Lymphatic malformation 6 (LMPHM6; hereditary lymphedema type III), also known as generalized lymphatic dysplasia of Fotiou, is an autosomal recessive generalized lymphatic dysplasia caused by biallelic loss-of-function variants in PIEZO1, which encodes a mechanically activated, calcium-permeable cation channel. Loss of PIEZO1 mechanotransduction in lymphatic endothelial cells impairs lymphatic valve morphogenesis and flow-driven lymphatic sprouting, producing widespread lymphatic dysfunction. The condition most often presents prenatally as non-immune hydrops fetalis with pleural and pericardial effusions and ascites, which may be lethal in the perinatal period; survivors frequently have complete resolution of the neonatal edema and re-present in childhood with peripheral, facial, and genital lymphedema, with or without persistent chylothorax or intestinal lymphangiectasia. Recurrent severe facial cellulitis is a characteristic and serious complication. Unlike Hennekam syndrome, the dysmorphic features, seizures, and intellectual disability are absent. Because monoallelic gain-of-function PIEZO1 variants cause dehydrated hereditary stomatocytosis, affected individuals and carriers may show subtle red-cell abnormalities (stomatocytes, spherocytes) without clinically significant hemolysis. Management is supportive; no PIEZO1-directed disease-modifying therapy is approved, although pharmacological rescue of mechanically insensitive mutant channels with the PIEZO1 agonist Yoda1 has been demonstrated in vitro.
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Conditions with similar clinical presentations that must be differentiated from Lymphatic malformation 6:
name: Lymphatic malformation 6
creation_date: "2026-08-18T00:00:00Z"
description: >-
Lymphatic malformation 6 (LMPHM6; hereditary lymphedema type III), also known as
generalized lymphatic dysplasia of Fotiou, is an autosomal recessive generalized
lymphatic dysplasia caused by biallelic loss-of-function variants in PIEZO1,
which encodes a mechanically activated, calcium-permeable cation channel. Loss
of PIEZO1 mechanotransduction in lymphatic endothelial cells impairs lymphatic
valve morphogenesis and flow-driven lymphatic sprouting, producing widespread
lymphatic dysfunction. The condition most often presents prenatally as
non-immune hydrops fetalis with pleural and pericardial effusions and ascites,
which may be lethal in the perinatal period; survivors frequently have complete
resolution of the neonatal edema and re-present in childhood with peripheral,
facial, and genital lymphedema, with or without persistent chylothorax or
intestinal lymphangiectasia. Recurrent severe facial cellulitis is a
characteristic and serious complication. Unlike Hennekam syndrome, the
dysmorphic features, seizures, and intellectual disability are absent. Because
monoallelic gain-of-function PIEZO1 variants cause dehydrated hereditary
stomatocytosis, affected individuals and carriers may show subtle red-cell
abnormalities (stomatocytes, spherocytes) without clinically significant
hemolysis. Management is supportive; no PIEZO1-directed disease-modifying
therapy is approved, although pharmacological rescue of mechanically insensitive
mutant channels with the PIEZO1 agonist Yoda1 has been demonstrated in vitro.
category: Mendelian
parents:
- lymphatic malformation
- hereditary disease
synonyms:
- LMPHM6
- generalized lymphatic dysplasia of Fotiou
- hereditary lymphedema type III
- LMPH3
- PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis
- PIEZO1-related lymphatic-related hydrops fetalis
disease_term:
preferred_term: lymphatic malformation 6
term:
id: MONDO:0014797
label: lymphatic malformation 6
classifications:
harrisons_chapter:
- classification_value: CARDIOVASCULAR
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
LMPHM6 is inherited in an autosomal recessive manner; affected individuals
carry biallelic (homozygous or compound heterozygous) loss-of-function PIEZO1
variants that co-segregate with disease in reported families. Heterozygous
carriers are unaffected by the lymphatic phenotype. A pedigree may
nonetheless look dominant: in family GLD08 a homozygous I2270T genotype
segregating through consanguinity produced affected individuals in
consecutive generations (the proband and his father), a pseudo-dominant
pattern that should not be mistaken for a dominant PIEZO1 disorder.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we report homozygous and compound heterozygous mutations in PIEZO1,
resulting in an autosomal recessive form of GLD with a high incidence of
non-immune hydrops fetalis and childhood onset of facial and four limb
lymphoedema.
explanation: >-
Homozygous and compound heterozygous PIEZO1 genotypes establish autosomal
recessive inheritance for LMPHM6.
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a
splicing variant leading to early truncation and a non-synonymous missense
variant) in a pair of siblings affected with persistent lymphoedema caused
by congenital lymphatic dysplasia.
explanation: >-
Independently confirms biallelic (compound heterozygous) PIEZO1 inheritance
in an affected sibship.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In GLD08, homozygosity of a single variant encoding Ile2270Thr (I2270T)
associated with disease in 3 family members
explanation: >-
A single homozygous PIEZO1 variant accounts for disease in three members of
one consanguineous family, the genotype underlying the apparently dominant
vertical transmission in that pedigree.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
GLD08 I.2 is the proband’s father. His parents are not known to be
consanguineous. He was diagnosed with spontaneous bilateral chylous
effusions at the age of 30 years.
explanation: >-
Documents an affected parent and affected child in the same pedigree - the
pseudo-dominant pattern that arises when a recessive allele is common in a
consanguineous kindred.
pathophysiology:
- name: PIEZO1 Loss of Function
biological_scale: MOLECULAR
description: >-
Biallelic nonsense, frameshift, splice-site, and missense variants in PIEZO1
abolish or severely reduce the activity of a mechanically activated,
calcium-permeable cation channel. Two mechanistically distinct routes to loss
of function are documented: reduced or absent PIEZO1 protein (truncating and
splice variants, shown by western blot to eliminate or reduce PIEZO1
expression) and reduced channel mechanical sensitivity despite surface
expression (cap and sub-cap missense variants that are mechanically
insensitive yet partly rescuable with the chemical agonist Yoda1).
genes:
- preferred_term: PIEZO1
term:
id: hgnc:28993
label: PIEZO1
molecular_functions:
- preferred_term: mechanically activated cation channel activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0008381
label: mechanosensitive monoatomic ion channel activity
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in PIEZO1, which encodes a mechanically activated ion channel,
have been reported with autosomal dominant dehydrated hereditary
stomatocytosis and non-immune hydrops of unknown aetiology.
explanation: >-
Identifies PIEZO1 as a mechanically activated ion channel and the causal
gene locus for this disorder.
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No truncated PIEZO1 protein products were identified in western blot
analysis in GLD1:II.3 and GLD2:II.2
explanation: >-
Direct protein-level demonstration that truncating alleles yield no stable
PIEZO1 protein, i.e. loss of function.
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Patch-clamp analysis of the missense PIEZO1 channel in a heterologous system
(a mammalian cell line derived from HEK293T cells) indicated strongly
diminished current amplitudes as compared with wild type, likely due to
reduced cell surface expression.
explanation: >-
Electrophysiological confirmation that the patient missense allele is
hypomorphic/loss-of-function.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
PIEZO1 variants have been associated with generalized lymphatic dysplasia
(GLD) through mechanisms involving reduced PIEZO1 expression. Here, we
report variants where the mechanism involves reduced channel mechanical
sensitivity.
explanation: >-
Establishes the second loss-of-function route: mechanical insensitivity of
an expressed channel, distinct from reduced expression.
downstream:
- target: Impaired Lymphatic Endothelial Mechanotransduction
causal_link_type: DIRECT
description: >-
Loss of PIEZO1 channel function removes the principal mechanosensor by which
lymphatic endothelial cells convert flow and stretch into calcium influx.
- name: Impaired Lymphatic Endothelial Mechanotransduction
biological_scale: CELLULAR
description: >-
PIEZO1 is abundantly expressed in lymphatic endothelial cells, where it
transduces oscillatory shear stress and membrane stretch into calcium entry.
Loss of PIEZO1 abrogates flow-induced calcium influx and the downstream
ORAI1/KLF2/Notch transcriptional programme that drives lymphatic sprouting,
and it removes the mechanical cue required for valve-forming cell behaviour.
cell_types:
- preferred_term: lymphatic endothelial cell
term:
id: CL:0002138
label: endothelial cell of lymphatic vessel
biological_processes:
- preferred_term: cellular response to fluid shear stress
modifier: DECREASED
term:
id: GO:0071498
label: cellular response to fluid shear stress
- preferred_term: response to mechanical stimulus
modifier: DECREASED
term:
id: GO:0009612
label: response to mechanical stimulus
evidence:
- reference: PMID:35701867
reference_title: Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the
laminar flow-induced calcium influx
explanation: >-
Demonstrates that PIEZO1 is required for flow-induced calcium signalling in
lymphatic endothelial cells.
- reference: PMID:38747287
reference_title: The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Yoda1 rapidly triggered nuclear FOXO1 extrusion in WT mesenteries but not in
Piezo1LEC–/– mesenteries, confirming the PIEZO1/FOXO1 axis in mesenteric
lymphatics
explanation: >-
Ex vivo mouse mesenteric lymphatics lacking endothelial PIEZO1 fail to
transduce channel activation into a downstream signalling response,
demonstrating that PIEZO1 loss abolishes lymphatic endothelial
mechanosignalling.
downstream:
- target: Disrupted ANGPT2-TIE-FOXO1 Signaling
causal_link_type: DIRECT
description: >-
PIEZO1 activation is the upstream trigger for ANGPT2 exocytosis and TIE
pathway engagement in lymphatic endothelial cells.
- target: Defective Lymphatic Valve Formation and Lymphangiogenesis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Loss of flow-triggered mechanotransduction removes the signal driving
valve-leaflet protrusion and flow-activated lymphatic sprouting.
- name: Disrupted ANGPT2-TIE-FOXO1 Signaling
biological_scale: MOLECULAR
description: >-
PIEZO1 activation in lymphatic endothelial cells triggers rapid exocytosis of
the TIE ligand ANGPT2, ADAM17-mediated ectodomain shedding of TIE1, increased
TIE/PI3K/AKT signaling, and nuclear export of the transcription factor FOXO1.
Loss of PIEZO1 function therefore silences a signaling network whose other
members (ANGPT2, TIE1) are themselves mutated in primary lymphedema, providing
a molecular bridge between channel function and lymphatic gene expression.
biological_processes:
- preferred_term: Tie signaling pathway
modifier: DECREASED
term:
id: GO:0048014
label: Tie signaling pathway
- preferred_term: PI3K/AKT signal transduction
modifier: DECREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
- preferred_term: FOXO1 nuclear export
modifier: DECREASED
term:
id: GO:0006611
label: protein export from nucleus
cell_types:
- preferred_term: lymphatic endothelial cell
term:
id: CL:0002138
label: endothelial cell of lymphatic vessel
evidence:
- reference: PMID:38747287
reference_title: The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
activation of the mechanosensory channel PIEZO1 in lymphatic endothelial
cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain
shedding of TIE1 by disintegrin and metalloproteinase domain-containing
protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by
nuclear export of the transcription factor FOXO1
explanation: >-
Establishes the PIEZO1 to ANGPT2/TIE/PI3K-AKT/FOXO1 signaling axis in
lymphatic endothelial cells.
downstream:
- target: Defective Lymphatic Valve Formation and Lymphangiogenesis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Loss of this transcriptional output contributes to defective lymphatic
vessel and valve development.
- name: Defective Lymphatic Valve Formation and Lymphangiogenesis
biological_scale: TISSUE
description: >-
Endothelial-specific Piezo1 deletion in mice dramatically reduces the number
of lymphatic valves and impairs the collective cell migration, actin
polymerization, and cell-cell junction remodeling that produce the valve
leaflet, while lymphatic-specific deletion phenocopies the sprouting defects
of Orai1 and Klf2 knockouts and postnatal deletion causes lymphatic
regression. Lymphatic valves are essential for unidirectional lymph flow, so
their loss renders the collecting lymphatics incompetent.
cell_types:
- preferred_term: lymphatic endothelial cell
term:
id: CL:0002138
label: endothelial cell of lymphatic vessel
biological_processes:
- preferred_term: lymph vessel development
modifier: DECREASED
term:
id: GO:0001945
label: lymph vessel development
- preferred_term: lymphangiogenesis
modifier: DECREASED
term:
id: GO:0001946
label: lymphangiogenesis
- preferred_term: lymph vessel morphogenesis
modifier: DECREASED
term:
id: GO:0036303
label: lymph vessel morphogenesis
evidence:
- reference: PMID:30482854
reference_title: Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre
or Lyve1Cre) and found that they exhibited pleural effusion and died
postnatally. Strikingly, the number of lymphatic valves was dramatically
reduced in these mice.
explanation: >-
Endothelial Piezo1 loss reduces lymphatic valve number and reproduces
pleural effusion in mice.
- reference: PMID:30482854
reference_title: Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the process of protrusion in the valve leaflets, which is associated with
collective cell migration, actin polymerization, and remodeling of cell-cell
junctions, was impaired in Tie2Cre;Piezo1cKO mice
explanation: >-
Identifies the specific cellular step of valve morphogenesis that requires
PIEZO1.
- reference: PMID:35701867
reference_title: Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting
defects shown in Orai1- or Klf2- knockout lymphatics during embryo
development. Postnatal deletion of Piezo1 induced lymphatic regression in
adults.
explanation: >-
Shows PIEZO1 is required both for developmental lymphatic sprouting and for
maintenance of adult lymphatics.
- reference: PMID:37159433
reference_title: Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PIEZO1 is required for lymphatic valve formation, and several lymphatic
abnormalities have been reported to be associated with autosomal recessive
PIEZO1 pathogenic variants including neonatal hydrops, lymphedema involving
various body regions, and chylothorax.
explanation: >-
Connects the valve-formation requirement to the human autosomal recessive
PIEZO1 clinical spectrum.
downstream:
- target: Generalized Lymphatic Dysplasia and Lymph Transport Failure
causal_link_type: DIRECT
description: >-
Incompetent, hypoplastic lymphatic collectors cannot clear interstitial
fluid and chyle.
- name: Generalized Lymphatic Dysplasia and Lymph Transport Failure
biological_scale: ORGANISM
description: >-
The resulting disorder is a uniform, widespread lymphatic dysplasia affecting
all body segments, with systemic involvement of the thoracic, pericardial, and
intestinal lymphatics. Lymphoscintigraphy in affected individuals shows a
strikingly consistent and symmetric pattern of deep and superficial rerouting,
indicating failure of superficial lymphatic collector function rather than
simple aplasia.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema
characterized by a uniform, widespread lymphoedema affecting all segments of
the body, with systemic involvement such as intestinal and/or pulmonary
lymphangiectasia, pleural effusions, chylothoraces and/or pericardial
effusions.
explanation: >-
Defines the generalized, multi-compartment lymphatic dysplasia phenotype
that PIEZO1 loss produces.
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The rerouting suggests failure of superficial lymphatic collector function.
explanation: >-
Lymphoscintigraphic evidence that the functional lesion is collector
failure, consistent with the valve defect.
downstream:
- target: Chylous Effusion and Fetal Fluid Accumulation
causal_link_type: DIRECT
description: >-
Failure of thoracic and abdominal lymph drainage causes chyle and serous
fluid to accumulate in body cavities, presenting in utero as hydrops.
- target: Chronic Peripheral and Facial Lymphedema
causal_link_type: DIRECT
description: >-
Failure of superficial collector function causes interstitial protein-rich
fluid to accumulate in the limbs, face, and genitalia.
- name: Chylous Effusion and Fetal Fluid Accumulation
biological_scale: ORGANISM
description: >-
In utero, lymphatic transport failure produces non-immune hydrops fetalis with
pleural and pericardial effusions and ascites. This may be lethal in the
perinatal period; in survivors the neonatal edema often resolves completely,
but chylothorax may persist or recur.
evidence:
- reference: PMID:36453701
reference_title: "Perinatal presentations of non-immune hydrops fetalis due to recessive PIEZO1 disease: A challenging fetal diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
One cause of NIHF is lymphatic malformation 6 (LMPHM6) due to biallelic
loss-of-function (LoF) variants in PIEZO1.
explanation: >-
Directly attributes non-immune hydrops fetalis to biallelic loss-of-function
PIEZO1 (LMPHM6).
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
biallelic variants have a high incidence of NIHF (7 of the 10 affected
cases). This may be lethal in the perinatal period (n=2).
explanation: >-
Quantifies the frequency and perinatal lethality of hydrops in the founding
cohort.
- name: Chronic Peripheral and Facial Lymphedema
biological_scale: ORGANISM
description: >-
Survivors typically re-present in childhood with lymphedema of the lower
limbs, arms, face, and genitalia, with or without chylothoraces and intestinal
lymphangiectasia. Recurrent severe facial cellulitis complicates the facial
lymphedema and is a major source of morbidity.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Survivors may present later with lymphoedema of the peripheries (mainly
lower limbs but also arms (n=4), face (n=3) and genitalia (n=1)), with or
without chylothoraces (n=2) and intestinal lymphangiectasia (n=1).
explanation: >-
Documents the postnatal distribution of lymphedema and its systemic
complications.
progression:
- phase: Prenatal and early-childhood onset
age_range: Fetal to early childhood
notes: >-
The classically reported course: non-immune fetal hydrops detected in the
second trimester, often resolving spontaneously after birth, followed by
facial and four-limb lymphedema appearing in infancy or early childhood.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we report homozygous and compound heterozygous mutations in PIEZO1,
resulting in an autosomal recessive form of GLD with a high incidence of
non-immune hydrops fetalis and childhood onset of facial and four limb
lymphoedema.
explanation: >-
Defines the prenatal-hydrops-then-childhood-lymphedema course of the
founding cohort.
- phase: Adolescent and adult onset
age_range: 11-30 years
notes: >-
A later-onset arm exists and is easily missed if LMPHM6 is treated as a
uniformly congenital disorder. In family GLD08 (homozygous I2270T) there was
no antenatal or neonatal disease at all; presentation began in adolescence
with chylous pleural and pericardial effusions, with lower-limb and scrotal
edema following years later and no facial edema. The affected father of that
proband presented at 30 years.
evidence:
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
in GLD08, there was disease only from adolescence that was characterized
first by pleural and pericardial effusions and then lower limb and scrotal
edema without facial edema
explanation: >-
Directly states an adolescent-onset presentation with a different
phenotype ordering from the congenital arm.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
From age 11 years he developed progressive breathlessness and reduced
exercise tolerance and was found to have bilateral chylous pleural
effusions
explanation: >-
Case-level detail of the adolescent onset in the GLD08 proband, whose
antenatal and neonatal period was uneventful.
phenotypes:
- name: Non-immune hydrops fetalis
category: Prenatal
diagnostic: true
frequency: FREQUENT
description: >-
Generalized fetal fluid accumulation with skin edema, pleural and pericardial
effusions, and ascites, typically detected at the second trimester and often
the presenting feature. It occurred in 7 of 10 affected individuals in the
founding cohort and may be lethal.
phenotype_term:
preferred_term: Nonimmune hydrops fetalis
term:
id: HP:0001790
label: Nonimmune hydrops fetalis
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
biallelic variants have a high incidence of NIHF (7 of the 10 affected
cases). This may be lethal in the perinatal period (n=2).
explanation: >-
7 of 10 affected individuals (70%) had non-immune hydrops fetalis, mapping
to the FREQUENT band.
- reference: PMID:36453701
reference_title: "Perinatal presentations of non-immune hydrops fetalis due to recessive PIEZO1 disease: A challenging fetal diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
During the pregnancy, most cases are revealed by isolated NIHF at second
trimester of gestation.
explanation: >-
Establishes the prenatal timing and the isolated-NIHF presentation.
- name: Polyhydramnios
category: Prenatal
frequency: OCCASIONAL
description: >-
Excess amniotic fluid complicating affected pregnancies, recorded alongside
non-immune fetal hydrops in two of the three families reported by Bee et al.
(GLD07 and GLD09). In GLD09 it was severe enough to require repeated
amnio-drainage.
phenotype_term:
preferred_term: Polyhydramnios
term:
id: HP:0001561
label: Polyhydramnios
evidence:
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Antenatal imaging (gestational date not noted) identified NIFH and
polyhydramnios.
explanation: >-
Documents polyhydramnios in the GLD07 proband's affected pregnancy.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The pregnancy was complicated by polyhydramnios requiring repeated
amnio-drainage at 27, 30 and 33 weeks.
explanation: >-
Independent occurrence in the GLD09 pregnancy, severe enough to require
repeated drainage.
notes: >-
Frequency is banded OCCASIONAL from the reported case detail (2 of 3 families
in this series, but not systematically ascertained across the whole reported
LMPHM6 cohort); no cohort-level frequency figure has been published.
- name: Lymphedema
category: Lymphatic
diagnostic: true
frequency: VERY_FREQUENT
description: >-
Chronic, often progressive lymphedema affecting the lower limbs, arms, face,
and genitalia. It may be present at birth or, more characteristically, appear
in early childhood after complete resolution of the neonatal hydrops.
phenotype_term:
preferred_term: Lymphedema
term:
id: HP:0001004
label: Lymphedema
temporality: CHRONIC
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Survivors may present later with lymphoedema of the peripheries (mainly
lower limbs but also arms (n=4), face (n=3) and genitalia (n=1)), with or
without chylothoraces (n=2) and intestinal lymphangiectasia (n=1).
explanation: >-
Lymphedema is the defining postnatal feature in surviving affected
individuals, supporting the VERY_FREQUENT band.
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At 42 months of age, she displays significant persistent lymphoedema of her
legs, torso and face
explanation: >-
Documents persistent multi-segment lymphedema in an independently reported
patient.
- name: Chylothorax
category: Respiratory
frequency: FREQUENT
description: >-
Accumulation of chyle in the pleural space, confirmed by pleural-fluid
analysis. It may be present at birth and can be persistent or recurrent,
sometimes requiring repeated drainage, dietary fat restriction, or octreotide.
phenotype_term:
preferred_term: Chylothorax
term:
id: HP:0010310
label: Chylothorax
temporality: RECURRENT
evidence:
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
II.1 presented at birth with hydrops and bilateral chylothorax, confirmed by
fluid analysis.
explanation: >-
Documents biochemically confirmed bilateral chylothorax at birth.
- reference: PMID:37159433
reference_title: Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hereditary Lymphedema type III can be associated with persistent chylothorax
that can vary in size over time.
explanation: >-
Establishes persistent/recurrent chylothorax as a recognized feature of
LMPHM6.
- name: Pleural effusion
category: Respiratory
frequency: FREQUENT
description: >-
Pleural fluid accumulation, frequently bilateral, detected prenatally as part
of hydrops or persisting postnatally as chronic effusions.
phenotype_term:
preferred_term: Pleural effusion
term:
id: HP:0002202
label: Pleural effusion
evidence:
- reference: PMID:36453701
reference_title: "Perinatal presentations of non-immune hydrops fetalis due to recessive PIEZO1 disease: A challenging fetal diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At post-mortem examination ascites, pleural effusions and telengectasies can
guide the etiological diagnosis.
explanation: >-
Pleural effusion is a consistent post-mortem finding in LMPHM6 fetuses.
- name: Pericardial effusion
category: Cardiovascular
frequency: OCCASIONAL
description: >-
Pericardial fluid accumulation is part of the generalized lymphatic dysplasia
spectrum and may contribute to the fetal hydrops.
phenotype_term:
preferred_term: Pericardial effusion
term:
id: HP:0001698
label: Pericardial effusion
evidence:
- reference: PMID:35646098
reference_title: A Novel Homozygous Missense Mutation of PIEZO1 Leading to Lymphatic Malformation-6 Identified in a Family With Three Adverse Pregnancy Outcomes due to Nonimmune Fetal Hydrops.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lymphatic malformation-6 (LMPHM6) is a rarer form of nonimmune hydrops that
often manifests as widespread lymphedema involving all segments of the body,
namely, subcutaneous edema, intestinal/pulmonary lymphangiectasia,
chylothoraces, and pleural/pericardial effusions.
explanation: >-
Lists pericardial effusion among the manifestations of LMPHM6.
- name: Ascites
category: Gastrointestinal
frequency: OCCASIONAL
description: >-
Free peritoneal fluid, typically part of the fetal hydrops picture and a
consistent post-mortem finding.
phenotype_term:
preferred_term: Ascites
term:
id: HP:0001541
label: Ascites
evidence:
- reference: PMID:36453701
reference_title: "Perinatal presentations of non-immune hydrops fetalis due to recessive PIEZO1 disease: A challenging fetal diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At post-mortem examination ascites, pleural effusions and telengectasies can
guide the etiological diagnosis.
explanation: >-
Documents ascites in LMPHM6 fetuses at post-mortem examination.
- name: Intestinal lymphangiectasia
category: Gastrointestinal
frequency: OCCASIONAL
description: >-
Dilated intestinal lymphatics causing enteric lymph loss; reported in a
minority of affected individuals (1 of 10 in the founding cohort).
phenotype_term:
preferred_term: Intestinal lymphangiectasia
term:
id: HP:0002593
label: Intestinal lymphangiectasia
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Survivors may present later with lymphoedema of the peripheries (mainly
lower limbs but also arms (n=4), face (n=3) and genitalia (n=1)), with or
without chylothoraces (n=2) and intestinal lymphangiectasia (n=1).
explanation: >-
Reports intestinal lymphangiectasia in 1 of 10 affected individuals,
supporting the OCCASIONAL band.
- name: Facial edema
category: Craniofacial
frequency: FREQUENT
description: >-
Facial swelling, often intermittent and severe, reflecting facial lymphatic
involvement; in the founding cohort facial lymphedema affected 3 of 10
individuals and intermittent severe facial swelling was attributed to
recurrent cellulitis.
phenotype_term:
preferred_term: Facial edema
term:
id: HP:0000282
label: Facial edema
temporality: RECURRENT
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two of the affected individuals suffer from intermittent, severe facial
swelling due to recurrent cellulitis. This is rarely seen in other forms of
primary lymphoedema.
explanation: >-
Documents intermittent severe facial swelling and notes it as
distinguishing from other primary lymphedemas.
- name: Recurrent cellulitis
category: Dermatologic
frequency: FREQUENT
description: >-
Severe recurrent facial cellulitis with high fever and frequent intensive-care
admission is a characteristic and serious complication, seen in 4 of 10
affected individuals in the founding cohort and rarely encountered in other
primary lymphedemas.
phenotype_term:
preferred_term: Cellulitis
term:
id: HP:0100658
label: Cellulitis
temporality: RECURRENT
severity: SEVERE
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Four patients of our cohort had severe, recurrent facial cellulitis with
significant morbidity (high pyrexia and frequent admission to intensive
care).
explanation: >-
4 of 10 affected individuals (40%) had severe recurrent facial cellulitis,
mapping to the FREQUENT band.
- name: Stomatocytosis
category: Hematologic
frequency: OCCASIONAL
description: >-
Subtle red-cell membrane abnormalities are detectable on careful blood-film
inspection in affected individuals and, less often, in heterozygous carriers,
reflecting the shared PIEZO1 basis with dehydrated hereditary stomatocytosis.
The changes are asymptomatic and are not accompanied by clinically significant
hemolysis.
phenotype_term:
preferred_term: Stomatocytosis
term:
id: HP:0004446
label: Stomatocytosis
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Careful inspection of blood films from our affected individuals demonstrates
occasional stomatocytes and spherocytes
explanation: >-
Documents stomatocytes on blood films of affected individuals.
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients and parents had blood counts including mean corpuscular volume
in the normal range.
explanation: >-
Counterbalancing observation that routine hematologic indices can be
entirely normal, so the red-cell finding is subtle and not universal.
- name: Spherocytosis
category: Hematologic
frequency: OCCASIONAL
description: >-
Marked spherocytosis was observed in one reported family, suggesting some
cases of spherocytosis may be attributable to PIEZO1 variants.
phenotype_term:
preferred_term: Spherocytosis
term:
id: HP:0004444
label: Spherocytosis
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Careful inspection of blood films from our affected individuals demonstrates
occasional stomatocytes and spherocytes
explanation: >-
Documents spherocytes on blood films of affected individuals.
genetic:
- name: PIEZO1
association: Causal biallelic loss-of-function variants
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: PIEZO1
term:
id: hgnc:28993
label: PIEZO1
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we report homozygous and compound heterozygous mutations in PIEZO1,
resulting in an autosomal recessive form of GLD with a high incidence of
non-immune hydrops fetalis and childhood onset of facial and four limb
lymphoedema.
explanation: >-
Establishes PIEZO1 as the causal gene, with biallelic variants, for this
form of generalized lymphatic dysplasia.
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results delineate a novel clinical category of PIEZO1-associated
hereditary lymphoedema.
explanation: >-
Independent contemporaneous report establishing PIEZO1-associated hereditary
lymphedema as a distinct entity.
- reference: PMID:37902181
reference_title: PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PIEZO1 variants causing AR NIHF were characterized by loss of function and
isolated NIHF phenotype.
explanation: >-
Confirms that the recessive (LMPHM6) mechanism is loss of function, in
contrast to the dominant gain-of-function red-cell disease.
variants:
- name: p.Glu1630Ter (c.4888G>T)
type: nonsense
clinical_significance: PATHOGENIC
description: >-
Recurrent nonsense PIEZO1 allele observed in two unrelated families in the
founding cohort; no truncated protein is detectable by western blot,
consistent with a null allele.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
one of which was the nonsense mutation (c.G4888T; p.E1630X) also observed
in family GLD1
explanation: >-
Identifies the recurrent nonsense allele shared between families.
- name: c.3796+1G>A
type: splice donor site
clinical_significance: PATHOGENIC
description: >-
Canonical splice-donor variant causing skipping of exon 26 and a measurable
reduction in PIEZO1 protein.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The c.3796+1G>A variant in GLD3 causes skipping of exon 26
explanation: >-
Establishes the splicing consequence of this allele.
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Western blot results of the c.3796+1G>A variant in GLD3 showed a reduction
in PIEZO1 expression levels
explanation: >-
Protein-level confirmation of reduced PIEZO1 expression for this allele.
- name: p.Ser1721Trp (c.5162C>G)
type: missense
clinical_significance: PATHOGENIC
description: >-
Homozygous missense PIEZO1 variant reported as a cause of LMPHM6 in a family
with three adverse pregnancy outcomes from non-immune fetal hydrops.
evidence:
- reference: PMID:35646098
reference_title: A Novel Homozygous Missense Mutation of PIEZO1 Leading to Lymphatic Malformation-6 Identified in a Family With Three Adverse Pregnancy Outcomes due to Nonimmune Fetal Hydrops.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we detected one rare and previously unobserved homozygous missense variant
in PIEZO1 (c.5162C>G, p.Ser1721Trp) as a novel genetic cause of autosomal
recessive LMPHM6, in a family with three adverse pregnancy outcomes due to
nonimmune fetal hydrops
explanation: >-
A specific homozygous missense allele established as causal for LMPHM6.
- name: p.Trp1287Ter (c.3860G>A)
type: nonsense
clinical_significance: LIKELY_PATHOGENIC
description: >-
Nonsense PIEZO1 allele reported in trans with a splice-acceptor deletion in a
child with persistent chylothorax; both were classified as likely pathogenic.
evidence:
- reference: PMID:37159433
reference_title: Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic testing revealed two deleterious variants in PIEZO1:
c.2330-2_2330-1del and c.3860G > A (p.Trp1287*), both of which were
classified as likely pathogenic.
explanation: >-
Documents the biallelic genotype in a patient with persistent chylothorax.
- name: p.Ile2270Thr (I2270T)
type: missense
description: >-
Missense PIEZO1 allele reported homozygously in family GLD08 - the
adolescent-onset pedigree - and in trans with E829V in GLD09. The reporting
authors interpreted the GLD07-09 variants collectively as likely pathogenic
or of uncertain significance, so no per-variant classification is asserted
here; the functional work in the same paper shows reduced channel
mechanical sensitivity rather than reduced expression.
evidence:
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In GLD08, homozygosity of a single variant encoding Ile2270Thr (I2270T)
associated with disease in 3 family members
explanation: >-
Segregation of the homozygous missense allele with disease in three
members of one family.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
PIEZO1 variants have been associated with generalized lymphatic dysplasia
(GLD) through mechanisms involving reduced PIEZO1 expression. Here, we
report variants where the mechanism involves reduced channel mechanical
sensitivity.
explanation: >-
Establishes the loss-of-function mechanism for this class of variant as
mechanical insensitivity of an expressed channel.
diagnosis:
- name: Molecular genetic testing of PIEZO1
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Identification of biallelic pathogenic PIEZO1 variants, typically by exome or
a primary-lymphedema/generalized-lymphatic-anomaly gene panel, confirms the
diagnosis. In prenatal exome series, PIEZO1 is the single most frequently
implicated gene in non-immune hydrops fetalis, so it should be prioritized
when hydrops is otherwise unexplained.
results: >-
Biallelic (homozygous or compound heterozygous) loss-of-function PIEZO1
variants confirm LMPHM6.
evidence:
- reference: PMID:37902181
reference_title: PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PIEZO1 variants were reported in 10% of NIHF cases diagnosed by prenatal
exome, making PIEZO1 the most common single gene reported in NIHF.
explanation: >-
Supports prioritizing PIEZO1 in the molecular workup of unexplained
non-immune hydrops fetalis.
- reference: PMID:26387913
reference_title: Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a
splicing variant leading to early truncation and a non-synonymous missense
variant) in a pair of siblings affected with persistent lymphoedema caused
by congenital lymphatic dysplasia.
explanation: >-
Exome sequencing is the demonstrated route to molecular diagnosis in this
disorder.
- name: Lymphoscintigraphy
diagnosis_term:
preferred_term: lymphoscintigraphy
term:
id: NCIT:C67262
label: Lymphoscintigraphy
description: >-
Radionuclide lymphoscintigraphy demonstrates the functional lymphatic lesion,
showing symmetric deep rerouting with popliteal nodal uptake and superficial
rerouting through the skin, indicating failure of superficial lymphatic
collector function rather than aplasia.
results: >-
Symmetric deep and superficial rerouting consistent with collector failure;
lymphangiectasia with chylothorax may also be demonstrated.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the lower limbs, all the patients have deep rerouting as demonstrated by
the popliteal lymph node uptake
explanation: >-
Describes the characteristic lymphoscintigraphic finding in affected
individuals.
- reference: PMID:37274623
reference_title: Case report of generalized lymphatic dysplasia with PIEZO1 mutation and review of the literature.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lymphoscintigraphy showed lymphangiectasia with chylothorax.
explanation: >-
Independent case confirming the diagnostic utility of lymphoscintigraphy.
treatments:
- name: Dietary fat restriction and medium-chain triglyceride feeding
description: >-
Restriction of long-chain dietary fat, with medium-chain triglyceride
substitution, reduces chyle production and thoracic-duct lymph flow and is
first-line conservative management of chylothorax and enteric lymph loss in
LMPHM6.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: dietary intervention
term:
id: NCIT:C15447
label: Dietary Intervention
target_mechanisms:
- target: Chylous Effusion and Fetal Fluid Accumulation
treatment_effect: MODULATES
description: >-
Reducing long-chain fat intake lowers chyle flow into the incompetent
thoracic lymphatics, reducing effusion volume.
evidence:
- reference: PMID:37159433
reference_title: Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She subsequently had recurrent pleural effusions involving both pleural
cavities, which tended to improve with restriction of her fat intake, and,
one occasion, subcutaneous octreotide.
explanation: >-
Documents clinical improvement of the recurrent effusions with dietary fat
restriction in a molecularly confirmed LMPHM6 patient.
- name: Octreotide
description: >-
Subcutaneous octreotide, a somatostatin analogue that reduces splanchnic blood
flow and lymph production, has been used as adjunctive therapy for refractory
chylothorax in LMPHM6. Evidence is limited to single-patient experience.
therapeutic_modality: PEPTIDE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: octreotide
term:
id: CHEBI:7726
label: octreotide
target_mechanisms:
- target: Chylous Effusion and Fetal Fluid Accumulation
treatment_effect: MODULATES
description: >-
Somatostatin-analogue reduction of lymph production decreases chyle
accumulation in the pleural space.
evidence:
- reference: PMID:37159433
reference_title: Persistent chylothorax associated with lymphatic malformation type 6 due to biallelic pathogenic variants in PIEZO1.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She subsequently had recurrent pleural effusions involving both pleural
cavities, which tended to improve with restriction of her fat intake, and,
one occasion, subcutaneous octreotide.
explanation: >-
Single-patient use of subcutaneous octreotide alongside dietary fat
restriction; the report does not isolate the octreotide effect, so support
is partial.
- name: Lymphedema supportive care
description: >-
Complete decongestive therapy - compression garments or bandaging, manual
lymphatic drainage, exercise, and meticulous skin care - is the mainstay of
chronic lymphedema management, together with prompt antibiotic treatment of
cellulitis, which is a major source of morbidity in this disorder.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
target_mechanisms:
- target: Chronic Peripheral and Facial Lymphedema
treatment_effect: MODULATES
description: >-
Decongestive therapy mechanically compensates for failed lymphatic collector
function.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Four patients of our cohort had severe, recurrent facial cellulitis with
significant morbidity (high pyrexia and frequent admission to intensive
care).
explanation: >-
Establishes the clinical burden (recurrent severe cellulitis complicating
lymphedema) that skin care and prompt antibiotic treatment address; the
paper does not itself report a supportive-care trial, so support is partial.
- name: Genetic counseling
description: >-
Counseling covers autosomal recessive inheritance and the 25% sibling
recurrence risk, carrier testing, and prenatal or preimplantation genetic
testing options once the familial biallelic PIEZO1 genotype is known.
Recurrent adverse pregnancy outcomes are a recognized presentation.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:35646098
reference_title: A Novel Homozygous Missense Mutation of PIEZO1 Leading to Lymphatic Malformation-6 Identified in a Family With Three Adverse Pregnancy Outcomes due to Nonimmune Fetal Hydrops.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we detected one rare and previously unobserved homozygous missense variant
in PIEZO1 (c.5162C>G, p.Ser1721Trp) as a novel genetic cause of autosomal
recessive LMPHM6, in a family with three adverse pregnancy outcomes due to
nonimmune fetal hydrops
explanation: >-
Recurrent pregnancy loss in a single family illustrates the recurrence risk
that counseling and molecular diagnosis address.
- name: PIEZO1 agonism (investigational)
description: >-
The small-molecule PIEZO1 agonist Yoda1 partly rescues the mechanical
sensitivity of mechanically insensitive LMPHM6 missense channels in vitro, and
an analogue with improved potency has been synthesized. This is a preclinical,
genotype-restricted concept - it cannot rescue null alleles, and systemic
PIEZO1 activation would also act on erythrocytes and the blood vasculature. No
PIEZO1-directed therapy is approved.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: PIEZO1 Loss of Function
treatment_effect: RESTORES
description: >-
Chemical agonism partly restores mechanical activation of variant channels
that are expressed but mechanically insensitive.
evidence:
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Patch-clamp studies of the cap and sub-cap variant channels revealed
abolished or reduced channel mechanical sensitivity with the possibility to
activate the channels and partly rescue mechanical sensitivity by the small
molecule Yoda1.
explanation: >-
In vitro pharmacological rescue of variant channels; no clinical evidence
exists, so support for this as a treatment is partial.
- reference: PMID:35701867
reference_title: Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we assessed a potential therapeutic value of Piezo1 activation in lymphatic
regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed
postsurgical lymphedema development.
explanation: >-
Mouse proof of concept that PIEZO1 agonism can reduce lymphedema; the model
is acquired postsurgical lymphedema, not biallelic PIEZO1 disease.
- name: Pleurodesis and other interventional management of refractory chylous effusion
description: >-
Pleurodesis, thoracic-duct ligation, and pleuro-peritoneal shunting are the
standard escalation options when chylous pleural effusion recurs despite
dietary fat restriction and octreotide. In LMPHM6 they are documented as
used, not as effective: in the one reported adolescent-onset family, effusion
control proved very difficult despite all three, and the proband's father had
persistent effusions and a restrictive lung defect after pleurodesis. No
LMPHM6-specific response rate has been established for any of these
procedures, and none targets the underlying lymphatic mechanism.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: therapeutic procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
target_mechanisms:
- target: Chylous Effusion and Fetal Fluid Accumulation
treatment_effect: MODULATES
description: >-
Obliterating the pleural space or diverting/interrupting thoracic-duct flow
limits accumulation of chyle in the pleural cavity; the incompetent
lymphatic network itself is unaltered.
evidence:
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment has proved very difficult and has involved pleurodesis, ligation
of the thoracic duct and pleuro-peritoneal shunting.
explanation: >-
Documents the interventional options actually used in a molecularly
confirmed LMPHM6 patient, while explicitly recording that control was
difficult - so this supports use, not efficacy.
- reference: PMID:40792030
reference_title: PIEZO1 mechanical insensitivity in generalized lymphatic dysplasia with the potential for pharmacological rescue.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Despite pleurodesis, his effusions are persistent resulting in a restrictive
lung defect and nocturnal hypoventilation requiring non-invasive
ventilation (NIV).
explanation: >-
A second affected individual in whom pleurodesis failed to control chylous
effusion, recording the limits of the intervention.
animal_models:
- name: Endothelial Piezo1 conditional knockout mouse (Tie2Cre or Lyve1Cre)
species: Mouse
genotype: Piezo1 conditional knockout (Tie2Cre;Piezo1fl/fl or Lyve1Cre;Piezo1fl/fl)
publication: PMID:30482854
modeled_mechanisms:
- target: Defective Lymphatic Valve Formation and Lymphangiogenesis
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Endothelial-specific Piezo1 deletion dramatically reduces lymphatic valve
number and impairs valve-leaflet protrusion, and the mice develop pleural
effusion - the murine counterpart of the human chylothorax/effusion
phenotype.
limitations: >-
The mice die postnatally, so the chronic childhood-onset peripheral
lymphedema of the human disorder cannot be assessed; conditional deletion is
a complete null in the endothelium, whereas human alleles include hypomorphic
missense variants with residual function.
readouts:
- name: Lymphatic valve number
target: Defective Lymphatic Valve Formation and Lymphangiogenesis
direction: DECREASED
interpretation: >-
Structural correlate of the valve-formation node in this model.
evidence:
- reference: PMID:30482854
reference_title: Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Strikingly, the number of lymphatic valves was dramatically reduced in
these mice.
explanation: >-
Reports the histological measurement behind this readout.
evidence:
- reference: PMID:30482854
reference_title: Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our analysis provides evidence that mechanically activated ion channel
PIEZO1 is a key regulator of lymphatic valve formation.
explanation: >-
Supports treating this model as informative for the valve-formation node.
- name: Lymphatic-specific Piezo1 conditional knockout mouse
species: Mouse
genotype: Lymphatic endothelial-specific conditional Piezo1 knockout; postnatal inducible deletion
publication: PMID:35701867
modeled_mechanisms:
- target: Impaired Lymphatic Endothelial Mechanotransduction
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Loss of Piezo1 in lymphatic endothelium abolishes flow-induced calcium
influx and the ORAI1/KLF2/Notch programme, phenocopying Orai1 and Klf2
knockout sprouting defects; postnatal deletion causes lymphatic regression.
limitations: >-
Mechanistic dissection relies on knockdown in cultured lymphatic endothelial
cells and on conditional nulls, whereas human LMPHM6 alleles are germline and
often hypomorphic; the therapeutic Yoda1 arm was tested in acquired
postsurgical lymphedema rather than in a Piezo1-mutant background.
readouts:
- name: Flow-induced calcium influx in lymphatic endothelial cells
target: Impaired Lymphatic Endothelial Mechanotransduction
direction: DECREASED
interpretation: >-
Functional correlate of the mechanotransduction node.
evidence:
- reference: PMID:35701867
reference_title: Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the
laminar flow-induced calcium influx
explanation: >-
Reports the calcium-imaging measurement behind this readout.
evidence:
- reference: PMID:35701867
reference_title: Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction
pathway and regulates lymphatic growth in response to external physical
stimuli.
explanation: >-
Supports treating this model as informative for the mechanotransduction
node.
differential_diagnoses:
- name: Hennekam lymphangiectasia-lymphedema syndrome 1
disease_term:
preferred_term: Hennekam lymphangiectasia-lymphedema syndrome 1
term:
id: MONDO:0009337
label: Hennekam lymphangiectasia-lymphedema syndrome 1
description: >-
The other major autosomal recessive generalized lymphatic dysplasia. Hennekam
syndrome is distinguished by characteristic facial dysmorphism (periorbital
edema, retrognathia, flat facial profile, gingival hypertrophy, microstomia),
seizures, and intellectual disability, none of which occur in LMPHM6.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The phenotype is distinct from Hennekam syndrome as none of our GLD patients
had the dysmorphic features associated with HS, nor the learning
disabilities or seizures, nor was the swelling severe
explanation: >-
States the clinical basis for separating LMPHM6 from Hennekam syndrome.
- name: Dehydrated hereditary stomatocytosis
disease_term:
preferred_term: dehydrated hereditary stomatocytosis
term:
id: MONDO:0008689
label: dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema
description: >-
The allelic autosomal dominant disorder caused by monoallelic gain-of-function
PIEZO1 variants, presenting with mild-to-moderate hemolytic anemia,
pseudohyperkalemia, and transient perinatal edema. The mechanism is opposite in
direction (gain versus loss of channel function), and the two entities overlap
only in the perinatal-edema phenotype.
evidence:
- reference: PMID:37902181
reference_title: PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PIEZO1 variants causing AD NIHF were characterized by gain of function in
red blood cells, scarcity in databases, and sporadic inheritance.
explanation: >-
Contrasts the dominant gain-of-function red-cell mechanism with the recessive
loss-of-function lymphatic mechanism of LMPHM6.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No disease-specific prevalence or incidence estimate exists. The founding
cohort comprised 10 affected individuals from 6 families, and subsequent
reports have been single families or small series. A widely quoted figure of
approximately 1 in 6,000 for generalized lymphatic dysplasia should not be
used as an LMPHM6 prevalence, as its denominator and molecular ascertainment
are not disease-specific.
evidence:
- reference: PMID:26333996
reference_title: Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In total, we identified 10 PIEZO1 variants in 6 families
explanation: >-
Supports the ultra-rare, literature-case-count basis for the occurrence
estimate.
- population: Fetuses with non-immune hydrops undergoing prenatal exome sequencing
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
Not a population prevalence: this records the diagnostic yield of PIEZO1
(both the recessive LMPHM6 and dominant gain-of-function forms) within an
ascertained NIHF cohort - 19 of 191 cases, i.e. 10%.
evidence:
- reference: PMID:37902181
reference_title: PIEZO1 is the most common monogenic etiology of non-immune hydrops fetalis detected by prenatal exome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In total, 19 of 191 NIHF cases diagnosed by prenatal exome were attributed
to PIEZO1.
explanation: >-
Quantifies the PIEZO1 contribution within an ascertained NIHF cohort.
notes: >-
No GeneReviews chapter exists for lymphatic malformation 6 / PIEZO1-related
generalized lymphatic dysplasia (PubMed searched 2026-08-18 for
"(lymphedema[TI] OR lymphatic[TI]) AND GeneReviews[TI]" and for the disease
name; the retrieved lymphatic GeneReviews chapters are Milroy disease (FLT4)
and lymphedema-distichiasis syndrome (FOXC2), which are different disorders).
MONDO:0014797 carries no textual definition, so disease identity was anchored on
the OMIM:616843 and Orphanet:568062 xrefs and on the MONDO RO:0004003 causal-gene
relationship to hgnc:28993 PIEZO1, verified with OAK. An Orphanet structured
reference (ORPHA:568062) could not be cited because that record is absent from
the committed references_cache and the Orphadata bulk refresh failed on a network
error at curation time.
clinical_trials: []
datasets: []
Lymphatic malformation 6 (LM6) is a rare Mendelian disorder of lymphatic development caused principally by biallelic loss-of-function variants in PIEZO1, which encodes a mechanically activated, calcium-permeable cation channel. It is best understood clinically as PIEZO1-related generalized lymphatic dysplasia (GLD). The characteristic spectrum comprises prenatal nonimmune hydrops fetalis, pleural or pericardial effusions, chylothorax, ascites, pulmonary or intestinal lymphangiectasia, and congenital or later-onset generalized lymphedema. Disease severity is highly variable, ranging from fetal death to transient prenatal edema followed by childhood- or adult-onset lymphatic disease. Founding human studies were published independently in September 2015 by Fotiou et al. and Lukacs et al. (PMIDs indexed for the disease association include 26333996 and 26387913). (OpenTargets Search: lymphatic malformation 6, iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2)
The strongest recent mechanistic advance is the 2024 demonstration that PIEZO1 activation in lymphatic endothelial cells induces ANGPT2 exocytosis, ADAM17-mediated TIE1 shedding, TIE/PI3K/AKT activation, and FOXO1 nuclear export. This complements earlier evidence that PIEZO1 controls lymphatic-valve morphogenesis, lymphatic sprouting, and vessel maintenance. No approved PIEZO1-directed treatment exists; small-molecule PIEZO1 agonism with Yoda1 remains preclinical. (du2024themechanosensorychannel pages 1-2, choi2022piezo1regulatedmechanotransductioncontrols pages 1-3, ludlow2023smallmoleculefunctionalrescue pages 14-16)
The following table summarizes the principal evidence and ontology-ready annotations.
| Domain | Key finding | Evidence type | Quantitative detail | Source / date / DOI / PMID | Knowledge-base ontology suggestions |
|---|---|---|---|---|---|
| Disease identity / gene | Lymphatic malformation 6 is linked to PIEZO1; disease-target association databases map LM6 to MONDO:0014797 and PIEZO1 as the only strong associated target | Curated disease-resource + human genetics | OpenTargets evidence size: 5 literature-backed links for PIEZO1–LM6 association | OpenTargets disease-target association for “lymphatic malformation 6” (MONDO_0014797) (OpenTargets Search: lymphatic malformation 6) | MONDO:0014797; HGNC:13866 PIEZO1; NCIT: C129043 Lymphatic Malformation |
| Founding human cohort | Autosomal recessive generalized lymphatic dysplasia (GLD) due to homozygous/compound-heterozygous PIEZO1 variants; frequent non-immune hydrops fetalis (NIHF) and childhood facial/four-limb lymphedema | Human clinical / human genetics | 6 families, 10 PIEZO1 variants reported; high incidence of NIHF; onset of facial and four-limb lymphedema in childhood | Fotiou et al., 2015-09, Nature Communications, DOI: https://doi.org/10.1038/ncomms9085 (PMID not available in context) (fotiou2015novelmutationsin pages 1-2) | HP:0001789 Lymphedema; HP:0001561 Hydrops fetalis; HP:0000978 Facial edema; HP:0002202 Pleural effusion; HP:0001744 Ascites; HP:0001733 Lymphangiectasia |
| Founding human cohort details | GLD phenotype includes widespread edema with systemic lymphatic involvement: intestinal/pulmonary lymphangiectasia, pleural/chylous/pericardial effusions; some prenatal demise, some postnatal hydrops resolution followed by later lymphedema | Human clinical | 5 patients across 4 families highlighted; hydrops in at least 2 families; one in utero demise at 34 weeks; postnatal lymphedema onset reported around 6–9 years in survivors | Fotiou et al., 2015-09, DOI: https://doi.org/10.1038/ncomms9085 (fotiou2015novelmutationsin pages 2-3) | HP:0003573 Congenital onset; HP:0001789 Lymphedema; HP:0010318 Chylothorax; HP:0001698 Pericardial effusion; UBERON:0005409 lymphatic vessel |
| Variant classes / function | Disease-associated PIEZO1 variants include nonsense, splice-site, and missense alleles with segregation in affected families; evidence supports loss of protein and/or loss of function | Human genetics + in vitro / ex vivo functional | Examples in context include nonsense variants p.E1630X, p.E755X, p.Q2228X and splice variant c.3796+1G>A; reduced/absent protein on Western blot; subtle RBC abnormalities noted | Fotiou et al., 2015-09, DOI: https://doi.org/10.1038/ncomms9085 (fotiou2015novelmutationsin pages 1-2, fotiou2015novelmutationsin pages 2-3) | SO:0001587 nonsense_variant; SO:0001629 splice_donor_variant; GO:0006816 calcium ion transport; GO:0008308 voltage-gated ion channel activity |
| Independent founding family | Biallelic PIEZO1 mutations identified in 2 siblings with persistent congenital lymphedema; affected alleles showed markedly reduced channel activity | Human clinical + human genetics + heterologous functional assay | 2 affected siblings; one splice/truncating allele plus one missense allele; channel function “greatly attenuated” | Lukacs et al., 2015-09, Nature Communications, DOI: https://doi.org/10.1038/ncomms9329 (PMID not available in context) (iyer2020lymphaticvalvesand pages 15-17) | HP:0001789 Lymphedema; HP:0003577 Congenital onset; MONDO:0014797; GO:0005262 calcium channel activity |
| Recent human variant interpretation | Four novel GLD-associated missense variants can reach the cell surface as full-length protein but still show reduced or abolished mechanical channel function, supporting pathogenic LOF mechanisms beyond absent trafficking | Human genetics + in vitro | Variants in context: E829V, G1978D, I2270T, R2335Q; all rare/ultra-rare, with no homozygotes in gnomAD noted in context | Ludlow et al., 2023-08, medRxiv preprint, DOI: https://doi.org/10.1101/2023.08.01.23292554 (ludlow2023smallmoleculefunctionalrescue pages 41-45, ludlow2023smallmoleculefunctionalrescue pages 5-8) | SO:0001583 missense_variant; GO:0005516 mechanosensitive ion channel activity; ECO:0001565 cell-based functional assay evidence |
| Recent families / phenotype expansion | Additional PIEZO1-GLD families show antenatal NIHF, polyhydramnios, congenital limb edema, chylothoraces and ascites; one family showed adult-onset bilateral chylothoraces in the 30s before later lymphedema | Human clinical | 3 families in context (GLD07-09); GLD09 hydrothoraces detected at 19 weeks gestation; pseudo-dominant appearance in one consanguineous family due to homozygous I2270T | Ludlow et al., 2023-08, DOI: https://doi.org/10.1101/2023.08.01.23292554 (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 14-16) | HP:0001561 Hydrops fetalis; HP:0002023 Polyhydramnios; HP:0002202 Pleural effusion; HP:0010318 Chylothorax; HP:0001744 Ascites; HP:0001789 Lymphedema |
| Preclinical rescue | Yoda1 and analogues rescued function of some GLD-associated PIEZO1 missense channels in vitro; this is preclinical, not an approved genotype-specific therapy | In vitro / preclinical | Missense variants showed ~65–90% reduction in Ca2+ signaling vs WT in context; Yoda1 restored mechanically evoked responses in rescue assays | Ludlow et al., 2023-08, DOI: https://doi.org/10.1101/2023.08.01.23292554 (preprint) (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 14-16) | CHEBI: not established here for Yoda1; NCIT suggestion: Experimental Therapeutic Procedure; GO:0051480 regulation of cytosolic calcium ion concentration |
| Valve-development mechanism | PIEZO1 is required for lymphatic valve formation; loss in endothelial/lymphatic endothelium reduces valve number and causes pleural effusion/postnatal lethality in mouse models | Mouse + cultured LECs | Endothelial-specific knockout mice showed dramatic reduction in lymphatic valves; pleural effusion and postnatal death reported | Nonomura et al., 2018-11, PNAS, DOI: https://doi.org/10.1073/pnas.1817070115 (PMID not available in context) (iyer2020lymphaticvalvesand pages 15-17) | GO:0001946 lymphangiogenesis; GO:0035239 tube morphogenesis; CL:0000115 endothelial cell; CL lymphatic endothelial cell; UBERON:0005409 lymphatic vessel |
| Valve development and maintenance | PIEZO1 senses oscillating shear stress and drives the genetic program for lymphatic valve development and maintenance; adult deletion causes valve degeneration | Mouse + in vitro LECs | Newborn endothelial or lymphatic-specific deletion inhibited valve formation; adult deletion caused “substantial” valve degeneration | Choi et al., 2019-05, JCI Insight, DOI: https://doi.org/10.1172/jci.insight.125068 (choi2019piezo1incorporatesmechanical pages 2-4, choi2019piezo1incorporatesmechanical pages 1-2) | GO:0034405 response to fluid shear stress; GO:0001946 lymphangiogenesis; HP:0002564 Lymphatic vessel abnormality |
| Sprouting / regression mechanism | PIEZO1 acts upstream of ORAI1 in flow-activated lymphatic expansion; deletion causes sprouting defects and adult lymphatic regression; activation enhances regeneration | Mouse + in vitro LECs | Lymphatic-specific conditional KO phenocopied sprouting defects; postnatal deletion induced regression; Yoda1 suppressed postsurgical lymphedema in mice | Choi et al., 2022-07, Circulation Research, DOI: https://doi.org/10.1161/circresaha.121.320565 (choi2022piezo1regulatedmechanotransductioncontrols pages 10-12, choi2022piezo1regulatedmechanotransductioncontrols pages 1-3) | GO:0001946 lymphangiogenesis; GO:0035556 intracellular signal transduction; NCIT: Preclinical Study |
| 2024 pathway advance | PIEZO1 functions upstream of ANGPT2/TIE/PI3K/AKT/FOXO1 signaling in lymphatic endothelial cells, linking mechanosensation to transcriptional regulation relevant to lymphedema biology | Mouse + in vitro LECs | PIEZO1 activation triggered rapid ANGPT2 exocytosis, TIE1 ectodomain shedding by ADAM17, increased TIE/PI3K/AKT, and FOXO1 nuclear export | Du et al., 2024-05, J Clin Invest, DOI: https://doi.org/10.1172/jci176577 (du2024themechanosensorychannel pages 1-2) | GO:0034405 response to fluid shear stress; GO:0014068 positive regulation of phosphatidylinositol 3-kinase signaling; GO:0001525 angiogenesis/lymphatic vascular development; CL:0000115 endothelial cell |
| Current understanding of pathophysiology | Consensus model: biallelic PIEZO1 LOF impairs lymphatic endothelial mechanosensation, disrupting valve morphogenesis, sprouting, and maintenance, producing fetal effusions/hydrops and later systemic lymphedema | Synthesis of human + in vitro + mouse evidence | Supported across 2015–2024 human genetics and mechanistic studies | Supported by Fotiou 2015, Lukacs 2015, Nonomura 2018, Choi 2019/2022, Du 2024 (du2024themechanosensorychannel pages 1-2, choi2019piezo1incorporatesmechanical pages 2-4, choi2022piezo1regulatedmechanotransductioncontrols pages 10-12, iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2) | MONDO:0014797; GO:0001946 lymphangiogenesis; GO:0034405 response to fluid shear stress; CL: lymphatic endothelial cell |
| Diagnostics | Most specific diagnostic evidence is molecular: exome sequencing/NGS identifying biallelic PIEZO1 variants, supported by segregation and functional testing when missense/VUS alleles are found | Human clinical / molecular diagnostics | WES identified causative variants in founding families and sibling pair; lymphoscintigraphy reported in Fotiou cohort; RBC film abnormalities can be supportive but nonspecific | Fotiou et al., 2015-09; Lukacs et al., 2015-09 (fotiou2015novelmutationsin pages 2-3, iyer2020lymphaticvalvesand pages 15-17) | NCIT: Whole Exome Sequencing; HP:0001789; LOINC/NCIT suggestions for lymphoscintigraphy not disease-specific |
| Prognosis / natural history | Prenatal course can include NIHF and fetal demise; in survivors, edema may partially/fully resolve postnatally then recur as persistent or childhood-onset lymphedema with systemic complications | Human clinical | Context notes fetal demise, postnatal hydrops resolution, onset around 6–9 years in some survivors, and adult presentations in later families | Fotiou 2015; Ludlow 2023 (fotiou2015novelmutationsin pages 2-3, ludlow2023smallmoleculefunctionalrescue pages 8-10, cheng2025piezo1variantimplications pages 3-4) | HP:0003573 Congenital onset; HP:0001789 Lymphedema; HP:0002202 Pleural effusion |
| Epidemiology | Disease-specific prevalence/incidence for LM6 is not established in retrieved sources; generalized lymphatic dysplasia is rare | Human clinical / review-level statement | No robust population rate found for LM6; one preprint excerpt mentioned GLD approx. 1 in 6000, but this appears to refer broadly and should be treated cautiously | Ludlow et al., 2023-08 preprint (context summary only) (ludlow2023smallmoleculefunctionalrescue pages 5-8) | MONDO:0014797; Orphan disease coding pending confirmation |
| Clinical treatment evidence | No approved PIEZO1-genotype-specific therapy was found in retrieved evidence; management in published human LM6 reports is largely supportive and complication-directed | Human clinical + evidence gap | No controlled LM6 treatment trial identified in retrieved sources | Evidence gap across retrieved LM6 literature (fotiou2015novelmutationsin pages 1-2, ludlow2023smallmoleculefunctionalrescue pages 8-10, fotiou2015novelmutationsin pages 2-3) | NCIT: Supportive Care; NCIT: Lymphedema Therapy |
| Generic lymphatic-malformation trials | Active LM/vascular-anomaly trials exist for sirolimus/rapamycin and alpelisib, but these are not PIEZO1-genotype-specific and should not be interpreted as LM6-targeted evidence | Clinical trials, non-genotype-specific | Examples: NCT06673290 recruiting, n=150; NCT03243019 recruiting, n=28; NCT06239480 active-not-recruiting, n=51; NCT05948943 recruiting, n=232; NCT00975819 completed, n=61 | ClinicalTrials.gov results retrieved in tool output (current statuses as returned) (OpenTargets Search: lymphatic malformation 6) | NCIT: Sirolimus; NCIT: Alpelisib; NCIT: Clinical Trial; note: not specific to MONDO:0014797 |
| Prevention / environment | No evidence supports environmental, infectious, lifestyle, or protective factors as causal for LM6; prevention is primarily genetic counseling/reproductive risk management in affected families | Human genetics / evidence gap | Autosomal recessive inheritance implies 25% recurrence risk for carrier-couple pregnancies, though exact counseling numbers were not directly quoted in retrieved contexts | Inference from AR inheritance established by Fotiou/Lukacs (iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2) | NCIT: Genetic Counseling; HP/GO not applicable |
| Model systems | Best-supported disease models are endothelial or lymphatic-specific Piezo1 knockout mice and cultured lymphatic endothelial cells; these recapitulate valve/sprouting defects and enable pathway dissection | Mouse + in vitro | Multiple conditional models: Tie2Cre, Lyve1Cre, Prox1-CreERT2, Cdh5(PAC)-CreERT2 reported in context | Nonomura 2018; Choi 2019; Choi 2022; Du 2024 (du2024themechanosensorychannel pages 1-2, choi2019piezo1incorporatesmechanical pages 2-4, choi2022piezo1regulatedmechanotransductioncontrols pages 10-12, iyer2020lymphaticvalvesand pages 15-17) | CL: lymphatic endothelial cell; GO:0001946 lymphangiogenesis; NCIT: Disease Model |
Table: This compact table organizes the key human, in vitro, mouse, and trial evidence for PIEZO1-related lymphatic malformation 6. It highlights the founding 2015 cohorts, recent mechanistic advances, and the important distinction between preclinical Yoda1 rescue and non-genotype-specific lymphatic-malformation trials.
No unique disease-specific ICD-10, ICD-11, or MeSH code was established in the retrieved evidence. Coding therefore generally relies on broader categories for congenital lymphatic malformation, primary lymphedema, hydrops fetalis, or chylous effusion. The evidence summarized here is principally aggregated disease-level information derived from published families and experimental studies, not individual EHR data.
Fotiou et al. defined GLD as “a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions.” They further reported “homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis.” Published September 2015; DOI: https://doi.org/10.1038/ncomms9085; PMID 26333996. (OpenTargets Search: lymphatic malformation 6, fotiou2015novelmutationsin pages 1-2)
Lukacs et al. reported: “Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 … in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia.” Published September 2015; DOI: https://doi.org/10.1038/ncomms9329; PMID 26387913. (OpenTargets Search: lymphatic malformation 6, iyer2020lymphaticvalvesand pages 15-17)
The established cause is biallelic pathogenic or likely pathogenic PIEZO1 variation, usually homozygous or compound heterozygous, producing absent protein, defective membrane trafficking, or impaired mechanically activated channel function. Reported classes include nonsense, canonical splice-site, frameshift/deletion, and missense variants. Ten variants were initially identified across six families; an independently reported sibling pair carried a splice/truncating allele and a missense allele. (iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2, cheng2025piezo1variantimplications pages 3-4)
Important genotype distinction:
Family history, parental consanguinity, and carriage of a pathogenic allele in each parent increase reproductive risk. A pseudo-dominant pedigree can occur when an affected homozygous person and a heterozygous carrier have affected children, as reported for the I2270T allele in a consanguineous family. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 14-16)
No reproducible toxin, radiation, infectious, dietary, smoking, alcohol, occupational, or other environmental cause has been demonstrated. There is likewise no established environmental protective factor or validated gene–environment interaction. Mechanical forces are essential physiological signals sensed by PIEZO1, but they are part of the molecular mechanism—not an avoidable environmental exposure.
No genetic protective allele has been validated for LM6. Variable residual PIEZO1 activity may modify severity, but this remains a genotype–function hypothesis rather than a clinically validated protective factor.
The phenotype is multisystemic and markedly variable. Reliable disease-specific percentages are unavailable because published cohorts are small.
Quality-of-life studies specific to LM6 were not retrieved. Expected burdens include chronic swelling, disfigurement, restricted mobility, recurrent infection, dyspnea from thoracic effusions, repeated drainage or hospitalization, and psychosocial effects. These impacts are clinically plausible but have not been quantified with EQ-5D, SF-36, or a disease-specific instrument in a sufficiently large LM6 cohort.
PIEZO1 encodes a large trimeric mechanosensitive ion channel that increases membrane permeability to calcium and other cations in response to membrane tension, stretch, and fluid shear. Disease-associated LM6 alleles generally reduce mechanosensitivity or channel abundance. (du2024themechanosensorychannel pages 1-2, iyer2020lymphaticvalvesand pages 15-17)
Reported variants in retrieved studies include truncating alleles p.E755X, p.E1630X, and p.Q2228X, splice donor c.3796+1G>A, and recent missense substitutions E829V, G1978D, I2270T, and R2335Q. The 2015 study also documented another splice-site allele, c.1669+1G>A. Exact transcript-dependent HGVS normalization should be verified against the current MANE transcript before database ingestion. (fotiou2015novelmutationsin pages 1-2, fotiou2015novelmutationsin pages 2-3, ludlow2023smallmoleculefunctionalrescue pages 41-45)
The early variants segregated with disease; most were absent from dbSNP, 1000 Genomes, and 900 controls, while two had reported minor-allele frequencies of approximately 0.0002. The four 2023 missense alleles were absent or ultra-rare in gnomAD, with no homozygotes reported. (fotiou2015novelmutationsin pages 1-2, ludlow2023smallmoleculefunctionalrescue pages 41-45)
Functional consequences include exon skipping or intron retention, premature truncation, reduced/absent protein, impaired surface trafficking, and channels that reach the membrane but have markedly reduced mechanosensitivity. In 2023 assays, the missense channels exhibited approximately 65–90% lower calcium signaling than wild type; I2270T produced no detectable stretch-activated current under the tested conditions. Yoda1 restored activity in several mutant channels. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 14-16)
No validated modifier gene, disease-specific methylation signature, recurrent chromosomal abnormality, or somatic mosaic mechanism has been established. The disorder is primarily a germline single-gene disease.
Environmental toxins, pollution, radiation, infection, diet, exercise, smoking, and alcohol have no established etiological role. Infection can occur secondarily as cellulitis in chronically edematous tissue but is not the primary cause. Lifestyle measures may reduce secondary lymphedema complications but cannot correct PIEZO1 deficiency.
Biallelic PIEZO1 loss of function → deficient lymphatic endothelial sensing of shear/stretch → reduced calcium-dependent mechanotransduction → disturbed valve-gene regulation, endothelial rearrangement, sprouting, and vessel maintenance → valve paucity/regression and malformed lymphatic networks → lymph reflux or failed drainage → fetal effusions/hydrops, lymphangiectasia, chylothorax, ascites, and chronic lymphedema. Human genetics establishes the upstream cause; cell and mouse studies establish the intervening mechanism. (du2024themechanosensorychannel pages 1-2, choi2019piezo1incorporatesmechanical pages 2-4, choi2022piezo1regulatedmechanotransductioncontrols pages 1-3, iyer2020lymphaticvalvesand pages 15-17, fotiou2015novelmutationsin pages 1-2)
Suggested annotations include GO:0034405 response to fluid shear stress, GO:0001946 lymphangiogenesis, calcium-ion transport/signaling, actin-cytoskeleton organization, cell–cell junction organization, and PI3K/AKT signaling. The principal cell is the lymphatic endothelial cell; use the current Cell Ontology identifier after release-specific validation. No robust LM6-specific metabolomic, lipidomic, proteomic, epigenomic, single-cell, spatial-transcriptomic, or multi-omic patient signature has been validated.
The primary lesion is distributed throughout the lymphatic vasculature, especially collecting vessels, intraluminal lymphatic valves, and lymphovenous drainage structures. Suggested anatomy annotations are UBERON:0005409 lymphatic vessel, lymphatic capillary, collecting lymphatic vessel, lymphatic valve, and lymphatic endothelium.
Secondary sites include subcutaneous connective tissue of all limbs and face; pleural and pericardial cavities; lungs; intestinal lymphatics; abdominal/peritoneal cavity; and occasionally genital tissue. Disease is typically generalized and often asymmetric in severity rather than strictly unilateral. At the subcellular level, PIEZO1 is a plasma-membrane channel, although intracellular channel pools were suggested by calcium-release experiments. (ludlow2023smallmoleculefunctionalrescue pages 8-10, ludlow2023smallmoleculefunctionalrescue pages 5-8)
Onset may be antenatal, congenital, childhood, or—less commonly—adult. Prenatal disease is chronic developmental rather than an acute acquired process. Hydrops may remit spontaneously around birth, but remission does not ensure cure: edema and systemic lymphatic complications can recur years later. Founding survivors developed lymphedema at approximately 6–9 years; a recent family included adult-onset bilateral chylothoraces in the 30s. (ludlow2023smallmoleculefunctionalrescue pages 8-10, fotiou2015novelmutationsin pages 2-3, cheng2025piezo1variantimplications pages 3-4)
There is no validated staging system. A pragmatic course is: prenatal effusions/hydrops; neonatal stabilization or death; latent/partially resolved interval in some survivors; then chronic lymphedema, lymphangiectasia, recurrent effusions, or infections. The disease is generally lifelong even if individual fluid collections resolve.
Inheritance is predominantly autosomal recessive, with variable expressivity and incompletely defined penetrance. For two confirmed carrier parents, standard Mendelian counseling predicts a 25% affected, 50% carrier, and 25% unaffected/noncarrier probability for each pregnancy. Pseudo-dominant inheritance can occur in consanguineous pedigrees. Germline mosaicism has not been established but cannot be excluded in apparently de novo recurrence. No founder allele, carrier frequency, ethnic enrichment, sex bias, anticipation, or geographic concentration is established. (fotiou2015novelmutationsin pages 1-2, ludlow2023smallmoleculefunctionalrescue pages 14-16)
Disease-specific prevalence and incidence are unknown. A broad estimate of approximately 1 in 6,000 was mentioned for generalized lymphatic dysplasia in a 2023 preprint, but it should not be used as an established LM6 prevalence because the denominator and molecular ascertainment were not disease-specific. (ludlow2023smallmoleculefunctionalrescue pages 5-8)
Prenatal ultrasound should evaluate skin edema, ascites, pleural/pericardial effusions, hydrothorax, placental edema, and polyhydramnios. Postnatal assessment may include ultrasound, echocardiography, chest radiography/CT or MRI, lymphoscintigraphy, and—where available—dynamic contrast MR lymphangiography to define central lymphatic flow. Lymphoscintigraphy was consistently abnormal in four founding-cohort patients. (fotiou2015novelmutationsin pages 2-3)
Laboratory evaluation is mainly directed toward complications: CBC and blood film; hemolysis indices where stomatocytosis is suspected; albumin, total protein, immunoglobulins and lymphocyte counts for intestinal lymph loss; electrolytes; and pleural-fluid triglycerides/chylomicrons for chylothorax. No validated circulating LM6 biomarker exists.
CMA or karyotyping is appropriate in fetal hydrops with multiple anomalies but does not specifically diagnose LM6. FISH, mitochondrial testing, and repeat-expansion testing are not routine LM6 investigations.
Differential diagnoses include PIK3CA-related lymphatic malformations, Hennekam lymphangiectasia-lymphedema syndrome, hereditary lymphedema caused by FLT4 or FOXC2, EPHB4-related lymphatic-related hydrops, RASopathies, Turner syndrome, congenital infection, fetal anemia, cardiac disease, and heterozygous PIEZO1-associated dehydrated hereditary stomatocytosis.
Prognosis is variable. Severe prenatal disease can cause miscarriage, stillbirth, or neonatal death; one reported fetus died at 34 weeks. Survivors may have complete early resolution of hydrops yet later develop chronic generalized lymphedema, recurrent cellulitis, respiratory compromise, chylothorax, pericardial effusion, ascites, or intestinal protein loss. No reliable five- or ten-year survival estimate, life-expectancy figure, validated prognostic score, or molecular prognostic biomarker exists. (fotiou2015novelmutationsin pages 1-2, fotiou2015novelmutationsin pages 2-3, cheng2025piezo1variantimplications pages 3-4)
Residual channel function, extent of thoracic/intestinal involvement, persistence of prenatal effusions, and ability to control chyle loss are plausible prognostic factors, but they have not been validated in a sufficiently large prospective cohort.
There is no approved disease-modifying or PIEZO1-genotype-specific therapy. Management should be coordinated through a multidisciplinary vascular-anomalies/primary-lymphedema team.
Current non-genotype-specific studies include NCT06673290 (sirolimus, recruiting, n=150), NCT03243019 (rapamycin, recruiting, n=28), NCT06239480 (topical rapamycin, phase 3, active-not-recruiting, n=51), NCT05948943 (alpelisib for PIK3CA-mutant malformations, recruiting, n=232), and completed NCT00975819 (sirolimus in complicated vascular anomalies, n=61). None should be represented as an LM6-specific trial. (OpenTargets Search: lymphatic malformation 6)
Yoda1 accelerated valve formation, promoted lymphatic sprouting, reduced postsurgical lymphedema in mice, and rescued several mechanically insensitive human mutant channels in vitro. The 2023 study stated that “The potential to pharmacologically overcome the loss of force sensing was demonstrated.” This is promising precision-therapy evidence but remains preclinical; systemic PIEZO1 activation could affect erythrocytes and other vascular tissues and requires rigorous safety evaluation. DOI: https://doi.org/10.1101/2023.08.01.23292554. (choi2022piezo1regulatedmechanotransductioncontrols pages 1-3, ludlow2023smallmoleculefunctionalrescue pages 14-16, ludlow2023smallmoleculefunctionalrescue pages 5-8)
Suggested NCIT annotations include Genetic Counseling, Supportive Care, Lymphedema Therapy, Compression Therapy, Sirolimus, Alpelisib, Pleurodesis, and Clinical Trial; exact NCIT identifiers should be release-validated.
No primary lifestyle or environmental prevention exists. The principal preventive strategy is genetic counseling with cascade testing of relatives, partner testing where appropriate, and discussion of prenatal diagnosis or preimplantation genetic testing when familial pathogenic variants are known. Prenatal molecular testing should be accompanied by serial ultrasound because severity is variable even within families.
Secondary prevention comprises early recognition of fetal effusions, anticipatory delivery planning at a tertiary center, and surveillance for recurrent pleural/pericardial effusion, intestinal lymph loss, and progressive edema. Tertiary prevention includes compression, meticulous skin care, prompt treatment of cellulitis, nutritional management of chyle loss, vaccination according to routine schedules, and rehabilitation. No vaccine or prophylactic medication prevents LM6 itself.
No well-established naturally occurring PIEZO1-LM6 counterpart in companion animals, livestock, or wildlife was retrieved, and there is no zoonotic or transmissible component. PIEZO1 and lymphatic-valve mechanobiology are evolutionarily conserved. Zebrafish possess lymphatic valves and are useful for comparative developmental studies, but a validated natural zebrafish LM6 disease was not identified.
The strongest models are genetically engineered mice and cultured lymphatic endothelial cells.
These models reproduce central mechanistic features but not the complete variability of human prenatal hydrops, multiorgan lymphangiectasia, or long-term treatment response. Consequently, Yoda1 rescue in cells or mice cannot yet be extrapolated to clinical efficacy.
LM6 remains exceptionally rare, and most clinical evidence consists of small pedigrees and case reports. Phenotype frequencies, penetrance, prevalence, survival, quality of life, and treatment-response rates therefore remain uncertain. The 2023 functional-rescue report was retrieved as a medRxiv preprint and should be labeled accordingly. Ontology identifiers suggested above should be checked against current HPO, GO, CL, UBERON, NCIT, and HGNC releases before production ingestion. Most importantly, treatment evidence for broad lymphatic malformations should not be attributed automatically to PIEZO1-related LM6.
References
(OpenTargets Search: lymphatic malformation 6): Open Targets Query (lymphatic malformation 6, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
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(fotiou2015novelmutationsin pages 2-3): Elisavet Fotiou, Silvia Martin-Almedina, Michael A. Simpson, Shin Lin, Kristiana Gordon, Glen Brice, Giles Atton, Iona Jeffery, David C. Rees, Cyril Mignot, Julie Vogt, Tessa Homfray, Michael P. Snyder, Stanley G. Rockson, Steve Jeffery, Peter S. Mortimer, Sahar Mansour, and Pia Ostergaard. Novel mutations in piezo1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nature Communications, Sep 2015. URL: https://doi.org/10.1038/ncomms9085, doi:10.1038/ncomms9085. This article has 380 citations and is from a highest quality peer-reviewed journal.
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| Unresolved (possible confabulation) | 0 |
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| References weighed for topical relevance | 10 |
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