A number sign (#) is used with this entry because of evidence that lymphatic malformation-6 (LMPHM6) is caused by homozygous or compound heterozygous mutation in the PIEZO1 gene (611184) on chromosome 16q24.

Lymphatic malformation-6 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPHM6, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema, but childhood onset of lymphedema with or without systemic involvement also occurs. Mild facial edema is often present. Patients have normal intelligence and no seizures (summary by Fotiou et al., 2015).

For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

Fotiou et al. (2015) identified 2 sib pairs and 1 sporadic case of GLD with mutations in the PIEZO1 gene. Nonimmune hydrops fetalis was documented in 2 of the families, with in utero death of 1 sib. Postnatally, the edema associated with the hydrops resolved completely in the other patients, but they re-presented with lymphedema of the peripheries in early childhood. Two of them suffered from intermittent, severe facial swelling due to recurrent cellulitis, which is rarely seen in other forms of primary lymphedema. There was no history of hemolytic anemia, and the immune profiles for both sibs were normal. None of the patients had dysmorphic features, learning disabilities, or seizures and the swelling was not severe. Fotiou et al. (2015) identified 5 additional patients from 3 similarly affected families with a PIEZO1 mutation. Of the 10 patients, 7 had NIHF and 2 died in utero; survivors re-presented with lymphedema of the peripheries (mainly lower limbs but also arms, 4 patients), face (3 patients), or genitalia (1 patient), with or without chylothoraces (2 patients) or intestinal lymphangiectasia (1 patient). Fotiou et al. (2015) inspected blood films of the patients and identified subtle changes consistent with a mild and asymptomatic form of dehydrated hereditary stomatocytosis (see DHS1, 194380). Two affected sibs showed marked spherocytosis, whereas the blood film from their carrier mother was unremarkable with only occasional spherocytes. Four patients had severe, recurrent facial cellulitis with significant morbidity (high pyrexia and frequent admission to intensive care).

Lymphatic malformation-6 is an autosomal recessive disorder (Fotiou et al., 2015).

Mucke et al. (1986) observed 2 brothers with chronic congenital lymphedema and proposed the existence of an X-linked or recessive form. In addition to edema of the limbs, they had abnormalities of the external genitalia as a deformation sequence resulting from intrauterine edema and had intestinal lymphedema. A prominent feature also was chemosis and injection of the conjunctiva.

In 10 patients from 6 families with generalized lymphatic dysplasia who did not have mutations in the CCBE1 (612753) or FAT4 (612411) genes, Fotiou et al. (2015) identified homozygous or compound heterozygous mutations in the PIEZO1 gene (see, e.g., 611184.0009-611184.0015). The first mutations were identified by whole-exome sequencing and later mutations were identified by exome sequencing of all PIEZO1 exons and their associated splice sites. The mutations segregated with the phenotype in the families. None of the variants, except for 2 found in cis, were found in the dbSNP or 1000 Genomes Project databases or in 900 control samples.