Case of the Week #551

Moshe Bronshtein,* Javier Cortejoso**
*Department Obstetrics Gynecology, Rambam Medical Center, Haifa, Israel; **Centro Médico Recoletas. Valladolid. Spain

Posting Dates: January 15 - January 31, 2022

A 26-year-old woman in a consanguinous relationship presented in the second trimester of pregnancy. Her first pregnancy resulted in a syndromic neonate.

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Video 2 © 2021 Moshe Bronshtein
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We present a case of Hennekam syndrome. Prenatal imaging revealed generalized edema involving the skin, extremities, and genitals. Additionally, facial anomalies included strabismus and a flat face.

Video 1 © 2021 Moshe Bronshtein

Discussion

Although some authors consider that a certain degree of lymphedema is present in all fetuses before birth [1], more severe congenital lymphedema is due to a primary or inherited cause in 11–25% of cases [2].

Hennekam syndrome, also known as Hennekam lymphangiectasia lymphedema syndrome, is an autosomal recessive disorder reported for the first time in 1989 by Raoul Hennekam in four patients from a highly inbred Dutch family [3]. It is characterized by congenital severe peripheral lymphedema, intestinal lymphangiectasia, facial anomalies, seizures, mild growth retardation and mental retardation.

Its incidence is low (<1 in 1,000,000), with around 100 cases reported in the literature, and it has been described in all ethnic groups [4]. The intrafamily variability is large, and there may be cases that are not recognized.

Hennekam syndrome is a genetically heterogeneous disorder; its genetic etiology is unknown in about half of the patients. Approximately 25% have a homozygous or compound heterozygous mutation in CCBE1 gene (located on the chromosome 18q21) (Hennekam lymphangiectasia-lymphedema syndrome-1, OMIM # 235510) and another 20% have mutations in FAT4 gene (4q28) (Hennekam lymphangiectasia-lymphedema syndrome-2, OMIM # 616006) [5]. In addition, ADAMTS3 gene (4q13) can be mutated in individuals affected by the Hennekam lymphangiectasia-lymphedema syndrome-3 (OMIM # 618154) [6]. Prenatal diagnosis is possible by genetic testing in families with known mutations or by whole exome sequencing [7]. Generally, it is considered an autosomal recessive entity with high lethality.

Generalized maldevelopment of the lymphatic system is the main characteristic of the syndrome, preferentially affecting limbs, intestines, and genitalia, although it can also be present in many other organs such as the lungs, pleura, pericardium, thyroid gland, and kidneys [8]. Due to the lymphatic developmental defect, there is pathologic dilation of lymph vessels, or lymphangiectasia, with leakage of the lymphatic fluid and deposit in the soft tissues of the body (lymphedema), and in the body cavities (chylothorax, chylous ascites).

Lymphedema is usually apparent at birth or in early infancy, manifests both in the face or limbs, and can be stable for a long period of time or progress. The facial anomalies include a flat midface with broad and depressed nasal bridge, hypertelorism, strabismus, smooth philtrum, small mouth, and low-set ears. Besides edema, the hands and feet show congenital camptodactyly and cutaneous syndactyly [8].

Intestinal lymphangiectasia may result in protein-losing enteropathy, peripheral edema, ascites, and mild growth retardation. Birth weight is highly variable. It is possible that during fetal life, maternal support compensates for the lymphatic vessel abnormalities in the intestines, which will lead to growth retardation postnatally. After birth, biological studies may reveal hypogammaglobulinemia, hypoalbuminemia, lymphopenia and increased alpha-1 antitrypsin excretion in the feces [9].

Congenital chylothorax, or pleural effusion of lymphatic origin, is the most frequent cause of pleural effusion in the newborn infant. Bellini et al (2003) published a case of a newborn girl with Hennekam syndrome who presented with chylothorax, nonimmune hydrops fetalis and congenital pulmonary lymphangiectasia [9]. Three years later, Wilson et al reported a male fetus with bilateral pleural effusion, preterm delivery, and prolonged neonatal course with death at 3 months of age [10]. Autopsy revealed congenital pulmonary lymphangiectasia without other congenital malformations. The common pathophysiology of these two cases was a general or localized disorder of lymphatic development, and their findings led to the postnatal diagnosis of congenital pulmonary lymphangiectasia or Hennekam syndrome. These two cases are the earliest diagnoses of the syndrome, but both were made after birth.

The differential diagnosis includes other entities associated with congenital lymphedema, such as Noonan syndrome, Milroy syndrome, lymphedema-distichiasis syndrome, cholestasis-lymphedema syndrome, and Van Maldergem syndrome [8]. Noonan syndrome is characterized by growth retardation, dysmorphic facies, pulmonary valve stenosis, and lymphatic dysplasia usually limited to pterygia colli and acral lymphedema. Lymphedema is also acral and isolated in Milroy disease and in lymphedema-distichiasis syndrome. Cholestasis-lymphedema syndrome (Aagenaes syndrome) is characterized by severe chronic lymphedema and neonatal intrahepatic cholestasis, without lymphangiectasia or mental retardation. There is a substantial overlap in phenotype of Van Maldergem and Hennekam syndromes, especially in facial appearance and mild to moderate intellectual disability, but lymphedema is not present in Van Maldergem syndrome.

References

[1]   Opitz JM. On congenital lymphedema. Am J Med Genet. 1986 May;24(1):127-9. PMID: 3706401.
[2]   Allanson JE. "Lymphatic system." Human malformations and related anomalies, 2nd edition. New York: Oxford University Press, 2006; p 145-181.
[3]   Hennekam RC, Geerdink RA, Hamel BC, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet. 1989 Dec;34(4):593-600. PMID: 2624276.
[4]   Hennekam R. "Hennekam syndrome." Orphanethttps://www.orpha.net/consor/cgi-bin/OC_Exp.php?Ing=en&Expert=2136.  Last update 7/2020. 
[5]   Frosk P, Chodirker B, Simard L, et al. A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature. BMC Med Genet. 2015 Apr 30;16:28. PMID: 25925991.
[6]   Brouillard P, Dupont L, Helaers R, et al. Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum Mol Genet. 2017 Nov 1;26(21):4095-4104. PMID: 28985353.
[7]   Melber DJ, Andreasen TS, Mao R, et al. Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1. Clin Case Rep. 2018 Oct 24;6(12):2358-2363. PMID: 30564329.
[8]   Van Balkom ID, Alders M, Allanson J. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet. 2002 Nov 1;112(4):412-21. PMID: 12376947.
[9]   Bellini C, Mazzella M, Arioni C, et al. Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia. Am J Med Genet A. 2003 Jul 1;120A(1):92-6. PMID: 12794699
[10] Wilson RD, Pawel B, Bebbington M, et al. Congenital pulmonary lymphangiectasis sequence: a rare, heterogeneous, and lethal etiology for prenatal pleural effusion. Prenat Diagn. 2006 Nov;26(11):1058-61. PMID: 16941717.

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