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A rare syndromic lymphedema characterized by the association of primary lymphedema, intestinal lymphangiectasia, intellectual deficit and unusual facial characteristics.
ORPHA:2136Classification level: Disorder
The exact prevalence is unknown but around 100 cases have been reported in the literature. The entity occurs in all ethnic groups.
The lymphedema has invariably been present at birth, and is mainly present in the lower limbs and genitalia, although it can also be present elsewhere, including ascites. Lymphangiectasia is common in the intestines but can also be present in lungs, pericardium, thyroid and kidneys. The degree of intellectual deficit is highly variable, even within a single family. Facial characteristics are a flat face, a broad and depressed nasal bridge, hypertelorism, epicanthi, a small mouth, and low-set ears with a narrow meatus. Other features include mild growth retardation, delayed puberty, tooth anomalies, gingival hypertrophy, seizures, and blood vessel anomalies.
The syndrome can be caused by bi-allelic variants in CCBE1 (18q21.32) or FAT4 (4q28.1) or ADAMTS3 (4q13.3) can cause Hennekam syndrome.
The diagnosis is based on the clinical phenotype. Intestinal lymphangiectasia may be suspected because of hypogammaglobulinemia, hypoalbuminemia, and lymphopenia, but a definitive diagnosis can only be made by biopsies (often several are needed). Molecular studies may confirm the clinical diagnosis.
The differential diagnosis includes other entities associated with congenital lymphedema such as Noonan syndrome, Milroy syndrome and cholestasis-lymphedema syndrome, and Van Maldergem syndrome.
Prenatal genetic testing is possible in families with known mutations.
The syndrome is transmitted as an autosomal recessive trait and genetic counseling is recommended.
Management and treatment
There is no curative therapy, only supportive management including decongestive therapy for edema control, typically needing lymphologists. Rarely surgery is performed. Medium-chain triglyceride-rich diet is usually helpful because of the intestinal lymphangiectasias but recurrent albumin infusions are not uncommon. Vitamin and electrolyte supplements should be considered. Pulmonary lymphangiectasia may need temporary artificial ventilation (positive end-expiratory pressure). Penicillin prophylaxis may be needed to prevent erysipelas.
The signs and symptoms vary widely among affected individuals and even those within the same family. The course of the lymphedema may vary considerably within a person, for instance by hormonal influences, but often for unknown reasons. Life expectancy depends on the severity of manifestations, and may lead to early death.