The cell count of the fluid was 1.1/mm3 white blood cell, of which 90% were lymphocytes. Simultaneous examination of the blood indicated 5.6/mm3 white blood cells, of which 60% were lymphocytes.
Primary lymphoedema arises because of abnormal development of the lymphatic system and is generally present at birth, although symptoms may not become apparent until later in life. Primary lymphoedema is rare, affecting B1.15/100 000 of the population younger than 20 years of age (Smeltzer et al., 1985). In most cases, the lymphoedema affects the lower limbs, but it can also affect upper limbs. Connell and colleagues proposed a classification system of the primary lymphatic dysplasias that is based on phenotype rather than age of onset. In Connell’s classification, phenotypes are divided into five categories (syndromic, systemic or visceral involvement, disturbed growth/cutaneous manifestations, congenital and age). Primary lymphoedema is a recognized feature of many syndromes, the more common conditions with primer lymphoedema are Turner, Noonan and Hennekam syndromes (Connell et al., 2013).
Clinical report Case 1
A 2-month-old boy who had been born at 36 weeks’ gestation, with a birth weight of 2800 g, was admitted to the neonatal ICU with respiratory difficulties. In the early postnatal period, he had generalized oedema and at that time serum total protein and serum albumin were very low. There was no hepatosplenomegaly. The cardiac examination and echocardiography were normal. Laboratory examinations indicated hypoproteinaemia (range between 3.1 and 5.2 g/l) and hypoalbuminaemia (range between 1.5 and 2.8 g/l). Investigations showed a normal complete blood count, renal function and liver function c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0962-8827
Clinical Dysmorphology 2014, 23:83–87 Keywords: ascites, Hennekam syndrome, octreotide, primary lymphoedema a
Division of Pediatric Cardiology and bDivision of Pediatric Gastroenterology, Erciyes University Faculty of Medicine, Kayseri, Turkey Correspondence to Abdullah Ozyurt, MD, Division of Pediatric Cardiology, Erciyes University Faculty of Medicine, Kayseri 38039, Turkey Tel: + 90 352 207 6666 x25036; fax: + 90 352 437 5825; e-mail: [email protected] Received 22 June 2013 Accepted 11 February 2014
The generalized lymphoedema resolved after periodical intravenous infusions of albumin, but ascites persisted. After resolution of the hydrops fetalis, distinctive facial features became apparent. These included a prominent forehead, hypertelorism, epicanthic folds, a broad and depressed nasal bridge, a bulbous nasal tip, small mouth, long philtrum, micrognathia and a high-arched palate (Fig. 1b and c). An upper gastrointestinal endoscopy study indicated widespread whitish patches with a snowflake appearance in the second and third parts of the duodenum. Histopathological examination of a biopsy specimen from the duodenum showed marked oedema in the lamina propria. Hennekam syndrome was diagnosed on the basis of the clinical and dysmorphic features together with the biochemical and endoscopic findings. Subcutaneous octreotide treatment and a medium-chain triglyceride-based formula, together with a low-fat, highprotein diet and fat-soluble vitamin supplements were administered. There was no need for albumin replacement as the albumin levels remained at 2–2.5 g/dl without albumin infusion. Currently, the patient is DOI: 10.1097/MCD.0000000000000036
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
84
Clinical Dysmorphology 2014, Vol 23 No 3
Fig. 1
Paracentesis fluid appearance typical of intestinal lymphangiectasia. (a) Facial phenotype typical for Hennekam syndrome: prominent forehead, hypertelorism, epicanthic folds, broad and depressed nasal bridge, a bulbous nasal tip, small mouth, long philtrum, micrognathia and high-arched palate, abdominal distention because of ascites (b and c).
1 year old and during this follow-up period, there has been no diarrhoea nor dyspneic attacks. Development is age appropriate.
Case 2
This 13-year-old girl was admitted to the emergency room with chest pain. A massive pericardial effusion with diastolic collapse of the right atrium was observed on echocardiography. Voltage suppression was evident on the ECG (Fig. 2a). Analysis of the pericardial fluid showed that it was noninfectious pericarditis. From the patient’s medical history, polyhydramnios had been noted during pregnancy. Dysmorphic facial features and lymphoedema of the hands, feet, lower legs and genitalia had been noted at birth. Initially, the lymphoedema in her left side of the body had been considered to be because of allergy, but this had not responded to multiple ointments. She had noninfectious diarrhoea attacks lasting 1 or 2 days and resolving spontaneously.
On examination, she had dysmorphic features comprising a small mouth, thin lips, low-set ears and long philtrum. The patient did not allow us to a take a photograph of her face. There was oedema especially on the left side of both lower extremities and the left side of the upper limb (Fig. 2b). She had normal intellectual development. Laboratory investigations indicated lymphopenia (1300/mm3), hypoproteinaemia (4.9 g/dl), hypoalbuminaemia (1.5 g/dl) and normal faecal a1 antitrypsin levels. Renal function was normal; there was no proteinuria. Bone age was 11 years old. Bone mineral density was found to be reduced on dual-energy X-ray absorptiometry. Abdominal ultrasound and cranial MRI were normal. Full-body radionuclide lymphoscintigraphy showed abnormal drainage, especially in the lower limbs and the left upper limb, particularly in the axilla (Fig. 3). Gastroduodenoscopy showed a snowflake appearance of the duodenum (Fig. 4). Small intestinal biopsy confirmed the diagnosis of intestinal lymphangiectasia. The patient’s clinical history, laboratory and imaging findings
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Primary lymphoedema Ozyurt et al. 85
Fig. 2
protein diet and fat-soluble vitamin supplements were administered to patient. Following this treatment, the oedema of the extremities resolved and the diarrhoea attacks stopped. During follow-up, the serum albumin level was elevated to the normal range and therefore albumin replacement was discontinued. The pericardial effusion has not recurred during the 1-year follow-up.
Discussion
Normal sinus rhythm and mild right axis deviation and diffuse QRS voltage suppression were observed in 12-lead standard ECG. (a) Oedema in all extremities except for the right side upper limb can be seen (b).
Fig. 3
Snowflake appearance consistent with duodenal intestinal lymphangiectasia was observed in gastroduodenoscopy of the second patient.
suggested a diagnosis of congenital multisegmental lymphatic dysplasia. In addition to subcutaneous octreotide treatment, a medium-chain triglyceride-based formula, a low-fat, high-
These two patients have different clinical presentations of primary congenital lymphatic dysplasia. Hennekam syndrome is a rare autosomal recessive syndrome originally described by Hennekam et al. (1989). Since the first report, 33 patients have been described. Generalized maldevelopment of the lymphatic system is characteristic of the syndrome, preferentially affecting the intestine, limbs and genitalia, but it can also affect the pleura, pericardium, thyroid gland, kidneys and the eye (Van Balkom et al., 2002; Bellini et al., 2003). Intestinal lymphangiectasia has been present in most, but not all patients. As documented by intestinal biopsy, this is characterized by dilatation of the intestinal mucosal lymphatic channels in the lamina propria. The snowflake appearance on gastroduodenoscopy, as found in our patients, is the macroscopic finding of intestinal lymphangiectasia (Al-Gazali et al., 2003). The facial features of Hennekam syndrome typically include a flat mid-face, a flat and broad nasal bridge, and hypertelorism. Other characteristics are a broad forehead, bilateral epicanthic folds, low-set and dysplastic ears with a narrow meatus, smooth philtrum and a small mouth with gingival hypertrophy. Additional features that have been demonstrated in some reported patients are a high palate, atretic ear canals, preauricular tags and craniosynostosis. There can be facial asymmetry. The variability of the phenotype has been stressed recently and it was suggested that the syndrome is possibly not homogeneous and that phenocopies may exist (Angle and Hersh, 1997; Van Balkom et al., 2002; Al-Gazali et al., 2003). Multisegmental lymphatic dysplasia with systemic involvement is characterized by a segmental pattern of lymphoedema affecting different body parts, together with systemic involvement. It may be associated with hemifacial swelling and conjunctival oedema on the affected side. More than one limb may be affected, but they may be contralateral. Intelligence is normal and there are no associated structural abnormalities (Connell et al., 2013). Our second case did not have typical facial features, but growth retardation, intestinal, pericardial and limb lymphangiectasia were present. Congenital lymphoedema can be caused by mutations in the lymphatic specific growth factor VEGFR3 (vascular endothelial growth factor receptor 3), and mutations in Gap junction gamma-2 (GJC2). Mutations in collagen and calcium-binding EGF-domain 1 (CCBE1) on
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
86
Clinical Dysmorphology 2014, Vol 23 No 3
Fig. 4
Because of abnormal drainage in both lower and upper left-sided extremities (especially the axillary region), pathological uptake is observed on radionuclide lymphoscintigraphy.
chromosome 18q21 have been identified as causal in Hennekam syndrome (Alders et al., 2009; Connell et al., 2013). We could not carry out molecular studies in our patients because of funding issues. In primary lymphatic dysplasias, the major symptoms are caused by protein loss, which results in peripheral oedema, ascites and hypogammaglobulinaemia. In addition, there can be loss of lymphocytes, causing lymphopenia, loss of fat-soluble substances such as vitamin A, D and E and loss of electrolytes (calcium, potassium, magnesium and zinc) (Yasunaga et al., 1993; Van Balkom et al., 2002). The calcium levels were normal in both of our patients, but bone mineral density was decreased, which could have been because of vitamin D malabsorption in patient 2. Patient 1, with presumed Hennekam syndrome, has intellectual impairment, but the second patient has normal intelligence. Hyperactivity and seizures may occur in association with primary lymphatic dysplasia, but some patients have normal psychomotor development (Huppke et al., 2000). In most cases, lymphoedema is present in the distal limbs (31/33) and face (23/32). The involvement of the limbs can be asymmetrical. Lymphoedema is usually apparent at birth or in early infancy and may be static for a prolonged period of time, but can also be progressive.
Pleural lymph vessel anomalies have been reported in 8/30 cases, pericardial lymph vessel anomalies in 8/27 and ascites 17/31. One boy with a massive pericardial effusion was reported (Ni ¸sli et al., 2008). Generalized lymphangiectasia involving the pleural/pulmonary lymph vessels was reported in another case with nonimmune hydrops (Bellini et al., 2003). Although there are a limited number of reports advising the use of octreotide in intestinal lymphangiectasia, octreotide treatment may be useful for such cases (Fedeli et al., 2011). Both of our patients’ symptoms improved with octreotide therapy. Conclusion
In addition to 33 cases presented in the literature, these two cases are presented to draw attention to the rare presentation of congenital lymphatic dysplasia. Massive pericardial effusion and nonimmune hydrops were rare clinical presentations in our cases. Radionuclide scintigraphy and gastroduodenal endoscopy may help in the diagnosis of primary congenital lymphoedema when the face is not typical for Hennekam syndrome.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Primary lymphoedema Ozyurt et al. 87
References Al-Gazali LI, Hertecant J, Ahmed R, Khan NA, Padmanabhan R (2003). Further delineation of Hennekam syndrome. Clin Dysmorphol 12:227–232. Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, et al. (2009). Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41:1272–1274. Angle B, Hersh JH (1997). Expansion of the phenotype in Hennekam syndrome: a case with new manifestations. Am J Med Genet 71:211–214. Bellini C, Mazzella N, Arioni C, Campone F, Massocco D, Mezzano P, et al. (2003). Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax and congenital pulmonary lymphangiectasia. Am J Med Genet 120:92–96. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. (2013). The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 84:303–314. Fedeli P, Gasbarrini A, Cammarota G (2011). Spectral endoscopic imaging: the multiband system for enhancing the endoscopic surface visualization. J Clin Gastroenterol 45:6–15.
Hennekam RCM, Geerdink RA, Hamel BCJ, Hennekam FA, Kraus P, Rammeloo JA, Tillemans AA (1989). Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34:593–600. Huppke P, Christen HJ, Sattler B, Hanefeld F (2000). Two brothers with Hennekam syndrome and cerebral abnormalities. Clin Dysmorphol 9: 21–24. Nisli ¸ K, Oner N, Kayserili H, Ertug˘rul T (2008). A case of Hennekam syndrome presenting with massive pericardial effusion. Turk Kardiyol Dern Ars 36: 325–328. Smeltzer DM, Stickler GB, Schirger A (1985). Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 76:206–218. Van Balkom IDC, Alders M, Allanson J, Bellini C, Frank U, De Jong G, et al. (2002). Lymphedema–lymphangiectasia–mental retardation (Hennekam) syndrome: a review. Am J Med Genet 112:412–421. Yasunaga M, Yamanaka C, Mayumi M, Momoi T, Mikawa H (1993). Protein losing gastroenteropathy with facial anomaly and growth retardation; a mild case of Hennekam syndrome. Am J Med Genet 45:477–480.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
