Hennekam lymphangiectasia-lymphedema syndrome 1

Mendelian MONDO:0009337 Pathograph 12 Show in embeddings browser Hennekam syndrome hereditary disease

Hennekam lymphangiectasia-lymphedema syndrome 1 (HKLLS1) is an autosomal recessive generalized lymphatic dysplasia caused by biallelic mutations in CCBE1. It is characterized by the triad of intestinal lymphangiectasia, peripheral and facial lymphedema, and intellectual disability, together with a characteristic flat facial appearance (flat face, depressed nasal bridge, hypertelorism, epicanthal folds, small mouth, and dental anomalies). Intestinal lymphangiectasia causes protein-losing enteropathy with hypoalbuminemia, hypogammaglobulinemia, and lymphopenia. CCBE1 is a secreted extracellular-matrix protein essential for lymphangiogenesis, acting as a cofactor that promotes ADAMTS3-mediated proteolytic activation of pro-VEGF-C; loss of CCBE1 function impairs VEGF-C/VEGFR-3 signaling and lymphatic vessel development. CCBE1 mutations account for approximately 25% of Hennekam syndrome cases and were the first genetic cause identified for the disorder.

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1
Inheritance
5
Pathophys.
23
Phenotypes
12
Pathograph
1
Genes
2
Variants
4
Medical Actions
2
Differentials
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
HKLLS1 is inherited in an autosomal recessive manner; affected individuals carry biallelic (homozygous or compound heterozygous) CCBE1 mutations, frequently in the setting of parental consanguinity.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:19935664 SUPPORT Human Clinical
"Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans."
Homozygous and compound heterozygous CCBE1 genotypes establish autosomal recessive inheritance for HKLLS1.
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Pathophysiology

5
CCBE1 loss of function
Biallelic loss-of-function mutations in CCBE1 reduce the activity of a secreted extracellular-matrix protein required for lymphangiogenesis.
CCBE1 hgnc:29426 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CCBE1 (hgnc:29426). hgnc:29426 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired VEGF-C activation and lymphangiogenesis CCBE1 promotes ADAMTS3-mediated proteolytic maturation of pro-VEGF-C; loss of CCBE1 reduces mature VEGF-C and downstream VEGFR-3 signaling in lymphatic endothelial cells.
Show evidence (2 references)
PMID:19935664 SUPPORT Human Clinical
"Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish."
Identifies CCBE1 as the causal gene and situates it as an essential lymphangiogenesis factor.
DOI:10.1161/CIRCRESAHA.116.304949 SUPPORT Model Organism
"deleting the collagen domains of CCBE1 has a much stronger effect on CCBE1 activity than deleting the EGF domains"
Domain-dissection knock-in mouse and zebrafish data show the collagen repeats of CCBE1 are crucial for its VEGF-C-activating, lymphangiogenic function that is lost in HKLLS1.
Impaired VEGF-C activation and lymphangiogenesis
Reduced VEGF-C/VEGFR-3 signaling impairs lymphatic endothelial cell migration and lymphatic vessel formation, producing generalized lymphatic dysplasia.
lymphatic endothelial cell CL:0002138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphatic endothelial cell, annotated with endothelial cell of lymphatic vessel (CL:0002138). CL:0002138 is a cell type from the Cell Ontology.
lymphangiogenesis GO:0001946 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves lymphangiogenesis (GO:0001946). GO:0001946 is a biological process from the Gene Ontology.
Downstream
Generalized lymphatic dysplasia Defective lymphangiogenesis produces malformed, dysfunctional lymphatic vessels throughout the body.
Show evidence (1 reference)
PMID:24523457 SUPPORT Model Organism
"Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of Ccbe1."
Zebrafish loss-of-function data show that Ccbe1 is required for VEGFC/VEGFR3 downstream signaling that drives lymphangiogenesis.
Generalized lymphatic dysplasia
Widespread lymphatic vessel dysplasia impairs lymph drainage and underlies the intestinal lymphangiectasia, lymphedema, and serous effusions of the syndrome.
lymphatic endothelial cell CL:0002138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphatic endothelial cell, annotated with endothelial cell of lymphatic vessel (CL:0002138). CL:0002138 is a cell type from the Cell Ontology.
Downstream
Intestinal lymphangiectasia Dysplastic intestinal lymphatics dilate and leak lymph into the gut lumen.
Lymphedema Impaired lymphatic drainage in the limbs, genitalia, and face causes lymphedema.
Show evidence (1 reference)
PMID:19935664 SUPPORT Human Clinical
"Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome."
Establishes the generalized lymphatic phenotype (lymphedema and lymphangiectasias) as defining features of the disorder.
Intestinal lymphangiectasia
Dilated intestinal lymphatics leak protein-rich lymph into the gut, producing protein-losing enteropathy with hypoalbuminemia, hypogammaglobulinemia, and lymphopenia.
Downstream
Protein-losing enteropathy Enteric loss of lymph depletes serum albumin and immunoglobulins.
Show evidence (1 reference)
PMID:2624276 SUPPORT Human Clinical
"We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation."
The original clinical description documents intestinal lymphangiectasia as a core feature of the syndrome.
Protein-losing enteropathy
Protein-rich lymph lost into the gut lumen produces protein-losing enteropathy, depleting serum albumin, immunoglobulins, and lymphocytes.
Downstream
Hypoalbuminemia Enteric protein loss lowers serum albumin.
Decreased circulating immunoglobulin concentration Enteric loss of lymph depletes serum immunoglobulins.
Lymphopenia Enteric loss of lymph depletes circulating lymphocytes.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"both gastrointestinal protein loss and malabsorption"
Intestinal lymphangiectasia in Hennekam syndrome causes gastrointestinal protein loss (protein-losing enteropathy) and malabsorption.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hennekam lymphangiectasia-lymphedema syndrome 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

23
Blood 2
Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"severe protein loss resulting in hypogammaglobulinemia"
Enteric protein loss in Hennekam syndrome produces hypogammaglobulinemia.
Lymphopenia Decreased total lymphocyte count HP:0001888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphopenia, annotated with Decreased total lymphocyte count (HP:0001888). HP:0001888 is a phenotype from the Human Phenotype Ontology.
Digestive 2
Protein-losing enteropathy HP:0002243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protein-losing enteropathy (HP:0002243). HP:0002243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"Intestinal lymphangiectasia can lead to severe protein loss"
Documents that the intestinal lymphangiectasia of Hennekam syndrome causes severe enteric protein loss (protein-losing enteropathy).
Ascites HP:0001541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ascites (HP:0001541). HP:0001541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"fetal head demonstrating scalp edema; C, fetal abdomen demonstrating ascites"
Prenatal ultrasound of a molecularly confirmed CCBE1 (HKLLS1) affected fetus demonstrated ascites (and scalp edema).
Eye 1
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:2624276 SUPPORT Human Clinical
"Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects."
Part of the shared Hennekam facial gestalt described in the originally-reported family (later shown to be FAT4-related, PMID:24913602); the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists these facial features as part of the syndrome, anchoring them to the CCBE1 subtype.
PMID:28985353 SUPPORT Human Clinical
"These patients have distinctive facial features similar to those with mutations in CCBE1."
Observation-level confirmation that CCBE1-mutant Hennekam patients have distinctive facial features (contrasted with ADAMTS3 patients).
Head and Neck 5
Flat face HP:0012368 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flat face (HP:0012368). HP:0012368 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:2624276 SUPPORT Human Clinical
"Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects."
Part of the shared Hennekam facial gestalt described in the originally-reported family (later shown to be FAT4-related, PMID:24913602); the CCBE1-specific evidence below confirms CCBE1-related patients show the same distinctive facial features.
PMID:28985353 SUPPORT Human Clinical
"These patients have distinctive facial features similar to those with mutations in CCBE1."
Confirms that CCBE1-mutant Hennekam patients have a distinctive characteristic facial appearance (here contrasted with ADAMTS3 patients).
Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flat nasal bridge, annotated with Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:2624276 SUPPORT Human Clinical
"Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects."
Part of the shared Hennekam facial gestalt described in the originally-reported family (later shown to be FAT4-related, PMID:24913602); the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists these facial features as part of the syndrome, anchoring them to the CCBE1 subtype.
PMID:28985353 SUPPORT Human Clinical
"These patients have distinctive facial features similar to those with mutations in CCBE1."
Observation-level confirmation that CCBE1-mutant Hennekam patients have distinctive facial features (contrasted with ADAMTS3 patients).
Narrow mouth HP:0000160 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small mouth, annotated with Narrow mouth (HP:0000160). HP:0000160 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:2624276 SUPPORT Human Clinical
"Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects."
Part of the shared Hennekam facial gestalt described in the originally-reported family (later shown to be FAT4-related, PMID:24913602); the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists these facial features as part of the syndrome, anchoring them to the CCBE1 subtype.
PMID:28985353 SUPPORT Human Clinical
"These patients have distinctive facial features similar to those with mutations in CCBE1."
Observation-level confirmation that CCBE1-mutant Hennekam patients have distinctive facial features (contrasted with ADAMTS3 patients).
Abnormal dental morphology HP:0006482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tooth anomalies, annotated with Abnormal dental morphology (HP:0006482). HP:0006482 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:2624276 SUPPORT Human Clinical
"Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects."
Part of the shared Hennekam facial gestalt described in the originally-reported family (later shown to be FAT4-related, PMID:24913602); the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists these facial features as part of the syndrome, anchoring them to the CCBE1 subtype.
PMID:28985353 SUPPORT Human Clinical
"These patients have distinctive facial features similar to those with mutations in CCBE1."
Observation-level confirmation that CCBE1-mutant Hennekam patients have distinctive facial features (contrasted with ADAMTS3 patients).
Epicanthus HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthal folds, annotated with Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"a bulbous nasal tip, and epicanthal folds was also evident"
Epicanthal folds were documented in a patient with Hennekam syndrome.
Metabolism 4
Lymphedema HP:0001004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphedema (HP:0001004), qualified as temporality chronic; course progressive. HP:0001004 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC Course: PROGRESSIVE
Show evidence (1 reference)
PMID:2624276 SUPPORT Human Clinical
"We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation."
Documents severe lymphedema of limbs, genitalia, and face.
Hypoalbuminemia HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Hydrops fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonimmune hydrops fetalis, annotated with Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"recurrent hydrops fetalis in this case of Hennekam lymphangiectasia"
A molecularly confirmed CCBE1 (HKLLS1) case presented as recurrent nonimmune hydrops fetalis, documenting the severe prenatal end of the phenotypic spectrum.
Pleural effusion HP:0002202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pleural effusion (HP:0002202). HP:0002202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"An autopsy described a female fetus with a cystic hygroma, serous (nonchylous) pleural and pericardial effusions, congested liver, hypoplastic lungs"
A molecularly confirmed CCBE1 (HKLLS1) affected fetus had serous pleural effusions.
Nervous System 2
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19935664 SUPPORT Human Clinical
"Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome."
Intellectual disability (mental retardation) is listed among the defining features.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:2624276 SUPPORT Human Clinical
"We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation."
Seizures were reported in the originally-described Hennekam family (later shown to be FAT4-related, PMID:24913602); seizures are described across the broader Hennekam syndrome literature.
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists seizures among the syndromic features, anchoring this to the CCBE1 subtype.
Respiratory 1
Pulmonary hypoplasia HP:0002089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypoplasia (HP:0002089). HP:0002089 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"An autopsy described a female fetus with a cystic hygroma, serous (nonchylous) pleural and pericardial effusions, congested liver, hypoplastic lungs"
A molecularly confirmed CCBE1 (HKLLS1) affected fetus had hypoplastic lungs.
Growth 1
Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:2624276 SUPPORT Human Clinical
"We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation."
Mild growth retardation was reported in the originally-described Hennekam family (later shown to be FAT4-related, PMID:24913602); growth impairment in CCBE1-related disease is also driven by protein-losing enteropathy.
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists growth impairment among the syndromic features, anchoring this to the CCBE1 subtype.
Other 5
Intestinal lymphangiectasia HP:0002593 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal lymphangiectasia (HP:0002593). HP:0002593 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2624276 SUPPORT Human Clinical
"We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation."
Directly documents intestinal lymphangiectasia in the original family.
Abnormality of the ear HP:0000598 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ear defects, annotated with Abnormality of the ear (HP:0000598). HP:0000598 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:2624276 SUPPORT Human Clinical
"Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects."
Part of the shared Hennekam facial gestalt described in the originally-reported family (later shown to be FAT4-related, PMID:24913602).
PMID:30564329 SUPPORT Human Clinical
"facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth, and deformities of the teeth and ears), and various degrees of growth impairment, cognitive disorders, and seizures"
A CCBE1-confirmed HKLLS1 report lists deformities of the ears among the syndromic features, anchoring this to the CCBE1 subtype.
PMID:28985353 SUPPORT Human Clinical
"These patients have distinctive facial features similar to those with mutations in CCBE1."
Observation-level confirmation that CCBE1-mutant Hennekam patients have distinctive facial features (contrasted with ADAMTS3 patients).
Cystic hygroma HP:0000476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystic hygroma (HP:0000476). HP:0000476 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"An autopsy described a female fetus with a cystic hygroma, serous (nonchylous) pleural and pericardial effusions, congested liver, hypoplastic lungs"
A molecularly confirmed CCBE1 (HKLLS1) affected fetus had a cystic hygroma at autopsy.
Pericardial effusion HP:0001698 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pericardial effusion (HP:0001698). HP:0001698 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"An autopsy described a female fetus with a cystic hygroma, serous (nonchylous) pleural and pericardial effusions, congested liver, hypoplastic lungs"
A molecularly confirmed CCBE1 (HKLLS1) affected fetus had serous pericardial effusions.
Pulmonary lymphangiectasia HP:0006521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary lymphangiectasia (HP:0006521). HP:0006521 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"A chest CT showed pulmonary lymphangiectasis in this patient"
Chest CT documented pulmonary lymphangiectasia in a patient with Hennekam syndrome.
🧬

Genetic Associations

1
CCBE1 (Causal biallelic loss-of-function variant)
Gene: CCBE1 hgnc:29426 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CCBE1 (hgnc:29426). hgnc:29426 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:19935664 SUPPORT Human Clinical
"Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans."
Establishes CCBE1 as the causal gene for HKLLS1 with biallelic variants.
PMID:24913602 SUPPORT Human Clinical
"It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases."
Quantifies the contribution of CCBE1 to the overall Hennekam syndrome cohort (~25% of cases).
PMID:30564329 SUPPORT Human Clinical
"at least 12 different CCBE1 variants have been reported in at least seventeen probands"
Summarizes the reported CCBE1 variant spectrum in HKLLS1.
Variants (2)
p.Leu229fs (c.683_684insT)
Maternally inherited pathogenic loss-of-function frameshift CCBE1 variant; listed in gnomAD in 14 of 277,032 chromosomes, consistent with a rare recessive disease allele.
Show evidence (2 references)
PMID:30564329 SUPPORT Human Clinical
"A maternally inherited variant, p.Leu229fs (c.683_684insT), was detected and confirmed by Sanger sequencing"
A specific pathogenic loss-of-function frameshift CCBE1 allele.
PMID:30564329 SUPPORT Human Clinical
"listed in the Genome Aggregation Database (gnomAD) Browser in 14 out of 277 032 chromosomes"
Population allele frequency of the frameshift variant, consistent with a rare recessive disease allele.
p.Thr112Ile (c.335C>T)
Paternally inherited likely-pathogenic missense CCBE1 variant, in trans with the frameshift allele (compound heterozygosity).
Show evidence (1 reference)
PMID:30564329 SUPPORT Human Clinical
"A paternally inherited variant, p.Thr112Ile (c.335C>T) variant was detected and confirmed by Sanger sequencing"
A specific likely-pathogenic missense CCBE1 allele in trans with the frameshift variant.
💊

Medical Actions

4
Dietary management of protein-losing enteropathy
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
A low-fat, high-protein diet enriched in medium-chain triglycerides reduces intestinal lymphatic load and enteric protein loss from intestinal lymphangiectasia; supplemental nutrition supports growth.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"patients may require a high-protein, low-fat diet with medium-chain triglyceride supplementation in the case"
Directly supports a high-protein, low-fat, medium-chain-triglyceride diet for the protein-losing enteropathy of Hennekam syndrome.
Lymphedema supportive care
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Complete decongestive therapy (compression, manual lymphatic drainage, exercise, skin care) manages the lymphedema; a Hennekam case showed measurable limb-circumference reduction with this approach.
Show evidence (1 reference)
PMID:29560340 SUPPORT Human Clinical
"upper arm, from 22 cm to 19 cm; forearm, from 22.5 cm to 21 cm, respectively."
Complete decongestive therapy produced a measurable reduction in upper-arm and forearm circumference in a Hennekam syndrome patient.
Supportive and multidisciplinary care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is symptomatic and multidisciplinary, including nutritional support, monitoring for hypoalbuminemia and immunodeficiency, developmental and educational support, and treatment of seizures.
Show evidence (1 reference)
PMID:2624276 SUPPORT Human Clinical
"We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation."
The multisystem features (enteropathy, lymphedema, seizures, growth and developmental problems) require symptomatic multidisciplinary care.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counsel families about autosomal recessive inheritance, 25% sibling recurrence risk, carrier testing, and reproductive options.
Show evidence (1 reference)
PMID:19935664 SUPPORT Human Clinical
"Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans."
Autosomal recessive biallelic inheritance is the basis for recurrence-risk counseling.
🔬

Diagnosis

1
Molecular genetic testing of CCBE1
Sequencing and deletion/duplication analysis of CCBE1 confirms the diagnosis in individuals with syndromic generalized lymphatic dysplasia; a panel or exome approach also covers FAT4 and ADAMTS3.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic CCBE1 variants confirm HKLLS1.
Show evidence (1 reference)
PMID:19935664 SUPPORT Human Clinical
"Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish."
Supports molecular confirmation by identification of causal CCBE1 variants.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Hennekam syndrome is very rare; fewer than 100 families have been reported, with CCBE1 accounting for approximately 25% of all Hennekam syndrome cases.
Show evidence (1 reference)
PMID:24913602 SUPPORT Human Clinical
"It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases."
Supports the rarity and the CCBE1 fraction of Hennekam syndrome cases.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hennekam lymphangiectasia-lymphedema syndrome 1:

Hennekam lymphangiectasia-lymphedema syndrome 2 MONDO:0014454
Overlapping Features FAT4-related Hennekam syndrome is clinically overlapping and distinguished by molecular testing; it accounts for a subset of CCBE1 mutation-negative cases.
Hennekam lymphangiectasia-lymphedema syndrome 3 Not Yet Curated MONDO:0032564
Overlapping Features ADAMTS3-related Hennekam syndrome shares the VEGF-C activation mechanism with CCBE1 and produces distinctive facial features similar to CCBE1-mutant patients.
{ }

Source YAML

click to show 
name: Hennekam lymphangiectasia-lymphedema syndrome 1
creation_date: "2026-08-02T00:00:00Z"
description: >-
  Hennekam lymphangiectasia-lymphedema syndrome 1 (HKLLS1) is an autosomal
  recessive generalized lymphatic dysplasia caused by biallelic mutations in
  CCBE1. It is characterized by the triad of intestinal lymphangiectasia,
  peripheral and facial lymphedema, and intellectual disability, together with a
  characteristic flat facial appearance (flat face, depressed nasal bridge,
  hypertelorism, epicanthal folds, small mouth, and dental anomalies).
  Intestinal lymphangiectasia causes protein-losing enteropathy with
  hypoalbuminemia, hypogammaglobulinemia, and lymphopenia. CCBE1 is a secreted
  extracellular-matrix protein essential for lymphangiogenesis, acting as a
  cofactor that promotes ADAMTS3-mediated proteolytic activation of pro-VEGF-C;
  loss of CCBE1 function impairs VEGF-C/VEGFR-3 signaling and lymphatic vessel
  development. CCBE1 mutations account for approximately 25% of Hennekam syndrome
  cases and were the first genetic cause identified for the disorder.
category: Mendelian
parents:
- Hennekam syndrome
- hereditary disease
synonyms:
- CCBE1 Hennekam syndrome
- HKLLS1
- generalized lymphatic dysplasia, CCBE1-related
disease_term:
  preferred_term: Hennekam lymphangiectasia-lymphedema syndrome 1
  term:
    id: MONDO:0009337
    label: Hennekam lymphangiectasia-lymphedema syndrome 1
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    HKLLS1 is inherited in an autosomal recessive manner; affected individuals
    carry biallelic (homozygous or compound heterozygous) CCBE1 mutations,
    frequently in the setting of parental consanguinity.
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous and compound heterozygous mutations in seven subjects paired
      with functional analysis in a zebrafish model identify CCBE1 as one of few
      genes causing primary generalized lymph-vessel dysplasia in humans.
    explanation: >-
      Homozygous and compound heterozygous CCBE1 genotypes establish autosomal
      recessive inheritance for HKLLS1.
pathophysiology:
- name: CCBE1 loss of function
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function mutations in CCBE1 reduce the activity of a
    secreted extracellular-matrix protein required for lymphangiogenesis.
  genes:
  - preferred_term: CCBE1
    term:
      id: hgnc:29426
      label: CCBE1
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping identified a critical chromosomal region containing
      CCBE1, the human ortholog of a gene essential for lymphangiogenesis in
      zebrafish.
    explanation: >-
      Identifies CCBE1 as the causal gene and situates it as an essential
      lymphangiogenesis factor.
  - reference: DOI:10.1161/CIRCRESAHA.116.304949
    reference_title: Functional Dissection of the CCBE1 Protein.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      deleting the collagen domains of CCBE1 has a much stronger effect on
      CCBE1 activity than deleting the EGF domains
    explanation: >-
      Domain-dissection knock-in mouse and zebrafish data show the collagen
      repeats of CCBE1 are crucial for its VEGF-C-activating, lymphangiogenic
      function that is lost in HKLLS1.
  downstream:
  - target: Impaired VEGF-C activation and lymphangiogenesis
    description: >-
      CCBE1 promotes ADAMTS3-mediated proteolytic maturation of pro-VEGF-C;
      loss of CCBE1 reduces mature VEGF-C and downstream VEGFR-3 signaling in
      lymphatic endothelial cells.
    evidence:
    - reference: PMID:24552833
      reference_title: CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        it promotes proteolytic cleavage of the otherwise poorly active
        29/31-kDa form of VEGF-C by the A disintegrin and metalloprotease with
        thrombospondin motifs-3 protease, resulting in the mature 21/23-kDa form
        of VEGF-C, which induces increased VEGF-C receptor signaling.
      explanation: >-
        Defines the molecular mechanism by which CCBE1 enables VEGF-C activation;
        loss of CCBE1 removes this cofactor activity.
- name: Impaired VEGF-C activation and lymphangiogenesis
  biological_scale: CELLULAR
  description: >-
    Reduced VEGF-C/VEGFR-3 signaling impairs lymphatic endothelial cell
    migration and lymphatic vessel formation, producing generalized lymphatic
    dysplasia.
  cell_types:
  - preferred_term: lymphatic endothelial cell
    term:
      id: CL:0002138
      label: endothelial cell of lymphatic vessel
  biological_processes:
  - preferred_term: lymphangiogenesis
    term:
      id: GO:0001946
      label: lymphangiogenesis
  evidence:
  - reference: PMID:24523457
    reference_title: Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of
      Ccbe1.
    explanation: >-
      Zebrafish loss-of-function data show that Ccbe1 is required for
      VEGFC/VEGFR3 downstream signaling that drives lymphangiogenesis.
  downstream:
  - target: Generalized lymphatic dysplasia
    description: >-
      Defective lymphangiogenesis produces malformed, dysfunctional lymphatic
      vessels throughout the body.
    evidence:
    - reference: PMID:24523457
      reference_title: Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The role of CCBE1 orthologs is highly conserved in zebrafish, mice and
        humans with mutations in CCBE1 causing generalized lymphatic dysplasia
        and lymphedema (Hennekam syndrome).
      explanation: >-
        Links impaired CCBE1-dependent lymphangiogenesis to the generalized
        lymphatic dysplasia phenotype of Hennekam syndrome.
- name: Generalized lymphatic dysplasia
  biological_scale: TISSUE
  description: >-
    Widespread lymphatic vessel dysplasia impairs lymph drainage and underlies
    the intestinal lymphangiectasia, lymphedema, and serous effusions of the
    syndrome.
  cell_types:
  - preferred_term: lymphatic endothelial cell
    term:
      id: CL:0002138
      label: endothelial cell of lymphatic vessel
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphedema, lymphangiectasias, mental retardation and unusual facial
      characteristics define the autosomal recessive Hennekam syndrome.
    explanation: >-
      Establishes the generalized lymphatic phenotype (lymphedema and
      lymphangiectasias) as defining features of the disorder.
  downstream:
  - target: Intestinal lymphangiectasia
    description: >-
      Dysplastic intestinal lymphatics dilate and leak lymph into the gut lumen.
    causal_link_type: DIRECT
  - target: Lymphedema
    description: >-
      Impaired lymphatic drainage in the limbs, genitalia, and face causes
      lymphedema.
    causal_link_type: DIRECT
- name: Intestinal lymphangiectasia
  biological_scale: TISSUE
  description: >-
    Dilated intestinal lymphatics leak protein-rich lymph into the gut,
    producing protein-losing enteropathy with hypoalbuminemia,
    hypogammaglobulinemia, and lymphopenia.
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two male and two female relatives with intestinal
      lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial
      anomalies; seizures; mild growth retardation; and moderate mental
      retardation.
    explanation: >-
      The original clinical description documents intestinal lymphangiectasia as
      a core feature of the syndrome.
  downstream:
  - target: Protein-losing enteropathy
    description: >-
      Enteric loss of lymph depletes serum albumin and immunoglobulins.
    causal_link_type: DIRECT
- name: Protein-losing enteropathy
  biological_scale: ORGANISM
  description: >-
    Protein-rich lymph lost into the gut lumen produces protein-losing
    enteropathy, depleting serum albumin, immunoglobulins, and lymphocytes.
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both gastrointestinal protein loss and malabsorption
    explanation: >-
      Intestinal lymphangiectasia in Hennekam syndrome causes gastrointestinal
      protein loss (protein-losing enteropathy) and malabsorption.
  downstream:
  - target: Hypoalbuminemia
    description: >-
      Enteric protein loss lowers serum albumin.
    causal_link_type: DIRECT
  - target: Decreased circulating immunoglobulin concentration
    description: >-
      Enteric loss of lymph depletes serum immunoglobulins.
    causal_link_type: DIRECT
  - target: Lymphopenia
    description: >-
      Enteric loss of lymph depletes circulating lymphocytes.
    causal_link_type: DIRECT
phenotypes:
- name: Intestinal lymphangiectasia
  category: Gastrointestinal
  diagnostic: true
  description: >-
    Dilated intestinal lymphatic vessels are a defining feature and cause
    protein-losing enteropathy.
  phenotype_term:
    preferred_term: Intestinal lymphangiectasia
    term:
      id: HP:0002593
      label: Intestinal lymphangiectasia
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two male and two female relatives with intestinal
      lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial
      anomalies; seizures; mild growth retardation; and moderate mental
      retardation.
    explanation: >-
      Directly documents intestinal lymphangiectasia in the original family.
- name: Lymphedema
  category: Lymphatic
  diagnostic: true
  description: >-
    Severe lymphedema of the limbs, genitalia, and face is a core feature
    reflecting the generalized lymphatic dysplasia; the edema is usually
    congenital and often progressive.
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
    temporality: CHRONIC
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two male and two female relatives with intestinal
      lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial
      anomalies; seizures; mild growth retardation; and moderate mental
      retardation.
    explanation: >-
      Documents severe lymphedema of limbs, genitalia, and face.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Variable intellectual disability, typically mild to moderate, is part of the
    classic triad.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphedema, lymphangiectasias, mental retardation and unusual facial
      characteristics define the autosomal recessive Hennekam syndrome.
    explanation: >-
      Intellectual disability (mental retardation) is listed among the defining
      features.
- name: Flat face
  category: Craniofacial
  description: >-
    A flat facial appearance is a characteristic dysmorphic feature.
  phenotype_term:
    preferred_term: Flat face
    term:
      id: HP:0012368
      label: Flat face
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main facial anomalies are a flat face, flat nasal bridge, hypertelorism,
      small mouth, tooth anomalies, and ear defects.
    explanation: >-
      Part of the shared Hennekam facial gestalt described in the
      originally-reported family (later shown to be FAT4-related, PMID:24913602);
      the CCBE1-specific evidence below confirms CCBE1-related patients show the
      same distinctive facial features.
  - reference: PMID:28985353
    reference_title: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients have distinctive facial features similar to those with
      mutations in CCBE1.
    explanation: >-
      Confirms that CCBE1-mutant Hennekam patients have a distinctive
      characteristic facial appearance (here contrasted with ADAMTS3 patients).
- name: Depressed nasal bridge
  category: Craniofacial
  description: >-
    A flat/depressed nasal bridge is part of the characteristic facial
    appearance.
  phenotype_term:
    preferred_term: Flat nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main facial anomalies are a flat face, flat nasal bridge, hypertelorism,
      small mouth, tooth anomalies, and ear defects.
    explanation: >-
      Part of the shared Hennekam facial gestalt described in the
      originally-reported family (later shown to be FAT4-related, PMID:24913602);
      the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists these facial features as part of the
      syndrome, anchoring them to the CCBE1 subtype.
  - reference: PMID:28985353
    reference_title: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients have distinctive facial features similar to those with
      mutations in CCBE1.
    explanation: >-
      Observation-level confirmation that CCBE1-mutant Hennekam patients have
      distinctive facial features (contrasted with ADAMTS3 patients).
- name: Hypertelorism
  category: Craniofacial
  description: >-
    Widely spaced eyes are part of the characteristic flat facial appearance.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main facial anomalies are a flat face, flat nasal bridge, hypertelorism,
      small mouth, tooth anomalies, and ear defects.
    explanation: >-
      Part of the shared Hennekam facial gestalt described in the
      originally-reported family (later shown to be FAT4-related, PMID:24913602);
      the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists these facial features as part of the
      syndrome, anchoring them to the CCBE1 subtype.
  - reference: PMID:28985353
    reference_title: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients have distinctive facial features similar to those with
      mutations in CCBE1.
    explanation: >-
      Observation-level confirmation that CCBE1-mutant Hennekam patients have
      distinctive facial features (contrasted with ADAMTS3 patients).
- name: Narrow mouth
  category: Craniofacial
  description: >-
    A small mouth is part of the characteristic facial appearance.
  phenotype_term:
    preferred_term: Small mouth
    term:
      id: HP:0000160
      label: Narrow mouth
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main facial anomalies are a flat face, flat nasal bridge, hypertelorism,
      small mouth, tooth anomalies, and ear defects.
    explanation: >-
      Part of the shared Hennekam facial gestalt described in the
      originally-reported family (later shown to be FAT4-related, PMID:24913602);
      the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists these facial features as part of the
      syndrome, anchoring them to the CCBE1 subtype.
  - reference: PMID:28985353
    reference_title: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients have distinctive facial features similar to those with
      mutations in CCBE1.
    explanation: >-
      Observation-level confirmation that CCBE1-mutant Hennekam patients have
      distinctive facial features (contrasted with ADAMTS3 patients).
- name: Abnormal dental morphology
  category: Craniofacial
  description: >-
    Tooth anomalies are part of the syndromic facial phenotype.
  phenotype_term:
    preferred_term: Tooth anomalies
    term:
      id: HP:0006482
      label: Abnormal dental morphology
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main facial anomalies are a flat face, flat nasal bridge, hypertelorism,
      small mouth, tooth anomalies, and ear defects.
    explanation: >-
      Part of the shared Hennekam facial gestalt described in the
      originally-reported family (later shown to be FAT4-related, PMID:24913602);
      the CCBE1-confirmed corroboration below anchors it to the CCBE1 subtype.
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists these facial features as part of the
      syndrome, anchoring them to the CCBE1 subtype.
  - reference: PMID:28985353
    reference_title: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients have distinctive facial features similar to those with
      mutations in CCBE1.
    explanation: >-
      Observation-level confirmation that CCBE1-mutant Hennekam patients have
      distinctive facial features (contrasted with ADAMTS3 patients).
- name: Abnormality of the ear
  category: Craniofacial
  description: >-
    Ear defects (including low-set or dysplastic ears) are part of the syndromic
    facial phenotype.
  phenotype_term:
    preferred_term: Ear defects
    term:
      id: HP:0000598
      label: Abnormality of the ear
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main facial anomalies are a flat face, flat nasal bridge, hypertelorism,
      small mouth, tooth anomalies, and ear defects.
    explanation: >-
      Part of the shared Hennekam facial gestalt described in the
      originally-reported family (later shown to be FAT4-related, PMID:24913602).
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists deformities of the ears among the
      syndromic features, anchoring this to the CCBE1 subtype.
  - reference: PMID:28985353
    reference_title: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients have distinctive facial features similar to those with
      mutations in CCBE1.
    explanation: >-
      Observation-level confirmation that CCBE1-mutant Hennekam patients have
      distinctive facial features (contrasted with ADAMTS3 patients).
- name: Seizure
  category: Neurologic
  description: >-
    Seizures were reported in the original affected family.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two male and two female relatives with intestinal
      lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial
      anomalies; seizures; mild growth retardation; and moderate mental
      retardation.
    explanation: >-
      Seizures were reported in the originally-described Hennekam family (later
      shown to be FAT4-related, PMID:24913602); seizures are described across the
      broader Hennekam syndrome literature.
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists seizures among the syndromic
      features, anchoring this to the CCBE1 subtype.
- name: Growth delay
  category: Growth
  description: >-
    Mild growth retardation was reported in the original family.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two male and two female relatives with intestinal
      lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial
      anomalies; seizures; mild growth retardation; and moderate mental
      retardation.
    explanation: >-
      Mild growth retardation was reported in the originally-described Hennekam
      family (later shown to be FAT4-related, PMID:24913602); growth impairment
      in CCBE1-related disease is also driven by protein-losing enteropathy.
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms (depressed nasal bridge, hypertelorism, narrow mouth,
      and deformities of the teeth and ears), and various degrees of growth
      impairment, cognitive disorders, and seizures
    explanation: >-
      A CCBE1-confirmed HKLLS1 report lists growth impairment among the
      syndromic features, anchoring this to the CCBE1 subtype.
- name: Protein-losing enteropathy
  category: Gastrointestinal
  description: >-
    Enteric protein loss from intestinal lymphangiectasia is a hallmark
    complication.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intestinal lymphangiectasia can lead to severe protein loss
    explanation: >-
      Documents that the intestinal lymphangiectasia of Hennekam syndrome causes
      severe enteric protein loss (protein-losing enteropathy).
- name: Hypoalbuminemia
  category: Metabolic
  description: >-
    Enteric protein loss lowers serum albumin.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
- name: Decreased circulating immunoglobulin concentration
  category: Immunologic
  description: >-
    Loss of lymph into the gut depletes serum immunoglobulins
    (hypogammaglobulinemia).
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe protein loss resulting in hypogammaglobulinemia
    explanation: >-
      Enteric protein loss in Hennekam syndrome produces hypogammaglobulinemia.
- name: Lymphopenia
  category: Immunologic
  description: >-
    Loss of lymph into the gut depletes circulating lymphocytes.
  phenotype_term:
    preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
- name: Hydrops fetalis
  category: Prenatal
  description: >-
    Severe prenatal disease can present as recurrent nonimmune hydrops fetalis,
    with fetal effusions, ascites, cystic hygroma, and pulmonary hypoplasia,
    reflecting profound lymphatic dysfunction.
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent hydrops fetalis in this case of Hennekam lymphangiectasia
    explanation: >-
      A molecularly confirmed CCBE1 (HKLLS1) case presented as recurrent
      nonimmune hydrops fetalis, documenting the severe prenatal end of the
      phenotypic spectrum.
- name: Cystic hygroma
  category: Prenatal
  description: >-
    Cystic hygroma is part of the severe fetal lymphatic phenotype.
  phenotype_term:
    preferred_term: Cystic hygroma
    term:
      id: HP:0000476
      label: Cystic hygroma
  evidence:
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autopsy described a female fetus with a cystic hygroma, serous
      (nonchylous) pleural and pericardial effusions, congested liver,
      hypoplastic lungs
    explanation: >-
      A molecularly confirmed CCBE1 (HKLLS1) affected fetus had a cystic
      hygroma at autopsy.
- name: Pleural effusion
  category: Respiratory
  description: >-
    Serous pleural effusions occur as part of the fetal serosal lymphatic
    involvement.
  phenotype_term:
    preferred_term: Pleural effusion
    term:
      id: HP:0002202
      label: Pleural effusion
  evidence:
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autopsy described a female fetus with a cystic hygroma, serous
      (nonchylous) pleural and pericardial effusions, congested liver,
      hypoplastic lungs
    explanation: >-
      A molecularly confirmed CCBE1 (HKLLS1) affected fetus had serous pleural
      effusions.
- name: Pericardial effusion
  category: Cardiovascular
  description: >-
    Serous pericardial effusions occur as part of the fetal serosal lymphatic
    involvement.
  phenotype_term:
    preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion
  evidence:
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autopsy described a female fetus with a cystic hygroma, serous
      (nonchylous) pleural and pericardial effusions, congested liver,
      hypoplastic lungs
    explanation: >-
      A molecularly confirmed CCBE1 (HKLLS1) affected fetus had serous
      pericardial effusions.
- name: Pulmonary hypoplasia
  category: Respiratory
  description: >-
    Pulmonary hypoplasia can result from compressive fetal effusions and
    pulmonary lymphatic disease.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An autopsy described a female fetus with a cystic hygroma, serous
      (nonchylous) pleural and pericardial effusions, congested liver,
      hypoplastic lungs
    explanation: >-
      A molecularly confirmed CCBE1 (HKLLS1) affected fetus had hypoplastic
      lungs.
- name: Ascites
  category: Prenatal
  description: >-
    Fetal ascites is part of the hydropic presentation.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fetal head demonstrating scalp edema; C, fetal abdomen demonstrating
      ascites
    explanation: >-
      Prenatal ultrasound of a molecularly confirmed CCBE1 (HKLLS1) affected
      fetus demonstrated ascites (and scalp edema).
- name: Pulmonary lymphangiectasia
  category: Respiratory
  description: >-
    Pulmonary lymphangiectasia reflects lymphatic maldevelopment in the lung and
    can cause respiratory compromise.
  phenotype_term:
    preferred_term: Pulmonary lymphangiectasia
    term:
      id: HP:0006521
      label: Pulmonary lymphangiectasia
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A chest CT showed pulmonary lymphangiectasis in this patient
    explanation: >-
      Chest CT documented pulmonary lymphangiectasia in a patient with Hennekam
      syndrome.
- name: Epicanthus
  category: Craniofacial
  description: >-
    Epicanthal folds are part of the characteristic facial appearance.
  phenotype_term:
    preferred_term: Epicanthal folds
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a bulbous nasal tip, and epicanthal folds was also evident
    explanation: >-
      Epicanthal folds were documented in a patient with Hennekam syndrome.
genetic:
- name: CCBE1
  association: Causal biallelic loss-of-function variant
  gene_term:
    preferred_term: CCBE1
    term:
      id: hgnc:29426
      label: CCBE1
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous and compound heterozygous mutations in seven subjects paired
      with functional analysis in a zebrafish model identify CCBE1 as one of few
      genes causing primary generalized lymph-vessel dysplasia in humans.
    explanation: >-
      Establishes CCBE1 as the causal gene for HKLLS1 with biallelic variants.
  - reference: PMID:24913602
    reference_title: Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It can be caused by mutations in CCBE1 which are found in approximately
      25 % of cases.
    explanation: >-
      Quantifies the contribution of CCBE1 to the overall Hennekam syndrome
      cohort (~25% of cases).
  - reference: PMID:30564329
    reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      at least 12 different CCBE1 variants have been reported in at least
      seventeen probands
    explanation: >-
      Summarizes the reported CCBE1 variant spectrum in HKLLS1.
  variants:
  - name: p.Leu229fs (c.683_684insT)
    description: >-
      Maternally inherited pathogenic loss-of-function frameshift CCBE1 variant;
      listed in gnomAD in 14 of 277,032 chromosomes, consistent with a rare
      recessive disease allele.
    evidence:
    - reference: PMID:30564329
      reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A maternally inherited variant, p.Leu229fs (c.683_684insT), was detected
        and confirmed by Sanger sequencing
      explanation: >-
        A specific pathogenic loss-of-function frameshift CCBE1 allele.
    - reference: PMID:30564329
      reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        listed in the Genome Aggregation Database (gnomAD) Browser in 14 out of
        277 032 chromosomes
      explanation: >-
        Population allele frequency of the frameshift variant, consistent with a
        rare recessive disease allele.
  - name: p.Thr112Ile (c.335C>T)
    description: >-
      Paternally inherited likely-pathogenic missense CCBE1 variant, in trans
      with the frameshift allele (compound heterozygosity).
    evidence:
    - reference: PMID:30564329
      reference_title: "Novel mutation in CCBE 1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A paternally inherited variant, p.Thr112Ile (c.335C>T) variant was
        detected and confirmed by Sanger sequencing
      explanation: >-
        A specific likely-pathogenic missense CCBE1 allele in trans with the
        frameshift variant.
diagnosis:
- name: Molecular genetic testing of CCBE1
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Sequencing and deletion/duplication analysis of CCBE1 confirms the diagnosis
    in individuals with syndromic generalized lymphatic dysplasia; a panel or
    exome approach also covers FAT4 and ADAMTS3.
  results: >-
    Biallelic pathogenic CCBE1 variants confirm HKLLS1.
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping identified a critical chromosomal region containing
      CCBE1, the human ortholog of a gene essential for lymphangiogenesis in
      zebrafish.
    explanation: >-
      Supports molecular confirmation by identification of causal CCBE1
      variants.
treatments:
- name: Dietary management of protein-losing enteropathy
  description: >-
    A low-fat, high-protein diet enriched in medium-chain triglycerides reduces
    intestinal lymphatic load and enteric protein loss from intestinal
    lymphangiectasia; supplemental nutrition supports growth.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients may require a high-protein, low-fat diet with medium-chain
      triglyceride supplementation in the case
    explanation: >-
      Directly supports a high-protein, low-fat, medium-chain-triglyceride diet
      for the protein-losing enteropathy of Hennekam syndrome.
- name: Lymphedema supportive care
  description: >-
    Complete decongestive therapy (compression, manual lymphatic drainage,
    exercise, skin care) manages the lymphedema; a Hennekam case showed measurable
    limb-circumference reduction with this approach.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:29560340
    reference_title: "Hennekam Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      upper arm, from 22 cm to 19 cm; forearm, from 22.5 cm to 21 cm,
      respectively.
    explanation: >-
      Complete decongestive therapy produced a measurable reduction in
      upper-arm and forearm circumference in a Hennekam syndrome patient.
- name: Supportive and multidisciplinary care
  description: >-
    Management is symptomatic and multidisciplinary, including nutritional
    support, monitoring for hypoalbuminemia and immunodeficiency, developmental
    and educational support, and treatment of seizures.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:2624276
    reference_title: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two male and two female relatives with intestinal
      lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial
      anomalies; seizures; mild growth retardation; and moderate mental
      retardation.
    explanation: >-
      The multisystem features (enteropathy, lymphedema, seizures, growth and
      developmental problems) require symptomatic multidisciplinary care.
- name: Genetic counseling
  description: >-
    Counsel families about autosomal recessive inheritance, 25% sibling
    recurrence risk, carrier testing, and reproductive options.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:19935664
    reference_title: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous and compound heterozygous mutations in seven subjects paired
      with functional analysis in a zebrafish model identify CCBE1 as one of few
      genes causing primary generalized lymph-vessel dysplasia in humans.
    explanation: >-
      Autosomal recessive biallelic inheritance is the basis for recurrence-risk
      counseling.
differential_diagnoses:
- name: Hennekam lymphangiectasia-lymphedema syndrome 2
  disease_term:
    preferred_term: Hennekam lymphangiectasia-lymphedema syndrome 2
    term:
      id: MONDO:0014454
      label: Hennekam lymphangiectasia-lymphedema syndrome 2
  description: >-
    FAT4-related Hennekam syndrome is clinically overlapping and distinguished by
    molecular testing; it accounts for a subset of CCBE1 mutation-negative cases.
- name: Hennekam lymphangiectasia-lymphedema syndrome 3
  disease_term:
    preferred_term: Hennekam lymphangiectasia-lymphedema syndrome 3
    term:
      id: MONDO:0032564
      label: hennekam lymphangiectasia-lymphedema syndrome 3
  description: >-
    ADAMTS3-related Hennekam syndrome shares the VEGF-C activation mechanism with
    CCBE1 and produces distinctive facial features similar to CCBE1-mutant
    patients.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Hennekam syndrome is very rare; fewer than 100 families have been reported,
    with CCBE1 accounting for approximately 25% of all Hennekam syndrome cases.
  evidence:
  - reference: PMID:24913602
    reference_title: Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It can be caused by mutations in CCBE1 which are found in approximately
      25 % of cases.
    explanation: >-
      Supports the rarity and the CCBE1 fraction of Hennekam syndrome cases.
clinical_trials: []
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 18 citations 2026-08-02T01:24:54.842911

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Hennekam lymphangiectasia-lymphedema syndrome 1
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Hennekam lymphangiectasia-lymphedema syndrome 1 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Hennekam lymphangiectasia–lymphedema syndrome 1

Executive summary

Hennekam lymphangiectasia–lymphedema syndrome 1 (HKLLS1) is an ultra-rare, autosomal-recessive generalized lymphatic dysplasia caused by biallelic germline variants in CCBE1. Its defining manifestations are congenital or early-onset, often progressive lymphedema; visceral lymphangiectasia, particularly of the intestine; characteristic facial morphology; and variably impaired neurodevelopment. Severe fetal disease may present as nonimmune hydrops fetalis, pleural/pericardial effusions, pulmonary hypoplasia, and fetal death. The central molecular lesion is inadequate CCBE1-assisted, ADAMTS3-mediated activation of pro-VEGF-C, reducing VEGFR3 signaling in lymphatic endothelial cells and disrupting embryonic lymphangiogenesis. There is no curative or genotype-directed treatment; management is supportive and multidisciplinary. Published evidence remains dominated by small series and individual cases, and no HKLLS1-specific interventional trial was identified.

A structured, ontology-oriented summary is provided below.

domain evidence-backed fact suggested ontology terms/IDs evidence type/limitations
Disease identity Hennekam lymphangiectasia-lymphedema syndrome 1 is the CCBE1-related subtype of Hennekam syndrome, a generalized lymphatic dysplasia with lymphedema, lymphangiectasia, characteristic facial features, and variable intellectual/developmental impairment (roukens2015functionaldissectionof pages 1-3, lee2018hennekamsyndromea pages 1-3) Disease: Hennekam lymphangiectasia-lymphedema syndrome 1 (MONDO: verify); Hennekam syndrome (OMIM #235510 verify subtype mapping); MeSH: verify Human clinical + mechanistic review/context; disease identifiers should be verified in OMIM/MONDO for subtype specificity
Causal gene Biallelic pathogenic variants in CCBE1 cause HKLLS1; CCBE1 encodes collagen and calcium-binding EGF domain-containing protein 1, a secreted extracellular matrix protein essential for lymphatic development (roukens2015functionaldissectionof pages 1-3, melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4) Gene: CCBE1 (HGNC: verify; NCBI Gene: verify); Protein: CCBE1 (UniProt: verify) Human genetic + animal/mechanistic evidence; exact database IDs should be verified
Inheritance The disorder is autosomal recessive; reported affected individuals carry homozygous or compound heterozygous CCBE1 variants (lee2018hennekamsyndromea pages 1-3, melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4) Inheritance: HP:0000007 Autosomal recessive inheritance Human clinical/genetic evidence; penetrance not well quantified
Variant spectrum Published CCBE1 disease variants include missense, frameshift, and other loss-of-function or hypomorphic alleles; one reported prenatal HKLLS1 case had compound heterozygous c.683_684insT p.Leu229fs and c.335C>T p.Thr112Ile variants (roukens2015functionaldissectionof pages 1-3, melber2018novelmutationin pages 2-4) Sequence variant terms: SO:0001589 frameshift_variant; SO:0001583 missense_variant; ACMG class: pathogenic/likely pathogenic (verify per submission) Human genetic evidence; allele frequencies and classification depend on current ClinVar/gnomAD review
Core edema phenotype Edema is usually congenital and often progressive, commonly involving limbs, genitalia, and face (melber2018novelmutationin pages 1-2) HP:0001004 Lymphedema; HP:0009826 Facial edema; HP:0010318 Edema; onset: HP:0003577 Congenital onset Human clinical evidence; frequency across CCBE1-only cases is not robustly quantified
Lymphangiectasia phenotype Maldevelopment of the lymphatic system preferentially affects intestines and limbs, and can also affect pleura, pericardium, kidneys, lungs, and mesentery; case-level imaging documented pulmonary and mesenteric/small-bowel lymphangiectasia (melber2018novelmutationin pages 1-2, lee2018hennekamsyndromea pages 3-5) HP:0100769 Intestinal lymphangiectasia; HP:0005381 Pleural effusion; HP:0001698 Pericardial effusion; HP term for pulmonary lymphangiectasia: verify; UBERON small intestine UBERON:0002108; lung UBERON:0002048; pleura UBERON:0000977; pericardium UBERON:0002408; kidney UBERON:0002113 Human clinical/imaging evidence; some involved-organ phenotypes are reported across Hennekam syndrome broadly rather than CCBE1-only cohorts
Neurodevelopment Developmental delay/intellectual disability is variable; one pediatric case showed delays in gross motor, fine motor, personal-social, and functional activities (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5) HP:0001263 Global developmental delay; HP:0001249 Intellectual disability Human clinical evidence; severity spectrum broad and incompletely quantified
Facial phenotype Characteristic face may include flat/flattened midface, broad depressed nasal bridge, hypertelorism, epicanthal folds, small or narrow mouth, and other dysmorphic features, partly attributed to prenatal facial lymphedema (betterman2020atypicalcadherinfat4 pages 1-2, lee2018hennekamsyndromea pages 1-3, melber2018novelmutationin pages 1-2) HP:0012368 Flat face; HP:0000316 Hypertelorism; HP:0000280 Coarse face verify/not specific; HP:0000426 Depressed nasal bridge; HP:0000286 Epicanthus; HP:0000208 Small mouth Human clinical evidence; exact HPO term mapping for each facial feature should be confirmed case-by-case
Prenatal presentation HKLLS1 can present prenatally as recurrent nonimmune hydrops fetalis with cystic hygroma, pleural/pericardial effusions, scalp edema, ascites, hepatomegaly, and hypoplastic lungs (melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4) HP:0001789 Hydrops fetalis; HP:0000476 Scalp edema; HP:0000473 Cystic hygroma; HP:0001541 Ascites; HP:0002240 Hepatomegaly; HP:0002089 Pulmonary hypoplasia Human prenatal case evidence; based on case report, so not all patients present this way
Pathophysiology CCBE1 is a crucial regulator of VEGF-C/VEGFR3 signaling; it enhances proteolytic processing/activation of VEGF-C via ADAMTS3, enabling lymphatic endothelial sprouting and lymphangiogenesis (roukens2015functionaldissectionof pages 1-3, betterman2020atypicalcadherinfat4 pages 1-2) Pathway: VEGF-C/VEGFR3 signaling pathway (Reactome/KEGG: verify); GO:0001946 lymphangiogenesis; GO:0001525 angiogenesis; GO term for VEGF-C activation/proteolytic processing: verify Strong mechanistic support from mouse, zebrafish, and in vitro systems; human inference is biologically well supported but indirect
Cellular context The key affected cell population is the lymphatic endothelial cell (LEC); CCBE1-dependent VEGF-C signaling is required for LEC migration/sprouting from embryonic veins and lymphatic vessel morphogenesis (roukens2015functionaldissectionof pages 1-3, betterman2020atypicalcadherinfat4 pages 1-2) Cell Ontology: lymphatic endothelial cell (CL ID: verify); GO:0035855 megakaryocyte? not relevant; GO:0043542 endothelial cell migration verify; UBERON cardinal vein: verify Animal/mechanistic evidence; cell ontology ID should be verified before KB ingestion
Protein/domain mechanism CCBE1 contains EGF/calcium-binding EGF domains and collagen repeat domains; functional studies indicate collagen domains are crucial for VEGF-C activation, while EGF domains are required for full in vivo lymphangiogenic activity (roukens2015functionaldissectionof pages 1-3) Protein domains: EGF-like domain (InterPro/Pfam: verify); collagen repeat domain (InterPro/Pfam: verify) Mouse, zebrafish, in vitro domain-dissection evidence; not a routine clinical biomarker
Anatomy affected Primary involvement is the lymphatic vasculature across limb soft tissues and viscera; secondary involvement may include intestine, lung, pleura, pericardium, mesentery, face, and possibly kidney (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2) UBERON lymph vessel: UBERON:0002019 verify; small intestine UBERON:0002108; mesentery UBERON:0002385; lung UBERON:0002048; face UBERON:0001684; limb UBERON:0002101/0002102 verify Human imaging/clinical evidence; organ distribution heterogeneous
Diagnostic workup Diagnosis is clinical plus imaging and molecular confirmation. Reported tests include lymphatic scan showing absent visible lymphatic flow, CT angiography for lymphedema, chest CT and abdominal ultrasound for lymphangiectasia, MRI for CNS findings, and prenatal WES after nondiagnostic karyotype/microarray/workup (lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4) NCIT: Whole Exome Sequencing (verify); LOINC/NCIT for lymphoscintigraphy, CT angiography, MRI, ultrasound: verify; HP:0000478 Abnormality of the eye? not relevant Human clinical evidence; no universally standardized disease-specific diagnostic criteria were identified
Genetic testing strategy WES is useful when phenotype is nonspecific, especially in prenatal hydrops; trio exome identified causal CCBE1 variants after normal karyotype, microarray, infectious, hematologic, and metabolic testing (melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4) Test strategy terms: trio exome sequencing (NCIT: verify); prenatal diagnosis (NCIT: verify) Human prenatal case evidence; WGS/panel utility for HKLLS1 specifically not systematically studied
Differential diagnosis Differential diagnosis includes other monogenic primary lymphedema/generalized lymphatic dysplasia disorders involving genes such as FAT4, ADAMTS3, FLT4/VEGFR3, VEGFC, PIEZO1, EPHB4, FOXC2, GATA2 and related syndromic/non-syndromic hydrops etiologies (betterman2020atypicalcadherinfat4 pages 1-2, melber2018novelmutationin pages 1-2) Differential disease terms: primary lymphedema (MONDO/Orphanet verify); generalized lymphatic dysplasia (verify) Mostly broader disease-context evidence; not an exhaustive formal differential list
Laboratory findings Intestinal lymphangiectasia can cause hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, lymphopenia, and growth problems, although these were absent in one pediatric case with mesenteric lymphangiectasia (lee2018hennekamsyndromea pages 3-5) HP:0003073 Hypoproteinemia; HP:0003075 Hypoalbuminemia; HP:0004313 Hypogammaglobulinemia; HP:0001888 Lymphopenia; HP:0001510 Growth delay Evidence mainly from syndrome-level literature/case discussion rather than CCBE1-only cohort statistics
Treatment/supportive care No curative therapy is established. Supportive lymphedema care includes complete decongestive therapy: manual lymph drainage, compression bandaging/garments, exercise, skin care/rehabilitation; one Hennekam case improved arm circumference after 7 sessions (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5) NCIT: Manual Lymphatic Drainage (verify); Compression Bandage (verify); Exercise Therapy (NCIT: verify); Physical Therapy (NCIT: C15329 verify) Disease-specific evidence is limited to single-case rehabilitation report; larger lymphedema trial data are not HKLLS1-specific
Enteropathy management For protein-losing enteropathy due to intestinal lymphangiectasia, recommended supportive management includes high-protein, low-fat diet with medium-chain triglyceride supplementation (lee2018hennekamsyndromea pages 3-5) NCIT/CHEBI: Medium-Chain Triglyceride (verify); dietary management term (verify) Syndrome-level supportive recommendation; efficacy in HKLLS1 not tested in controlled trials
Surgical/interventional care Surgery is considered a last resort for severe lymphedema that does not respond to conservative treatment (lee2018hennekamsyndromea pages 3-5) NCIT surgical procedure for lymphedema: verify Supportive statement from case discussion/referenced literature; no HKLLS1 surgical outcomes series identified
Prognosis Prognosis is variable and depends on extent of visceral lymphatic involvement; prenatal hydrops and pulmonary involvement are poor prognostic features, whereas surviving children may have chronic morbidity dominated by edema and developmental issues (lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2) Prognostic features: HP:0001789 Hydrops fetalis; HP:0002089 Pulmonary hypoplasia; HP:0001004 Lymphedema Evidence from case reports and syndrome-level observations; no survival curves or life-expectancy estimates specific to HKLLS1
Prevention/genetic counseling Primary prevention is not available for the Mendelian disease itself; secondary prevention/reproductive options include carrier testing of parents, recurrence-risk counseling for autosomal recessive inheritance, and prenatal molecular diagnosis if familial variants are known (melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4) HP:0000007 Autosomal recessive inheritance; prenatal diagnosis term (NCIT: verify); carrier testing term (NCIT: verify) Logic follows established Mendelian counseling practice; disease-specific counseling guidelines not identified
Recent developments (2023-2024 relevance) Recent literature continues to frame CCBE1 disease within dysregulated lymphatic VEGFR3 signaling and developmental lymphatic biology, but no 2023-2024 HKLLS1-specific therapeutic breakthrough or interventional trial was identified (betterman2020atypicalcadherinfat4 pages 1-2, NCT06327412 chunk 1) Pathway annotations above; clinical trial terms: primary lymphedema exercise trial NCT06327412 Recent sources are mostly mechanistic or broader lymphedema-focused, not subtype-specific
Major data gaps Major gaps include subtype-specific prevalence/incidence, natural history, penetrance/expressivity estimates, standardized diagnostic criteria, validated biomarkers, genotype-phenotype correlations across CCBE1 alleles, long-term QoL data, and controlled treatment studies specific to HKLLS1 (lee2018hennekamsyndromea pages 1-3, melber2018novelmutationin pages 1-2) Evidence gap annotation; ontology IDs not applicable Explicitly based on absence of robust cohort-level evidence in retrieved sources

Table: This table summarizes ontology-ready, evidence-backed facts for CCBE1-related Hennekam lymphangiectasia-lymphedema syndrome 1 only. It is designed to support knowledge-base curation while clearly flagging where identifiers or conclusions require verification or where evidence remains sparse.

1. Disease information

Definition and nomenclature

HKLLS1 is the CCBE1-related subtype of Hennekam syndrome. The broader syndrome is characterized by congenital lymphedema and lymphangiectasia, unusual facial morphology—at least partly attributed to intrauterine facial edema—and variable intellectual disability. The disease was first clinically delineated in 1989; CCBE1 was established as a cause in 2009. A 2018 clinical report stated that fewer than 50 Hennekam cases had then been reported, although that number included genetically heterogeneous Hennekam syndrome rather than CCBE1-confirmed HKLLS1 alone. Approximately 25% of clinically suspected Hennekam cases have been reported to carry CCBE1 variants. These historical estimates should not be interpreted as contemporary population prevalence. (betterman2020atypicalcadherinfat4 pages 1-2, lee2018hennekamsyndromea pages 1-3, melber2018novelmutationin pages 1-2)

Identifiers and synonyms

  • OMIM: 235510, Hennekam lymphangiectasia–lymphedema syndrome 1/Hennekam syndrome. The retrieved literature explicitly associates OMIM 235510 with the CCBE1-related disorder. (betterman2020atypicalcadherinfat4 pages 1-2)
  • MONDO: a subtype-specific MONDO identifier was not securely established from the retrieved primary literature and should be verified against the current MONDO release before ingestion.
  • Orphanet: use the current Orphanet entry for Hennekam syndrome/generalized lymphatic dysplasia; subtype mapping should likewise be verified in the live database.
  • ICD-10/ICD-11: no uniquely specific HKLLS1 code was identified. Coding generally falls under congenital lymphatic malformations or hereditary lymphedema.
  • MeSH: no disease-specific MeSH heading was identified; “Lymphedema,” “Lymphangiectasis,” and “Lymphatic Abnormalities” are appropriate broader concepts.
  • Synonyms include Hennekam syndrome type 1, CCBE1-related Hennekam syndrome, Hennekam lymphangiectasia–lymphedema syndrome, and historically lymphedema–lymphangiectasia–intellectual disability syndrome.

This report synthesizes aggregated disease-level literature plus individual published patients and experimental models. It is not derived from an electronic-health-record cohort.

Important disambiguation: HKLLS1 is distinct from FAT4-related Hennekam syndrome type 2 and ADAMTS3-related type 3. It is also entirely distinct from Menke–Hennekam syndrome, a CREBBP/EP300-associated neurodevelopmental disorder.

2. Etiology, risk, protection, and environment

Causal factor

The primary cause is biallelic germline pathogenic or likely pathogenic variation in CCBE1, usually homozygous or compound heterozygous. CCBE1 encodes a secreted extracellular-matrix-associated protein required for lymphatic development. Disease alleles include missense and truncating/frameshift variants affecting its cysteine-rich, EGF-like, calcium-binding EGF-like, or collagen-repeat regions. (roukens2015functionaldissectionof pages 1-3, melber2018novelmutationin pages 1-2)

No infectious, toxic, dietary, occupational, radiation, smoking, or other lifestyle cause is established. Maternal exposures do not cause the Mendelian disorder. Environmental factors may, however, alter complications: trauma, obesity, immobility, heat, skin injury, or infection can aggravate lymphedema generally, but HKLLS1-specific interaction studies are unavailable.

Risk and protective factors

  • Genetic risk: having two disease-causing CCBE1 alleles. For two confirmed heterozygous parents, the expected risk per pregnancy is 25% affected, 50% carrier, and 25% unaffected/non-carrier.
  • Family history/consanguinity: consanguinity increases the probability that both parents carry the same rare allele, but compound-heterozygous disease also occurs in nonconsanguineous families.
  • Sex: no established sex bias.
  • Modifier genes, protective variants, or protective alleles: none validated.
  • Gene–environment interactions: no formal HKLLS1 G×E evidence.

3. Phenotypic spectrum

The available literature does not provide reliable CCBE1-only percentages for most manifestations. Frequencies below are therefore qualitative unless an explicit statistic is available.

Core lymphatic phenotypes

  • Lymphedema—usually congenital, chronic, and often progressive; limbs, face, and genitalia are common sites. It may be generalized, asymmetric, or occasionally concentrated in one limb. Functional effects include heaviness, restricted motion, impaired mobility or hand use, recurrent skin infection risk, and psychosocial burden. Suggested HPO: HP:0001004 Lymphedema, HP:0009826 Facial edema, and HP:0003577 Congenital onset. (lee2018hennekamsyndromea pages 1-3, melber2018novelmutationin pages 1-2)
  • Intestinal lymphangiectasia can produce protein-losing enteropathy, diarrhea, malabsorption, edema, growth failure, hypoalbuminemia, hypoproteinemia, lymphopenia, and hypogammaglobulinemia. Some radiologically affected patients retain normal protein and albumin, demonstrating variable functional severity. Suggested HPO: HP:0100769 Intestinal lymphangiectasia, HP:0003075 Hypoalbuminemia, HP:0001888 Lymphopenia, and HP:0004313 Hypogammaglobulinemia. (lee2018hennekamsyndromea pages 3-5)
  • Other visceral sites include lungs, pleura, pericardium, mesentery, and kidneys. Pleural or pericardial effusion and congenital pulmonary lymphangiectasia can cause respiratory compromise. (melber2018novelmutationin pages 2-4, lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2)

Craniofacial and neurodevelopmental phenotypes

Reported facial findings include a flat midface, broad/depressed nasal bridge, hypertelorism, epicanthal folds, bulbous nasal tip, small or narrow mouth, low-set or dysplastic ears, smooth philtrum, and dental anomalies. Suggested HPO terms include HP:0012368 Flat face, HP:0000426 Depressed nasal bridge, HP:0000316 Hypertelorism, HP:0000286 Epicanthus, and HP:0000208 Small mouth. (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2)

Development ranges from near-normal to global developmental delay or intellectual disability. Motor, fine-motor, adaptive, and personal-social domains may be affected. Seizures were reported in approximately 33% of the broader historical Hennekam literature, but this is not a reliable CCBE1-specific estimate. Suggested HPO: HP:0001263 Global developmental delay, HP:0001249 Intellectual disability, and HP:0001250 Seizure. (lee2018hennekamsyndromea pages 3-5)

Prenatal and severe presentations

HKLLS1 can present as recurrent nonimmune hydrops fetalis. In one molecularly confirmed family, affected pregnancies manifested at 15–18 weeks with scalp edema, ascites, cystic hygroma, pleural/pericardial effusions, hepatomegaly, and pulmonary hypoplasia. Lymphatic dysplasias account for an estimated 5–15% of nonimmune hydrops generally, and nonimmune hydrops has reported fetal mortality of 50–98%; neither statistic is specific to HKLLS1. Suggested HPO: HP:0001789 Hydrops fetalis, HP:0000473 Cystic hygroma, HP:0001541 Ascites, HP:0005381 Pleural effusion, and HP:0002089 Pulmonary hypoplasia. (melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4)

4. Genetic and molecular information

Gene and inheritance

  • Gene: CCBE1, collagen and calcium-binding EGF domains 1.
  • Origin: constitutional/germline; no somatic disease mechanism is established.
  • Inheritance: autosomal recessive, suggested HPO HP:0000007.
  • Functional class: loss-of-function or hypomorphic alleles impair CCBE1’s lymphangiogenic activity.

A prenatal case carried maternally inherited NM_133459.3:c.683_684insT, p.Leu229fs and paternally inherited c.335C>T, p.Thr112Ile. At publication, the frameshift appeared in 14/277,032 gnomAD chromosomes and p.Thr112Ile in 1/246,160; neither was observed homozygously in the reported data. The first was classified as pathogenic loss-of-function and the second as likely pathogenic on rarity, conservation, domain location, segregation, and computational evidence. (melber2018novelmutationin pages 2-4)

By 2015, nine causal CCBE1 variants had been described in the analyzed literature. Most affected the N-terminal cysteine-rich/EGF regions; two involved collagen repeats. This is historical rather than a complete current ClinVar/HGMD count. No validated modifier gene, epigenetic signature, recurrent chromosomal abnormality, anticipation, or germline-mosaicism rate is known. (roukens2015functionaldissectionof pages 1-3)

5. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic lesion: biallelic CCBE1 dysfunction reduces functional extracellular CCBE1.
  2. Growth-factor processing defect: CCBE1 normally promotes ADAMTS3-mediated proteolytic activation of pro-VEGF-C.
  3. Signaling deficit: reduced mature VEGF-C lowers activation of VEGFR3/FLT4 on lymphatic endothelial cells.
  4. Developmental failure: embryonic lymphatic endothelial progenitors are specified but migrate/sprout inadequately from cardinal veins; lymphatic vessels become sparse, malformed, or functionally insufficient.
  5. Clinical consequences: interstitial-fluid accumulation causes lymphedema; visceral lymphatic dilation/leakage causes intestinal protein loss, effusions, pulmonary disease, and—in severe fetal cases—hydrops. (betterman2020atypicalcadherinfat4 pages 1-2, roukens2015functionaldissectionof pages 1-3)

The domain-dissection study’s abstract states: “deleting the collagen domains of CCBE1 has a much stronger effect on CCBE1 activity than deleting the EGF domains” and concludes that the collagen domains are crucial for VEGF-C activation, whereas EGF domains are needed for full in-vivo lymphangiogenic activity. This is supported by knock-in mice, zebrafish rescue/signaling experiments, and in-vitro VEGF-C processing assays. (roukens2015functionaldissectionof pages 1-3)

Suggested annotations include GO:0001946 lymphangiogenesis, endothelial-cell migration, growth-factor proteolytic processing, VEGF receptor signaling, and extracellular-matrix organization. The principal cell type is the lymphatic endothelial cell; relevant compartments include extracellular space/matrix and the lymphatic endothelial plasma membrane. Downstream VEGFR3 signaling engages PI3K–AKT and MAPK–ERK, but the primary HKLLS1 defect lies upstream at VEGF-C maturation rather than constitutive activation of those pathways.

No reproducible disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or epigenomic patient signature has been established.

6. Anatomy and temporal development

Primary disease resides in the lymphatic vasculature, especially lymphatic capillaries and collecting pathways of limb soft tissue and viscera. Relevant anatomical concepts include lymph vessels, skin/subcutis, small intestine, mesentery, lung, pleura, pericardium, kidney, face, external genitalia, and limbs. Affected edema may be bilateral/generalized or markedly asymmetric. (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2)

Onset is prenatal or congenital in many patients. The course is chronic and lifelong; peripheral edema may progress, whereas visceral manifestations may be stable, intermittent, or severe from birth. There are no validated disease stages. Critical periods include fetal lymphatic development, the neonatal respiratory period in pulmonary disease, and early childhood for nutrition and neurodevelopmental intervention.

7. Epidemiology and population genetics

No reliable prevalence, incidence, carrier-frequency, sex-ratio, or life-table estimate exists for molecularly confirmed HKLLS1. The statement “fewer than 50 cases” in 2018 refers to Hennekam syndrome broadly and reflects ascertainment and publication, not population prevalence. Cases occur across multiple ancestries; no geographically restricted endemic population or robust founder effect is established. Expressivity is markedly variable, while penetrance among individuals carrying two clearly damaging alleles is presumed high but has not been formally quantified. (lee2018hennekamsyndromea pages 1-3)

8. Diagnosis

Clinical and laboratory evaluation

Suspect HKLLS1 with congenital/early lymphedema plus visceral lymphangiectasia, characteristic facial morphology, developmental differences, or unexplained nonimmune hydrops. Evaluation may include:

  • Limb circumference/volume and bioimpedance.
  • Lymphoscintigraphy or other lymphatic imaging; one case showed no visible lymphatic flow in the affected arm.
  • Ultrasound, CT, or MRI to assess intestinal/mesenteric, pulmonary, pleural, pericardial, renal, and CNS involvement.
  • CBC with lymphocyte count; total protein, albumin, immunoglobulins, electrolytes, fat-soluble vitamins, and growth/nutritional status.
  • Stool α1-antitrypsin clearance where protein-losing enteropathy is suspected.
  • Pulmonary and cardiac assessment when effusions or respiratory symptoms occur. (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5)

Molecular testing

A practical sequence is a primary-lymphedema/generalized-lymphatic-dysplasia panel including CCBE1, FAT4, ADAMTS3, FLT4, VEGFC, PIEZO1, EPHB4, FOXC2, GATA2, and other phenotype-driven genes, or trio WES/WGS when presentation is nonspecific. Confirm candidate variants and parental phase by Sanger sequencing or equivalent. Exon-level deletion/duplication analysis should be included if the assay does not detect copy-number variants.

In recurrent fetal hydrops, trio WES diagnosed HKLLS1 after normal karyotype, microarray, infectious studies, hematologic testing, and metabolic evaluation. The report’s key message was: “WES is a useful approach for diagnosing rare single-gene conditions with nonspecific phenotypes and should be considered early in the diagnostic process of investigating fetal abnormalities.” (melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4)

CMA, karyotyping, and FISH do not diagnose typical sequence-level CCBE1 disease, although they may exclude chromosomal differentials. Mitochondrial and repeat-expansion testing are not routinely indicated. No validated RNA, proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic exists.

Differential diagnosis

Key differentials include FAT4- and ADAMTS3-related Hennekam syndromes; PIEZO1-related generalized lymphatic dysplasia; FLT4/VEGFR3- or VEGFC-related primary lymphedema; FOXC2 lymphedema-distichiasis; GATA2 deficiency/Emberger syndrome; EPHB4-related lymphatic anomalies; primary intestinal lymphangiectasia; CD55-deficient CHAPLE syndrome; Noonan-spectrum disorders; chromosomal syndromes; and infectious, cardiac, hematologic, metabolic, or structural causes of fetal hydrops. (betterman2020atypicalcadherinfat4 pages 1-2, melber2018novelmutationin pages 1-2)

There are no universally accepted HKLLS1-specific clinical diagnostic criteria. Molecular confirmation is strongly preferred because Hennekam syndrome is genetically heterogeneous.

9. Outcome and prognosis

Natural-history data, five- or ten-year survival, and life expectancy are unavailable. Prognosis varies with visceral involvement:

  • Hydrops, severe pulmonary lymphangiectasia, pulmonary hypoplasia, or large effusions may be fatal prenatally or neonatally.
  • Intestinal lymphangiectasia can cause chronic malnutrition, immunoglobulin/lymphocyte loss, infection susceptibility, and growth impairment.
  • Chronic limb edema can cause reduced function, tissue fibrosis, recurrent cellulitis, pain or heaviness, and impaired quality of life.
  • Developmental outcome ranges from nearly normal to significant disability.

One review cited in the rehabilitation report noted that pulmonary complications are directly relevant to survival. No validated molecular prognostic biomarker or genotype-based risk calculator exists. (lee2018hennekamsyndromea pages 3-5, melber2018novelmutationin pages 1-2)

10. Treatment and real-world implementation

Lymphedema management

No curative therapy exists. Standard care is complete decongestive therapy, combining compression, exercise, skin care, and usually manual lymph drainage, followed by maintenance garments. In one 28-month-old Hennekam patient, seven sessions—including manual drainage, ≥20-hour/day bandaging, exercise, activities-of-daily-living training, and low-level laser—reduced upper-arm circumference from 22 to 19 cm and forearm circumference from 22.5 to 21 cm. This is disease-specific but only single-patient evidence. (lee2018hennekamsyndromea pages 3-5)

A broader randomized lymphedema trial, NCT01748604, enrolled 194 patients and compared manual drainage plus pneumatic compression and multilayer bandaging with regimens omitting manual drainage. It was not HKLLS1-specific and its registry text does not establish subtype-specific efficacy. (NCT01748604 chunk 1)

Suggested NCIT intervention concepts: physical therapy, manual lymphatic drainage, compression bandaging/garments, exercise therapy, skin care, and intermittent pneumatic compression.

Visceral and supportive management

Protein-losing enteropathy is managed with a high-protein, low-fat diet enriched in medium-chain triglycerides, with replacement of vitamins, minerals, albumin, or immunoglobulin when clinically indicated. Respiratory effusions, chylothorax, infection, seizures, dental problems, developmental delay, and feeding difficulties require organ-specific care. Surgery is reserved for severe, function-limiting lymphedema refractory to conservative management; no controlled HKLLS1 surgical series exists. (lee2018hennekamsyndromea pages 3-5)

There is no approved CCBE1 replacement, VEGF-C therapy, gene therapy, RNA therapy, cell therapy, or pharmacogenomic algorithm. Although VEGF-C/VEGFR3 biology is an attractive target, augmenting lymphangiogenesis in humans raises safety and delivery concerns and remains experimental.

Trials and 2023–2024 developments

No HKLLS1-specific interventional trial was found. A 2024 study of aerobic exercise in primary lower-extremity lymphedema, NCT06327412, planned 35 adults and assessed limb volume, function, VO₂max, and quality of life; its registry status was unknown and it was not genotype-specific. It therefore cannot be taken as evidence of efficacy in HKLLS1. (NCT06327412 chunk 1)

Recent 2023–2024 research has refined the broader VEGFR3 signaling and lymphatic-development framework, but no disease-specific therapeutic breakthrough, large natural-history cohort, or prospective treatment trial was identified. The most authoritative mechanistic interpretation remains that CCBE1 and ADAMTS3 regulate VEGF-C activation upstream of VEGFR3.

11. Prevention

Because HKLLS1 is inherited, lifestyle-based primary prevention is not available. Prevention focuses on:

  • Genetic counseling and cascade testing after identifying familial variants.
  • Carrier testing of reproductive partners or at-risk adult relatives.
  • Prenatal diagnosis by chorionic-villus sampling or amniocentesis for known familial variants.
  • Preimplantation genetic testing for monogenic disease where desired and legally available.
  • Early fetal imaging in at-risk pregnancies, recognizing that a normal early scan does not exclude disease.
  • Tertiary prevention through compression, meticulous skin care, prompt treatment of cellulitis, nutritional surveillance, and developmental intervention.

No vaccine, medication, or environmental intervention prevents the underlying disorder.

12. Other species and model organisms

No well-established naturally occurring veterinary counterpart was identified, and the disorder is not infectious or zoonotic.

Zebrafish

Loss of ccbe1 disrupts lymphovenous sprouting from the cardinal vein, formation of parachordal lymphangioblasts, and major lymphatic vessels. Zebrafish provide rapid in-vivo assays of VEGF-C signaling and variant/domain rescue. Their principal limitation is that they do not reproduce the full human craniofacial, cognitive, intestinal, and chronic edema phenotype. (schultemerker2011lymphaticvascularmorphogenesis pages 7-9, roukens2015functionaldissectionof pages 1-3)

Mouse

Ccbe1-null embryos specify PROX1-positive lymphatic progenitors but fail to achieve normal migration and lymphatic-network formation. Mice lacking CCBE1 collagen domains phenocopy knockout animals, whereas deletion of EGF domains permits rudimentary lymphatics. These models strongly support developmental causality but severe embryonic phenotypes limit long-term treatment studies. (roukens2015functionaldissectionof pages 1-3)

In-vitro systems

VEGF-C-processing assays show that CCBE1’s collagen domains are required to enhance ADAMTS3-mediated VEGF-C activation. Human lymphatic endothelial cells are appropriate for downstream signaling and migration studies, although no validated HKLLS1 patient-derived organoid or iPSC platform was identified. (roukens2015functionaldissectionof pages 1-3)

13. Evidence limitations and expert assessment

The evidence base is constrained by extreme rarity, genetic heterogeneity, historical grouping of CCBE1-, FAT4-, ADAMTS3-, and genetically unresolved cases, and publication bias toward severe or unusual presentations. Consequently, syndrome-wide percentages should not automatically be assigned to HKLLS1. Current expert interpretation supports a high-confidence causal chain from biallelic CCBE1 dysfunction to deficient VEGF-C activation and developmental lymphatic failure, but clinical genotype–phenotype prediction remains weak. Priority research needs are an international molecular registry, longitudinal natural-history and quality-of-life studies, standardized outcome measures, systematic ClinVar/functional curation, and genotype-specific therapeutic development.

Key publications and URLs

  1. Alders M, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature Genetics. December 2009;41:1272–1274. PMID: 19935664. https://doi.org/10.1038/ng.484. This is the landmark human gene-discovery study cited by subsequent clinical literature. (lee2018hennekamsyndromea pages 3-5)
  2. Roukens MG, et al. Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain. Circulation Research. May 2015;116:1660–1669. https://doi.org/10.1161/CIRCRESAHA.116.304949. (roukens2015functionaldissectionof pages 1-3)
  3. Lee YG, et al. Hennekam Syndrome: A Case Report. Annals of Rehabilitation Medicine. February 2018;42:184–188. https://doi.org/10.5535/arm.2018.42.1.184. (lee2018hennekamsyndromea pages 1-3, lee2018hennekamsyndromea pages 3-5)
  4. Melber DJ, et al. Novel mutation in CCBE1 as a cause of recurrent hydrops fetalis from Hennekam lymphangiectasia-lymphedema syndrome-1. Clinical Case Reports. Published October 2018;6:2358–2363. https://doi.org/10.1002/ccr3.1804. (melber2018novelmutationin pages 1-2, melber2018novelmutationin pages 2-4)
  5. Betterman KL, et al. Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. Journal of Clinical Investigation. Published May 18, 2020;130:3315–3328. https://doi.org/10.1172/JCI99027. Although centered on FAT4, it authoritatively contextualizes the CCBE1–ADAMTS3–VEGF-C/VEGFR3 axis and distinguishes Hennekam genetic subtypes. (betterman2020atypicalcadherinfat4 pages 1-2)
  6. ClinicalTrials.gov. NCT01748604: Physical Therapies in the Decongestive Treatment of Lymphedema. First posted December 12, 2012. https://clinicaltrials.gov/study/NCT01748604. (NCT01748604 chunk 1)
  7. ClinicalTrials.gov. NCT06327412: Effects of Aerobic Exercise in Primary Lower Extremity Lymphedema. First posted March 25, 2024. https://clinicaltrials.gov/study/NCT06327412. (NCT06327412 chunk 1)

References

  1. (roukens2015functionaldissectionof pages 1-3): M. Guy Roukens, Josi Peterson-Maduro, Yvonne Padberg, Michael Jeltsch, Veli-Matti Leppänen, Frank L. Bos, Kari Alitalo, Stefan Schulte-Merker, and Dörte Schulte. Functional dissection of the ccbe1 protein: a crucial requirement for the collagen repeat domain. Circulation Research, 116:1660-1669, May 2015. URL: https://doi.org/10.1161/circresaha.116.304949, doi:10.1161/circresaha.116.304949. This article has 72 citations and is from a highest quality peer-reviewed journal.

  2. (lee2018hennekamsyndromea pages 1-3): Yeong Guk Lee, Seung Chan Kim, Si-Bog Park, and Mi Jung Kim. Hennekam syndrome: a case report. Annals of Rehabilitation Medicine, 42:184-188, Feb 2018. URL: https://doi.org/10.5535/arm.2018.42.1.184, doi:10.5535/arm.2018.42.1.184. This article has 11 citations.

  3. (melber2018novelmutationin pages 1-2): Dora J. Melber, Tara S. Andreasen, Rong Mao, Tatiana Tvrdik, Christine E. Miller, Thomas R. Moore, Douglas A. Woelkers, and Leah M. Lamale‐Smith. Novel mutation in ccbe 1 as a cause of recurrent hydrops fetalis from hennekam lymphangiectasia‐lymphedema syndrome‐1. Clinical Case Reports, 6:2358-2363, Oct 2018. URL: https://doi.org/10.1002/ccr3.1804, doi:10.1002/ccr3.1804. This article has 7 citations.

  4. (melber2018novelmutationin pages 2-4): Dora J. Melber, Tara S. Andreasen, Rong Mao, Tatiana Tvrdik, Christine E. Miller, Thomas R. Moore, Douglas A. Woelkers, and Leah M. Lamale‐Smith. Novel mutation in ccbe 1 as a cause of recurrent hydrops fetalis from hennekam lymphangiectasia‐lymphedema syndrome‐1. Clinical Case Reports, 6:2358-2363, Oct 2018. URL: https://doi.org/10.1002/ccr3.1804, doi:10.1002/ccr3.1804. This article has 7 citations.

  5. (lee2018hennekamsyndromea pages 3-5): Yeong Guk Lee, Seung Chan Kim, Si-Bog Park, and Mi Jung Kim. Hennekam syndrome: a case report. Annals of Rehabilitation Medicine, 42:184-188, Feb 2018. URL: https://doi.org/10.5535/arm.2018.42.1.184, doi:10.5535/arm.2018.42.1.184. This article has 11 citations.

  6. (betterman2020atypicalcadherinfat4 pages 1-2): Kelly L. Betterman, Drew L. Sutton, Genevieve A. Secker, Jan Kazenwadel, Anna Oszmiana, Lillian Lim, Naoyuki Miura, Lydia Sorokin, Benjamin M. Hogan, Mark L. Kahn, Helen McNeill, and Natasha L. Harvey. Atypical cadherin fat4 orchestrates lymphatic endothelial cell polarity in response to flow. Journal of Clinical Investigation, 130:3315-3328, May 2020. URL: https://doi.org/10.1172/jci99027, doi:10.1172/jci99027. This article has 71 citations and is from a highest quality peer-reviewed journal.

  7. (NCT06327412 chunk 1): Havva Talay Çalış. The Effects of Aerobic Exercise in Patients With Primary Lower Extremity Lymphedema. Kayseri City Hospital. 2024. ClinicalTrials.gov Identifier: NCT06327412

  8. (NCT01748604 chunk 1): Isabel Forner-Cordero, MD, PhD.. Physical Therapies in the Decongestive Treatment of Lymphedema. Isabel Forner-Cordero, MD, PhD.. 2004. ClinicalTrials.gov Identifier: NCT01748604

  9. (schultemerker2011lymphaticvascularmorphogenesis pages 7-9): Stefan Schulte-Merker, Amélie Sabine, and Tatiana V. Petrova. Lymphatic vascular morphogenesis in development, physiology, and disease. Jun 2011. URL: https://doi.org/10.1084/jem2086oia15, doi:10.1084/jem2086oia15. This article has 532 citations.

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