CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non‐immune hydrops fetalis

To the Editor : Generalized lymphatic dysplasia (GLD) results from an inherent developmental abnormality of the lymphatic system involving the viscera. The onset of failure of lymphatic drainage can be preor postnatal and can result in any combination of peripheral lymphoedema, pleural and pericardial effusions, ascites, chylous effusions and pulmonary or intestinal lymphangiectasia (1). GLD, in its more severe form, can present prenatally as hydrops fetalis (HF) (abnormal accumulation of fluid in two or more fetal compartments). Until recently, the only genes known to cause lymphatic disease were those implicated in disorders characterized by predominantly peripheral disease; FLT4 (VEGFR3 ) in Milroy disease and FOXC2 in lymphoedema distichiasis. In 2009, Connell et al. (2) described a pedigree in which a homozygous mutation in CCBE1 was identified as causing an autosomal recessively inherited GLD. In the family described, there were three affected siblings, all of whom presented in utero with HF. Two died and the third child had a phenotype consistent with Hennekam syndrome, an autosomal recessive GLD disorder characterized by lymphoedema, lymphangiectasia, mental retardation and dysmorphic facies (3). Alders et al. (4) described homozygous and compound heterozygote CCBE1 mutations in 5/22 families with Hennekam syndrome. The role of CCBE1 in lymphangiogenesis was described by Hogan et al. (5), who showed that ccbe1 acts at the same stage of development as vegfc and is necessary for lymphangioblast budding and angiogenic sprouting from venous endothelium. The ‘full of fluid ’ (fof ) mutant zebrafish showed a loss of function effect, absence of the thoracic duct and intersegmental and dorsal longitudinal lymphatic vessels (all trunk lymphatic vessels). The blood vasculature was seemingly normal. These mutants had severe oedema and only 3/28 embryos survived to 36 days postfertilization (5). Although Hennekam syndrome is rare, HF is not, and we therefore investigated whether CCBE1 mutations occurred in 20 cases of HF or in 24 cases of GLD. HF is diagnosed on ultrasound scan if there is skin oedema >5 mm associated with other serous effusions. It is classified as ‘immune (fetomaternal allo-immunization)’ or ‘non-immune’ (6). Non-immune hydrops fetalis (NIHF) is more common, comprising 76–87% of all HF cases. NIHF has multifactorial causes and the associated mortality is high, reported to be between 40% and 60% and previously as high as >80% (7, 8). A review of over 6000 NIHF cases by Bellini et al. (9) found that the causes could be classified into the following diagnostic categories; cardiovascular (21.7%), haematological (10.4%), chromosomal (13.4%), syndromic (4.4%), inborn errors of metabolism (1.1%), infection (6.7%), thoracic (6.0%), urinary tract malformation (2.3%), extra thoracic tumours (0.7%), TTTF-placental (5.6%), gastrointestinal (0.5%), miscellaneous (3.7%) and idiopathic (17.8%). Lymphatic dysplasias accounted for 5.7% (9).