Mandibulofacial Dysostosis with Alopecia

🏷

Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0014608 mandibulofacial dysostosis with alopecia

Primary MONDO disease identifier for this mandibulofacial dysostosis with alopecia entry.

👪

Inheritance

1

Autosomal dominant (de novo) HP:0000006

Reported cases arise from de novo heterozygous missense variants and the condition appears to be inherited in an autosomal dominant fashion. One reported individual carried the p.Glu303Lys substitution in somatic mosaic form and had previously been diagnosed as Johnson-McMillin syndrome, so mosaicism should be considered when the phenotype is atypical or asymmetric.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:32133772 SUPPORT Human Clinical

"results from gain-of-function variants in EDNRA and appears to be inherited in an autosomal dominant fashion"

States both the gain-of-function mechanism and the autosomal dominant inheritance pattern of MFDA.

PMID:25772936 SUPPORT Human Clinical

"The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome."

Documents the somatic mosaic case and its earlier alternative diagnosis.

?

Discussions and Knowledge Gaps

2

Why does a mouse carrying the exact homologous Ednra Y129F substitution reproduce the entire craniofacial and ossicular phenotype but not the scalp-patterned alopecia that names the human syndrome?

HUMAN MODEL MISMATCH OPEN mismatch_mfda_mouse_nonskeletal_features

Attached to

phenotypes#Alopecia phenotypes#Cleft Palate pathophysiology#Multi-Element First and Second Arch Malformation

This is a model-fidelity question rather than an absence of evidence: the knock-in carries the identical residue change, was phenotyped through a standardized pipeline, and positively reproduces the skeletal arm — so the negative result on alopecia is informative rather than uninformative. It is also the one non-skeletal negative that holds across both independently generated models, which is why the mismatch is framed on alopecia alone. Two readings are open. Either endothelin signalling has a role in human hair follicle development that the mouse does not share, in which case the model is simply silent on the human syndrome's most diagnostic feature; or the relevant murine tissue is not sensitised under standard husbandry — murine hair cycling is synchronised and stage-dependent, so a follicular defect could be masked by the sampling stage. The distinction determines whether this mouse can be used at all for preclinical work on the alopecia, which is the feature patients present with. Deliberately excluded from the mismatch: eyelid defects. The ENU Y129F line was reported free of them, but the CRISPR knock-ins of both MFDA alleles show open eyelids at birth and periocular skin erosion, so there is no cross-model murine negative to set against the human lower eyelid coloboma. The two reports may genuinely disagree, or the lines may differ in background or construction; either way a blanket "the mouse has no eyelid phenotype" is not supportable and is not asserted here. Cleft palate is retained in attaches_to on its own footing: the human phenotype now has a primary clinical source, and the ENU Y129F line is explicitly reported free of cleft palate, so this is a genuine cross-species negative rather than a placeholder for a missing citation. It is not folded into the framing above because it rests on the single ENU report, whereas the alopecia negative holds across both models.

Proposed experiments

Hair-cycle-staged and tissue-conditional phenotyping of Ednra Y129F mice

exp_mfda_mouse_hair_cycle_staged_phenotyping

Re-phenotype the Ednra Y129F mouse for follicular morphology across defined anagen/catagen/telogen stages rather than at a single timepoint, and in parallel generate a skin-restricted conditional allele to test whether local expression is sufficient. Map Edn3 availability in murine versus human scalp dermis at the corresponding stage. A staged defect would rescue the model for preclinical use; a flat negative across all stages with confirmed local expression would establish a genuine species difference and redirect work to human follicle systems.

By what mechanism does an EDNRA gain-of-function variant cause scalp alopecia, a phenotype outside the pharyngeal arch skeleton and absent from the knock-in mouse?

KNOWLEDGE GAP OPEN gap_mfda_alopecia_mechanism

Attached to

phenotypes#Alopecia phenotypes#Generalized Hypopigmentation pathophysiology#Multi-Element First and Second Arch Malformation

Alopecia is the feature that names the syndrome and distinguishes it from auriculocondylar syndrome and oro-oto-cardiac syndrome, yet it has no mechanistic account. Hair follicles are not pharyngeal arch derivatives, so the serial-homology module that explains the craniofacial phenotype does not reach it. The Ednra Y129F mouse reproduces the entire skeletal phenotype but shows no alopecia, and neither does the E303K knock-in, so the models offer no route in. Two possibilities are open: the endothelin axis has a direct role in human hair follicle or follicular neural-crest-derived melanocyte biology that the mouse does not share, or the alopecia is secondary to a shared upstream neural crest defect that the skeletal readout happens to capture more sensitively. Nothing in the current literature distinguishes them, but the generalized hypopigmentation curated in the p.Glu303Lys patient is the one observation that bears on the choice: a pigmentary phenotype in the same patient is what the melanocyte-lineage reading predicts, and it is a reason to look at follicular melanocytes rather than at receptor pharmacology alone.

Proposed experiments

EDNRA/EDN3 expression and signalling in human scalp follicle at the relevant developmental stage

exp_mfda_ednra_scalp_follicle_expression_and_signalling

Map EDNRA and EDN3 expression across human embryonic and fetal scalp, distinguishing follicular epithelium, dermal papilla and neural-crest-derived follicular melanocytes, and test whether the MFDA variants alter endothelin-3-driven signalling in follicle-derived cells using the same BRET and pharmacological assays already applied to the craniofacial phenotype. A positive result would place alopecia on a direct EDNRA arm; a negative result would redirect attention to a shared upstream neural crest defect and would specifically motivate lineage tracing rather than further receptor pharmacology.

⚙

Pathophysiology

4

EDNRA Gain-of-Function Variant

Two recurrent de novo missense substitutions in EDNRA cause MFDA. Neither sits in the orthosteric ligand-binding site; both act allosterically. Tyr129 is the residue that normally enforces ETAR selectivity for endothelin 1 over endothelin 3, and p.Tyr129Phe raises affinity for endothelin 3 by two orders of magnitude by disrupting the sodium-water network beneath the binding pocket. Glu303 lies at the intracellular end of transmembrane helix 6, and p.Glu303Lys increases the flexibility of that helix, favouring G protein binding and thereby enhancing agonist affinity from the cytoplasmic side. The two variants thus converge on the same functional outcome — enhanced endothelin 3 responsiveness — by structurally opposite routes.

EDNRA hgnc:3179

endothelin receptor type A (ETAR) activity GO:0004962 ⇑ GAIN OF FUNCTION

Downstream

Ectopic ETAR Activation in the Maxillary Prominence Enhanced endothelin 3 responsiveness activates ETAR in a territory where endothelin 1 is not normally available to signal.

Show evidence (3 references)

PMID:25772936 SUPPORT In Vitro

"Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude."

Quantifies the ligand-selectivity shift that is the proximate molecular consequence of the commonest MFDA variant.

PMID:36637912 SUPPORT In Vitro

"Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3."

Direct pharmacological confirmation that both variants are gain of function and that the gain is endothelin-3 dependent.

PMID:36637912 SUPPORT Computational

"E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein-mediated enhancement of agonist affinity."

Molecular dynamics simulation providing the structural mechanism for the p.Glu303Lys allosteric gain of function.

Ectopic ETAR Activation in the Maxillary Prominence

In normal craniofacial development endothelin 1 is secreted by the epithelium and core mesoderm of the ventral pharyngeal arch and acts on ETAR-expressing cranial neural crest cells, establishing mandibular identity ventrally while the dorsal (maxillary) territory remains ETAR-unstimulated. A receptor that now responds to endothelin 3 is activated in the maxillary prominence, where endothelin 3 is available but endothelin 1 is not. Genetic rescue makes the dependency explicit: deleting Edn3 in the knock-in mice abolishes the craniofacial transformation.

cranial neural crest cell CL:0000008

G protein-coupled receptor signaling pathway GO:0007186 ↑ INCREASED

Animal models

Ednra E303K knock-in mouse Mouse recapitulates Both knock-in alleles produce a partial maxillary-to-mandibular transformation, and crossing onto an Edn3-null background rescues it. This is the genetic epistasis experiment that identifies ectopic endothelin-3-driven ETAR activation as the operative mechanism rather than an inferred one.

Downstream

Maxillary-to-Mandibular Homeotic Transformation Imposing the ETAR-dependent ventral identity program on maxillary neural crest respecifies upper-jaw skeletal elements toward lower-jaw identity.

Show evidence (2 references)

PMID:36637912 SUPPORT Model Organism

"Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3)."

The Edn3 deletion rescue is the decisive experiment showing that the pathology depends on ectopic endothelin-3-driven ETAR activation.

PMID:36637912 SUPPORT Model Organism

"In craniofacial development, ET1 is secreted from the epithelium and core mesoderm in the ventral domain of the pharyngeal arches (PAs) to act on ETAR-expressing migrating cranial NCCs"

Establishes the normal spatial restriction of endothelin-1-to-ETAR signalling that the MFDA variants violate.

Maxillary-to-Mandibular Homeotic Transformation

ETAR signalling in cranial neural crest acts through the Dlx5/Dlx6 code that assigns ventral (mandibular) identity within the first arch. Ectopic activation in the dorsal territory drives upper-jaw skeletal elements toward a lower-jaw program, giving the partial maxillary-to-mandibular transformation seen in the knock-in mice. The human radiographic correlate is a zygomatic arch that resembles that of mice with experimentally induced ectopic maxillary ETAR activation, together with absent temporomandibular joints, flattened condyles and a thickened malar bone. Note that MFDA is not a pure gain: the reported functional consequences are complex and territory-dependent, with the upper jaw showing aberrant ETAR signalling while the lower jaw appears to show disrupted signalling. That dual character is what makes the phenotype a dysostosis with micrognathia rather than a straightforward duplication of the mandible.

regionalization GO:0003002 ⚠ ABNORMAL embryonic skeletal system morphogenesis GO:0048704 ⚠ ABNORMAL

Downstream

Multi-Element First and Second Arch Malformation The respecified arch program produces a coordinated malformation across the serially related skeletal derivatives of the first and second arches.

Show evidence (4 references)

PMID:25772936 SUPPORT Human Clinical

"The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation"

Anchors the human skeletal phenotype to the experimental ectopic-activation model and names the direction of the transformation.

PMID:36637912 SUPPORT Model Organism

"the expression of Dlx5 and Dlx6, homeobox transcription factors that act downstream of ET1-ETAR signaling to determine ventral identity in PA1, extended dorsally in mutant embryos (Figure 2M). These results suggest that the Ednra mutations had an ectopic gain-of-function effect in the dorsal PA1"

Direct, same-direction evidence for this node: in embryos carrying the MFDA alleles themselves (Ednra Y129F and E303K), the Dlx5/Dlx6 ventral-identity code expands dorsally, which the authors read as an ectopic gain of function in dorsal PA1. This is the dorsal respecification the node asserts, measured in the MFDA genotype rather than inferred from the reciprocal knockout.

PMID:15110048 SUPPORT Model Organism

"the expression of Dlx5 and Dlx6, Distalless-related homeobox genes determining the ventral identity of the anterior branchial arches, and of the mandibular marker gene Pitx1 is significantly downregulated in the ET-1(-/-) mutant"

Establishes that Dlx5/Dlx6 ventral identity is endothelin-dependent at all, via the reciprocal loss-of-function experiment. Retained as axis-defining background only; the direction-matched claim for MFDA rests on the PMID:36637912 item above.

+ 1 more reference

Multi-Element First and Second Arch Malformation

The clinical phenotype is a coordinated malformation across serially related arch derivatives rather than an isolated defect: mandible, maxilla, malar and zygomatic bone, temporomandibular joint, external ear and middle-ear ossicles are all involved. This is the serial-homology signature the module encodes. Alopecia and the eyelid and palatal defects sit outside that skeletal pattern and are not explained by it.

Animal models

Ednra Y129F knock-in mouse Mouse partially recapitulates The mouse reproduces the full skeletal arch-derivative phenotype — jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, absent squamosal zygomatic process, ossicular abnormality with hearing impairment — but none of the non-skeletal features.

Ednra Y129F knock-in mouse Mouse fails to recapitulate This ENU line does not reproduce the alopecia, cleft palate or eyelid defects that are part of the human syndrome. Recorded as an explicit negative claim rather than left as a caveat in prose. Alopecia is the durable part of that negative: it is absent from both independently generated mouse models and the authors state the species difference directly. The eyelid half does not generalize beyond this line, because the CRISPR knock-ins do show ocular adnexal abnormalities.

Show evidence (2 references)

PMID:27671791 SUPPORT Model Organism

"Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals."

Enumerates the multi-element arch-derivative phenotype shared by the mouse model and MFDA patients.

PMID:27671791 SUPPORT Model Organism

"mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles"

Extends the malformation to the middle-ear ossicles, second-arch derivatives, and links them to the hearing phenotype.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Ear 1

Conductive Hearing Impairment HP:0000405

Show evidence (3 references)

PMID:36637912 SUPPORT Human Clinical

"She has hearing aids for conductive hearing loss"

Names the conductive classification directly in a molecularly confirmed MFDA patient, so the bound HP term is supported by a human audiological statement rather than inferred from ossicular localisation in the model.

PMID:36637912 SUPPORT Human Clinical

"CT scans also showed abnormalities of the middle ear, including hypoplasia of the long process of the incus"

Supplies the human ossicular lesion that accounts for the conductive mechanism, in the same patient.

PMID:27671791 SUPPORT Model Organism

"As observed in MFDA-affected individuals, mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles"

Corroborates the ossicular basis of the hearing impairment in the model. PARTIAL because the mouse data do not themselves classify the loss as conductive; the human quotes above carry that claim.

Head and Neck 2

Mandibular Hypoplasia Micrognathia HP:0000347

Show evidence (2 references)

PMID:36637912 SUPPORT Human Clinical

"the mandible (especially the proximal region) is more dysplastic in patients with MFDA than the mutant mice"

Human primary support for mandibular dysplasia, and for it being more severe in patients than in the model. PARTIAL rather than SUPPORT because the sentence establishes mandibular dysplasia without itself naming micrognathia, which is the bound HP term.

PMID:27671791 SUPPORT Model Organism

"Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints"

The mouse model reproduces micrognathia as described for MFDA-affected individuals. Corroborating rather than sole support, since the human statement above now carries the phenotype.

Cleft Palate HP:0000175

Show evidence (1 reference)

PMID:20583178 SUPPORT Human Clinical

"We describe a patient with a phenotype characterized by mandibulofacial dysostosis with severe lower eyelid coloboma, cleft palate, abnormal ears, alopecia, delayed eruption and crowded teeth, and sensorioneural hearing loss."

Human observation of cleft palate in a patient with the MFDA phenotype, replacing the mouse-negative snippet this phenotype previously had no valid support for. PARTIAL because the 2010 report predates the identification of EDNRA as the MFDA gene: it is a clinical delineation of the tetrad in a TCOF1-negative patient, not a molecularly confirmed EDNRA case.

Integument 2

Alopecia HP:0001596

Show evidence (2 references)

PMID:36637912 SUPPORT Human Clinical

"sparse scalp hair with persistent frontal balding"

Direct human observation of the scalp phenotype in a molecularly confirmed MFDA patient (8%-11% mosaic EDNRA p.E303K), so the phenotype no longer rests on model-organism evidence alone.

PMID:27671791 SUPPORT Model Organism

"without showing any cleft palates, eyelid defects, or alopecia"

Secondary, and deliberately not the primary support: this records the absence of alopecia in the otherwise faithful mouse, so it evidences the human/mouse discordance rather than the human phenotype itself.

Generalized Hypopigmentation HP:0007513

Show evidence (1 reference)

PMID:36637912 SUPPORT Human Clinical

"generalized hypopigmentation compared with first degree relatives"

Direct human observation of the pigmentary phenotype, with first-degree relatives as the stated comparator.

Other 4

Temporomandibular Joint Dysplasia Abnormality of the temporomandibular joint HP:0010754

Show evidence (1 reference)

PMID:36637912 SUPPORT Human Clinical

"Patients with the p.Y129F mutation have no temporomandibular joints, flattened condyles, and a thickened malar bone"

Directly describes the temporomandibular joint and condylar phenotype in p.Tyr129Phe patients.

Malar and Zygomatic Anomaly Abnormal zygomatic bone morphology HP:0010668

Show evidence (1 reference)

PMID:36637912 SUPPORT Human Clinical

"flattened condyles, and a thickened malar bone, highly reminiscent of mice with ectopic ETAR activation in the upper jaw"

Documents the malar bone abnormality in patients. The bound HP term is direction-neutral, so it accommodates the reported thickening; PARTIAL because this quote covers the thickened malar bone but not the absent squamosal zygomatic process also asserted in the description.

External Ear Anomaly Abnormality of the outer ear HP:0000356

Show evidence (2 references)

PMID:36637912 SUPPORT Human Clinical

"We investigated a girl presenting with symmetrical dysplastic ears"

Direct human observation of auricular dysmorphism in the molecularly confirmed EDNRA p.Glu303Lys mosaic patient, so the phenotype no longer rests on model-organism evidence alone.

PMID:27671791 SUPPORT Model Organism

"dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals"

Auricular dysmorphism is listed among the features described for MFDA-affected individuals and reproduced in the model.

Lower Eyelid Coloboma HP:0000652

Show evidence (1 reference)

PMID:36637912 SUPPORT Human Clinical

"asymmetric lower eyelid coloboma that required surgery on the right side"

Direct human observation of the eyelid defect in a molecularly confirmed MFDA patient.

🧬

Genetic Associations

1

EDNRA (Causative)

Gene: EDNRA hgnc:3179

Show evidence (3 references)

PMID:25772936 SUPPORT Human Clinical

"Three of the four individuals have the same substitution, p.Tyr129Phe."

Establishes p.Tyr129Phe as the recurrent MFDA allele in the founding cohort.

PMID:36637912 SUPPORT Human Clinical

"we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F"

Establishes p.Glu303Lys as the second recurrent MFDA allele with a concordant craniofacial phenotype.

PMID:32133772 SUPPORT Human Clinical

"This homozygous variant is thus the first reported loss-of-function EDNRA allele, resulting in a syndrome we have named Oro-Oto-Cardiac Syndrome."

Documents the opposite-direction EDNRA allele and its distinct disease, supporting the allelic-series caveat in these notes.

🗃️

External Assertions

1

OMIM mandibulofacial dysostosis with alopecia

OMIM disease record OMIM:616367

OMIM phenotype entry for MFDA, the EDNRA gain-of-function craniofacial dysostosis syndrome.

📊

Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

MFDA is exceptionally rare. The defining 2015 report described four unrelated individuals, and a fifth patient with the p.Glu303Lys variant was characterized in detail in 2023.

Show evidence (1 reference)

PMID:25772936 SUPPORT Human Clinical

"We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA)"

The founding cohort of four unrelated individuals establishes the extreme rarity of the condition.

🐁

Animal Models

2

Ednra Y129F knock-in mouse

A viable dominant mouse carrying the exact human MFDA substitution, recovered from an ENU mutagenesis programme and phenotyped through the German Mouse Clinic pipeline. Its viability is itself informative: Ednra-null mice die neonatally from mechanical asphyxia, so a viable point-mutant supports the inference that MFDA retains substantial EDNRA signalling.

Species

Mouse

Genotype

Ednra c.386A>T (p.Tyr129Phe), heterozygous and homozygous

Publication

PMID:27671791

Pathograph links

Multi-Element First and Second Arch Malformation partially recapitulates fidelity: moderate The mouse reproduces the full skeletal arch-derivative phenotype — jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, absent squamosal zygomatic process, ossicular abnormality with hearing impairment — but none of the non-skeletal features.

Limitations: Neither heterozygous nor homozygous mutants of this ENU line show cleft palate, eyelid defects or alopecia, so the model cannot be used to investigate the syndrome's named feature. Scope the eyelid half of that negative to this line: the separately generated CRISPR knock-ins reported in PMID:36637912 do show ocular adnexal abnormalities, so "the mouse has no eyelid phenotype" is not a claim this entry makes. Expressivity also varies between individual mice, as it does between patients, which limits its use for quantitative genotype-phenotype work.

Readouts

Craniofacial skeletal phenotype

Direction: ALTERED

Interpretation: Standardized craniofacial phenotyping reproduces the human arch-derivative malformation set.

Show evidence (1 reference)

PMID:27671791 SUPPORT Model Organism

"Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals."

Reports the craniofacial features scored in the model.

Show evidence (1 reference)

PMID:27671791 SUPPORT Model Organism

"Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches"

Supports the model as informative for the first- and second-arch malformation node specifically.

Multi-Element First and Second Arch Malformation fails to recapitulate fidelity: low This ENU line does not reproduce the alopecia, cleft palate or eyelid defects that are part of the human syndrome. Recorded as an explicit negative claim rather than left as a caveat in prose. Alopecia is the durable part of that negative: it is absent from both independently generated mouse models and the authors state the species difference directly. The eyelid half does not generalize beyond this line, because the CRISPR knock-ins do show ocular adnexal abnormalities.

Limitations: The failure may reflect a genuine species difference in an endothelin-dependent process outside the arch skeleton, or simply that the relevant tissue is not sensitised in the mouse; the study does not discriminate. Either way the model must not be used as evidence that alopecia is not part of MFDA.

Show evidence (2 references)

PMID:27671791 SUPPORT Model Organism

"without showing any cleft palates, eyelid defects, or alopecia"

Direct statement of the features this ENU line fails to reproduce.

+ 1 more reference

Ednra E303K knock-in mouse

Knock-in mouse for the second MFDA allele, used together with the Y129F model and an Edn3 cross to establish ligand dependence.

Species

Mouse

Genotype

Ednra p.Glu303Lys knock-in

Publication

PMID:36637912

Pathograph links

Ectopic ETAR Activation in the Maxillary Prominence recapitulates fidelity: high Both knock-in alleles produce a partial maxillary-to-mandibular transformation, and crossing onto an Edn3-null background rescues it. This is the genetic epistasis experiment that identifies ectopic endothelin-3-driven ETAR activation as the operative mechanism rather than an inferred one.

Limitations: The rescue establishes ligand dependence in the mouse; the endothelin 3 expression domain in the human maxillary prominence has not been mapped directly, so the spatial premise is transferred from mouse rather than demonstrated in human tissue.

Readouts

Maxillary-to-mandibular transformation, Edn3-dependent

Direction: ABOLISHED

Interpretation: The transformation is abolished when Edn3 is deleted, establishing that the phenotype requires the non-preferred ligand.

Show evidence (1 reference)

PMID:36637912 SUPPORT Model Organism

"which was rescued by deleting the ligand endothelin 3 (ET3/EDN3)"

Reports the Edn3-deletion rescue result.

Show evidence (1 reference)

PMID:36637912 SUPPORT Model Organism

"Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation"

Establishes that both MFDA alleles produce the transformation in vivo.

{ }

Source YAML

click to show

name: Mandibulofacial Dysostosis with Alopecia
creation_date: "2026-08-20T00:00:00Z"
category: Mendelian
description: >-
  Mandibulofacial dysostosis with alopecia (MFDA) is a rare craniofacial
  neurocristopathy caused by de novo heterozygous missense variants in EDNRA,
  which encodes the endothelin receptor type A (ETAR), a class A G
  protein-coupled receptor expressed on migrating cranial neural crest cells.
  Affected individuals have malar and mandibular hypoplasia, absent or dysplastic
  temporomandibular joints with flattened condyles, a thickened malar bone with
  loss of the squamosal zygomatic process, external-ear anomalies with conductive
  hearing loss, cleft palate, eyelid defects, and a distinctive scalp alopecia.
  Two recurrent variants account for the reported cases, p.Tyr129Phe and
  p.Glu303Lys; both act allosterically to increase receptor affinity for
  endothelin 3, its normally non-preferred ligand, and both behave
  pharmacologically as gain of function.
  The mechanistic signature of MFDA is a partial maxillary-to-mandibular homeotic
  transformation: ectopic ETAR activation in the maxillary prominence imposes a
  lower-jaw identity on upper-jaw skeletal elements. This is the exact inverse of
  auriculocondylar syndrome, in which loss of EDN1-EDNRA signalling transforms the
  mandible toward a maxillary identity. MFDA and auriculocondylar syndrome are
  therefore opposite-direction lesions of one arch-patterning axis, and are
  modelled here as separate diseases rather than as variants of a common entry.
  Unlike Ednra-null mice, MFDA patients have no cardiovascular malformations,
  which indicates that substantial EDNRA signalling is retained.
parents:
- Genetic Disease
disease_term:
  preferred_term: mandibulofacial dysostosis with alopecia
  term:
    id: MONDO:0014608
    label: mandibulofacial dysostosis with alopecia
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014608
      label: mandibulofacial dysostosis with alopecia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease identifier for this mandibulofacial dysostosis with
      alopecia entry.
external_assertions:
- name: OMIM mandibulofacial dysostosis with alopecia
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:616367
  description: >-
    OMIM phenotype entry for MFDA, the EDNRA gain-of-function craniofacial
    dysostosis syndrome.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:25772936
      reference_title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA."
      explanation: >-
        MFDA is a single-gene disorder caused by de novo EDNRA missense variants,
        supporting classification under genetics.
inheritance:
- name: Autosomal dominant (de novo)
  description: >-
    Reported cases arise from de novo heterozygous missense variants and the
    condition appears to be inherited in an autosomal dominant fashion. One
    reported individual carried the p.Glu303Lys substitution in somatic mosaic
    form and had previously been diagnosed as Johnson-McMillin syndrome, so
    mosaicism should be considered when the phenotype is atypical or asymmetric.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:32133772
    reference_title: "Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "results from gain-of-function variants in EDNRA and appears to be inherited in an autosomal dominant fashion"
    explanation: >-
      States both the gain-of-function mechanism and the autosomal dominant
      inheritance pattern of MFDA.
  - reference: PMID:25772936
    reference_title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome."
    explanation: >-
      Documents the somatic mosaic case and its earlier alternative diagnosis.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    MFDA is exceptionally rare. The defining 2015 report described four unrelated
    individuals, and a fifth patient with the p.Glu303Lys variant was
    characterized in detail in 2023.
  evidence:
  - reference: PMID:25772936
    reference_title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA)"
    explanation: >-
      The founding cohort of four unrelated individuals establishes the extreme
      rarity of the condition.
pathophysiology:
- name: EDNRA Gain-of-Function Variant
  biological_scale: MOLECULAR
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Cranial Neural Crest and Pharyngeal Arch Program Perturbation"
  description: >
    Two recurrent de novo missense substitutions in EDNRA cause MFDA. Neither sits
    in the orthosteric ligand-binding site; both act allosterically. Tyr129 is the
    residue that normally enforces ETAR selectivity for endothelin 1 over
    endothelin 3, and p.Tyr129Phe raises affinity for endothelin 3 by two orders
    of magnitude by disrupting the sodium-water network beneath the binding
    pocket. Glu303 lies at the intracellular end of transmembrane helix 6, and
    p.Glu303Lys increases the flexibility of that helix, favouring G protein
    binding and thereby enhancing agonist affinity from the cytoplasmic side. The
    two variants thus converge on the same functional outcome — enhanced
    endothelin 3 responsiveness — by structurally opposite routes.
  genes:
  - preferred_term: EDNRA
    term:
      id: hgnc:3179
      label: EDNRA
  molecular_functions:
  - preferred_term: endothelin receptor type A (ETAR) activity
    term:
      id: GO:0004962
      label: endothelin receptor activity
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: Ectopic ETAR Activation in the Maxillary Prominence
    description: >
      Enhanced endothelin 3 responsiveness activates ETAR in a territory where
      endothelin 1 is not normally available to signal.
  evidence:
  - reference: PMID:25772936
    reference_title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude."
    explanation: >-
      Quantifies the ligand-selectivity shift that is the proximate molecular
      consequence of the commonest MFDA variant.
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3."
    explanation: >-
      Direct pharmacological confirmation that both variants are gain of function
      and that the gain is endothelin-3 dependent.
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein-mediated enhancement of agonist affinity."
    explanation: >-
      Molecular dynamics simulation providing the structural mechanism for the
      p.Glu303Lys allosteric gain of function.
- name: Ectopic ETAR Activation in the Maxillary Prominence
  biological_scale: CELLULAR
  description: >
    In normal craniofacial development endothelin 1 is secreted by the epithelium
    and core mesoderm of the ventral pharyngeal arch and acts on ETAR-expressing
    cranial neural crest cells, establishing mandibular identity ventrally while
    the dorsal (maxillary) territory remains ETAR-unstimulated. A receptor that
    now responds to endothelin 3 is activated in the maxillary prominence, where
    endothelin 3 is available but endothelin 1 is not. Genetic rescue makes the
    dependency explicit: deleting Edn3 in the knock-in mice abolishes the
    craniofacial transformation.
  biological_processes:
  - preferred_term: G protein-coupled receptor signaling pathway
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
    modifier: INCREASED
  cell_types:
  - preferred_term: cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  downstream:
  - target: Maxillary-to-Mandibular Homeotic Transformation
    description: >
      Imposing the ETAR-dependent ventral identity program on maxillary neural
      crest respecifies upper-jaw skeletal elements toward lower-jaw identity.
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3)."
    explanation: >-
      The Edn3 deletion rescue is the decisive experiment showing that the
      pathology depends on ectopic endothelin-3-driven ETAR activation.
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In craniofacial development, ET1 is secreted from the epithelium and core mesoderm in the ventral domain of the pharyngeal arches (PAs) to act on ETAR-expressing migrating cranial NCCs"
    explanation: >-
      Establishes the normal spatial restriction of endothelin-1-to-ETAR
      signalling that the MFDA variants violate.
- name: Maxillary-to-Mandibular Homeotic Transformation
  biological_scale: TISSUE
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Disrupted Pharyngeal-Arch Patterning and Neural-Crest Skeletogenesis"
  description: >
    ETAR signalling in cranial neural crest acts through the Dlx5/Dlx6 code that
    assigns ventral (mandibular) identity within the first arch. Ectopic
    activation in the dorsal territory drives upper-jaw skeletal elements toward a
    lower-jaw program, giving the partial maxillary-to-mandibular transformation
    seen in the knock-in mice. The human radiographic correlate is a zygomatic
    arch that resembles that of mice with experimentally induced ectopic
    maxillary ETAR activation, together with absent temporomandibular joints,
    flattened condyles and a thickened malar bone.

    Note that MFDA is not a pure gain: the reported functional consequences are
    complex and territory-dependent, with the upper jaw showing aberrant ETAR
    signalling while the lower jaw appears to show disrupted signalling. That
    dual character is what makes the phenotype a dysostosis with micrognathia
    rather than a straightforward duplication of the mandible.
  biological_processes:
  - preferred_term: regionalization
    term:
      id: GO:0003002
      label: regionalization
    modifier: ABNORMAL
  - preferred_term: embryonic skeletal system morphogenesis
    term:
      id: GO:0048704
      label: embryonic skeletal system morphogenesis
    modifier: ABNORMAL
  downstream:
  - target: Multi-Element First and Second Arch Malformation
    description: >
      The respecified arch program produces a coordinated malformation across the
      serially related skeletal derivatives of the first and second arches.
  evidence:
  - reference: PMID:25772936
    reference_title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation"
    explanation: >-
      Anchors the human skeletal phenotype to the experimental ectopic-activation
      model and names the direction of the transformation.
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the expression of Dlx5 and Dlx6, homeobox transcription factors that act downstream of ET1-ETAR signaling to determine ventral identity in PA1, extended dorsally in mutant embryos (Figure 2M). These results suggest that the Ednra mutations had an ectopic gain-of-function effect in the dorsal PA1"
    explanation: >-
      Direct, same-direction evidence for this node: in embryos carrying the
      MFDA alleles themselves (Ednra Y129F and E303K), the Dlx5/Dlx6
      ventral-identity code expands dorsally, which the authors read as an
      ectopic gain of function in dorsal PA1. This is the dorsal respecification
      the node asserts, measured in the MFDA genotype rather than inferred from
      the reciprocal knockout.
  - reference: PMID:15110048
    reference_title: "Endothelin-1 regulates the dorsoventral branchial arch patterning in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the expression of Dlx5 and Dlx6, Distalless-related homeobox genes determining the ventral identity of the anterior branchial arches, and of the mandibular marker gene Pitx1 is significantly downregulated in the ET-1(-/-) mutant"
    explanation: >-
      Establishes that Dlx5/Dlx6 ventral identity is endothelin-dependent at
      all, via the reciprocal loss-of-function experiment. Retained as
      axis-defining background only; the direction-matched claim for MFDA rests
      on the PMID:36637912 item above.
  - reference: PMID:32133772
    reference_title: "Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the upper jaw, there is likely aberrant EDNRA signaling, while in the lower jaw, there appears to be disruption of EDNRA signaling"
    explanation: >-
      Supports the territory-dependent, dual character of the MFDA signalling
      defect that this node records; it is a stated interpretation rather than a
      direct measurement, hence PARTIAL.
- name: Multi-Element First and Second Arch Malformation
  biological_scale: ORGANISM
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Serially Homologous Craniofacial Malformation Across Arch Derivatives"
  description: >
    The clinical phenotype is a coordinated malformation across serially related
    arch derivatives rather than an isolated defect: mandible, maxilla, malar and
    zygomatic bone, temporomandibular joint, external ear and middle-ear ossicles
    are all involved. This is the serial-homology signature the module encodes.
    Alopecia and the eyelid and palatal defects sit outside that skeletal pattern
    and are not explained by it.
  downstream: []
  evidence:
  - reference: PMID:27671791
    reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals."
    explanation: >-
      Enumerates the multi-element arch-derivative phenotype shared by the mouse
      model and MFDA patients.
  - reference: PMID:27671791
    reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles"
    explanation: >-
      Extends the malformation to the middle-ear ossicles, second-arch
      derivatives, and links them to the hearing phenotype.
phenotypes:
- category: Craniofacial
  name: Mandibular Hypoplasia
  description: >
    Micrognathia with jaw dysplasia is a cardinal feature. It coexists with the
    maxillary-to-mandibular transformation rather than contradicting it, because
    the MFDA receptor behaves differently in the two territories. No frequency
    band is asserted anywhere in this entry: with roughly four to six reported
    probands worldwide, and with the available quotable statements coming from
    the mouse model rather than a human case series, no band is supportable.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mandible (especially the proximal region) is more dysplastic in patients with MFDA than the mutant mice"
    explanation: >-
      Human primary support for mandibular dysplasia, and for it being more severe
      in patients than in the model. PARTIAL rather than SUPPORT because the
      sentence establishes mandibular dysplasia without itself naming micrognathia,
      which is the bound HP term.
  - reference: PMID:27671791
    reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints"
    explanation: >-
      The mouse model reproduces micrognathia as described for MFDA-affected
      individuals. Corroborating rather than sole support, since the human
      statement above now carries the phenotype.
- category: Craniofacial
  name: Temporomandibular Joint Dysplasia
  description: >
    Patients with the p.Tyr129Phe variant lack temporomandibular joints
    altogether and have flattened mandibular condyles — a defect closely
    reminiscent of mice with ectopic ETAR activation in the upper jaw.
  phenotype_term:
    preferred_term: Absent or dysplastic temporomandibular joint
    term:
      id: HP:0010754
      label: Abnormality of the temporomandibular joint
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with the p.Y129F mutation have no temporomandibular joints, flattened condyles, and a thickened malar bone"
    explanation: >-
      Directly describes the temporomandibular joint and condylar phenotype in
      p.Tyr129Phe patients.
- category: Craniofacial
  name: Malar and Zygomatic Anomaly
  description: >
    A thickened malar bone with absence of the squamosal zygomatic process. The
    abnormal shape of the zygomatic arch is the specific radiographic feature that
    matched MFDA to the ectopic-activation mouse and thereby identified the
    direction of the transformation.
  phenotype_term:
    preferred_term: Malar bone anomaly
    term:
      id: HP:0010668
      label: Abnormal zygomatic bone morphology
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flattened condyles, and a thickened malar bone, highly reminiscent of mice with ectopic ETAR activation in the upper jaw"
    explanation: >-
      Documents the malar bone abnormality in patients. The bound HP term is
      direction-neutral, so it accommodates the reported thickening; PARTIAL
      because this quote covers the thickened malar bone but not the absent
      squamosal zygomatic process also asserted in the description.
- category: Auditory
  name: External Ear Anomaly
  description: >
    Auricular dysmorphism is part of the second-arch component of the phenotype.
  phenotype_term:
    preferred_term: Auricular dysmorphism
    term:
      id: HP:0000356
      label: Abnormality of the outer ear
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a girl presenting with symmetrical dysplastic ears"
    explanation: >-
      Direct human observation of auricular dysmorphism in the molecularly
      confirmed EDNRA p.Glu303Lys mosaic patient, so the phenotype no longer rests
      on model-organism evidence alone.
  - reference: PMID:27671791
    reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals"
    explanation: >-
      Auricular dysmorphism is listed among the features described for
      MFDA-affected individuals and reproduced in the model.
- category: Auditory
  name: Conductive Hearing Impairment
  description: >
    Hearing impairment attributable to malformation of the middle-ear ossicles,
    which are themselves first- and second-arch derivatives — so the deafness is
    part of the arch phenotype rather than a separate association.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has hearing aids for conductive hearing loss"
    explanation: >-
      Names the conductive classification directly in a molecularly confirmed MFDA
      patient, so the bound HP term is supported by a human audiological statement
      rather than inferred from ossicular localisation in the model.
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CT scans also showed abnormalities of the middle ear, including hypoplasia of the long process of the incus"
    explanation: >-
      Supplies the human ossicular lesion that accounts for the conductive
      mechanism, in the same patient.
  - reference: PMID:27671791
    reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As observed in MFDA-affected individuals, mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles"
    explanation: >-
      Corroborates the ossicular basis of the hearing impairment in the model.
      PARTIAL because the mouse data do not themselves classify the loss as
      conductive; the human quotes above carry that claim.
- category: Integument
  name: Alopecia
  description: >
    Scalp alopecia is the feature that names the syndrome and distinguishes it
    clinically from the other endothelin-pathway craniofacial disorders. It is
    also the feature with no mechanistic account: it is not a pharyngeal arch
    derivative, it is not part of the serial-homology pattern, and the Ednra
    Y129F mouse does not reproduce it.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sparse scalp hair with persistent frontal balding"
    explanation: >-
      Direct human observation of the scalp phenotype in a molecularly confirmed
      MFDA patient (8%-11% mosaic EDNRA p.E303K), so the phenotype no longer
      rests on model-organism evidence alone.
  - reference: PMID:27671791
    reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "without showing any cleft palates, eyelid defects, or alopecia"
    explanation: >-
      Secondary, and deliberately not the primary support: this records the
      absence of alopecia in the otherwise faithful mouse, so it evidences the
      human/mouse discordance rather than the human phenotype itself.
- category: Integument
  name: Generalized Hypopigmentation
  description: >
    Skin hypopigmentation generalized relative to first-degree relatives, reported
    in the EDNRA p.Glu303Lys mosaic patient.

    Curated deliberately alongside the alopecia rather than as an incidental
    finding: follicular melanocytes are neural-crest derivatives and the endothelin
    axis is a known melanocyte-lineage signal, so a pigmentary phenotype in the
    same patient is the one available observation that speaks to whether the
    alopecia runs through a follicular neural-crest arm. It is a single patient and
    is not asserted as a recurrent MFDA feature; see
    gap_mfda_alopecia_mechanism.
  phenotype_term:
    preferred_term: Generalized hypopigmentation
    term:
      id: HP:0007513
      label: Generalized hypopigmentation
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized hypopigmentation compared with first degree relatives"
    explanation: >-
      Direct human observation of the pigmentary phenotype, with first-degree
      relatives as the stated comparator.
- category: Ophthalmologic
  name: Lower Eyelid Coloboma
  description: >
    Asymmetric lower eyelid coloboma severe enough to require surgical repair.
    Together with the ocular adnexal findings in the knock-in mice this is the
    eyelid component of the syndrome, and it is what makes the blanket claim that
    the mouse shows no eyelid defects unsupportable.
  phenotype_term:
    preferred_term: Lower eyelid coloboma
    term:
      id: HP:0000652
      label: Lower eyelid coloboma
  evidence:
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "asymmetric lower eyelid coloboma that required surgery on the right side"
    explanation: >-
      Direct human observation of the eyelid defect in a molecularly confirmed MFDA
      patient.
- category: Craniofacial
  name: Cleft Palate
  description: >
    Cleft palate is part of the human MFDA phenotype and is among the features
    the Ednra Y129F mouse does not reproduce.

    Evidence caveat, stated rather than papered over: the human source is the
    pre-molecular clinical delineation of the syndrome, which reports cleft
    palate in a patient described before EDNRA was implicated. That patient was
    karyotypically normal and TCOF1-negative but was never tested for EDNRA, so
    the report establishes cleft palate as a feature of the clinically defined
    entity rather than of a molecularly confirmed EDNRA case. The only other
    quotable sentence in this entry's references is the mouse-negative one,
    which supports "the mouse lacks it", not "patients have it".
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:20583178
    reference_title: "Mandibulofacial dysostosis, severe lower eyelid coloboma, cleft palate, and alopecia: A new distinct form of mandibulofacial dysostosis or a severe form of Johnson-McMillin syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with a phenotype characterized by mandibulofacial dysostosis with severe lower eyelid coloboma, cleft palate, abnormal ears, alopecia, delayed eruption and crowded teeth, and sensorioneural hearing loss."
    explanation: >-
      Human observation of cleft palate in a patient with the MFDA phenotype,
      replacing the mouse-negative snippet this phenotype previously had no
      valid support for. PARTIAL because the 2010 report predates the
      identification of EDNRA as the MFDA gene: it is a clinical delineation of
      the tetrad in a TCOF1-negative patient, not a molecularly confirmed EDNRA
      case.
genetic:
- name: EDNRA
  gene_term:
    preferred_term: EDNRA
    term:
      id: hgnc:3179
      label: EDNRA
  association: Causative
  notes: >
    EDNRA encodes the endothelin receptor type A (ETAR), a class A GPCR that binds
    endothelin 1 and endothelin 2 with much higher affinity than endothelin 3.
    Two recurrent de novo missense variants cause MFDA: p.Tyr129Phe (three of the
    four individuals in the founding report) and p.Glu303Lys (one somatic mosaic
    case, plus a later fully characterized patient). Allelic series note: the same
    gene produces three distinct clinical entities depending on the direction and
    magnitude of the signalling change. Gain of function gives MFDA; biallelic
    loss of function gives oro-oto-cardiac syndrome, with severe mandibular
    hypoplasia, anotia and cardiac defects; and loss of function in the downstream
    partners EDN1, PLCB4 and GNAI3 gives auriculocondylar syndrome. Interpreting a
    novel EDNRA variant therefore requires a functional assay establishing the
    direction of effect, not merely a pathogenicity prediction.
  evidence:
  - reference: PMID:25772936
    reference_title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the four individuals have the same substitution, p.Tyr129Phe."
    explanation: >-
      Establishes p.Tyr129Phe as the recurrent MFDA allele in the founding
      cohort.
  - reference: PMID:36637912
    reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F"
    explanation: >-
      Establishes p.Glu303Lys as the second recurrent MFDA allele with a
      concordant craniofacial phenotype.
  - reference: PMID:32133772
    reference_title: "Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This homozygous variant is thus the first reported loss-of-function EDNRA allele, resulting in a syndrome we have named Oro-Oto-Cardiac Syndrome."
    explanation: >-
      Documents the opposite-direction EDNRA allele and its distinct disease,
      supporting the allelic-series caveat in these notes.
animal_models:
- name: Ednra Y129F knock-in mouse
  species: Mouse
  genotype: Ednra c.386A>T (p.Tyr129Phe), heterozygous and homozygous
  publication: PMID:27671791
  description: >
    A viable dominant mouse carrying the exact human MFDA substitution, recovered
    from an ENU mutagenesis programme and phenotyped through the German Mouse
    Clinic pipeline. Its viability is itself informative: Ednra-null mice die
    neonatally from mechanical asphyxia, so a viable point-mutant supports the
    inference that MFDA retains substantial EDNRA signalling.
  modeled_mechanisms:
  - target: Multi-Element First and Second Arch Malformation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      The mouse reproduces the full skeletal arch-derivative phenotype — jaw
      dysplasia, micrognathia, dysplastic temporomandibular joints, auricular
      dysmorphism, absent squamosal zygomatic process, ossicular abnormality with
      hearing impairment — but none of the non-skeletal features.
    limitations: >-
      Neither heterozygous nor homozygous mutants of this ENU line show cleft
      palate, eyelid defects or alopecia, so the model cannot be used to
      investigate the syndrome's named feature. Scope the eyelid half of that
      negative to this line: the separately generated CRISPR knock-ins reported in
      PMID:36637912 do show ocular adnexal abnormalities, so "the mouse has no
      eyelid phenotype" is not a claim this entry makes. Expressivity also varies
      between individual mice, as it does between patients, which limits its use
      for quantitative genotype-phenotype work.
    readouts:
    - name: Craniofacial skeletal phenotype
      target: Multi-Element First and Second Arch Malformation
      direction: ALTERED
      interpretation: >-
        Standardized craniofacial phenotyping reproduces the human arch-derivative
        malformation set.
      evidence:
      - reference: PMID:27671791
        reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals."
        explanation: Reports the craniofacial features scored in the model.
    evidence:
    - reference: PMID:27671791
      reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches"
      explanation: >-
        Supports the model as informative for the first- and second-arch
        malformation node specifically.
  - target: Multi-Element First and Second Arch Malformation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >
      This ENU line does not reproduce the alopecia, cleft palate or eyelid defects
      that are part of the human syndrome. Recorded as an explicit negative claim
      rather than left as a caveat in prose.

      Alopecia is the durable part of that negative: it is absent from both
      independently generated mouse models and the authors state the species
      difference directly. The eyelid half does not generalize beyond this line,
      because the CRISPR knock-ins do show ocular adnexal abnormalities.
    limitations: >-
      The failure may reflect a genuine species difference in an
      endothelin-dependent process outside the arch skeleton, or simply that the
      relevant tissue is not sensitised in the mouse; the study does not
      discriminate. Either way the model must not be used as evidence that
      alopecia is not part of MFDA.
    evidence:
    - reference: PMID:27671791
      reference_title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "without showing any cleft palates, eyelid defects, or alopecia"
      explanation: >-
        Direct statement of the features this ENU line fails to reproduce.
    - reference: PMID:36637912
      reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The most significant difference is alopecia in patients with MFDA but not in mouse models."
      explanation: >-
        Independent confirmation that alopecia is absent across both mouse models,
        which is what licenses the alopecia arm of this negative claim as a species
        difference rather than a single-line result.
- name: Ednra E303K knock-in mouse
  species: Mouse
  genotype: Ednra p.Glu303Lys knock-in
  publication: PMID:36637912
  description: >
    Knock-in mouse for the second MFDA allele, used together with the Y129F model
    and an Edn3 cross to establish ligand dependence.
  modeled_mechanisms:
  - target: Ectopic ETAR Activation in the Maxillary Prominence
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Both knock-in alleles produce a partial maxillary-to-mandibular
      transformation, and crossing onto an Edn3-null background rescues it. This
      is the genetic epistasis experiment that identifies ectopic
      endothelin-3-driven ETAR activation as the operative mechanism rather than
      an inferred one.
    limitations: >-
      The rescue establishes ligand dependence in the mouse; the endothelin 3
      expression domain in the human maxillary prominence has not been mapped
      directly, so the spatial premise is transferred from mouse rather than
      demonstrated in human tissue.
    readouts:
    - name: Maxillary-to-mandibular transformation, Edn3-dependent
      target: Ectopic ETAR Activation in the Maxillary Prominence
      direction: ABOLISHED
      interpretation: >-
        The transformation is abolished when Edn3 is deleted, establishing that
        the phenotype requires the non-preferred ligand.
      evidence:
      - reference: PMID:36637912
        reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "which was rescued by deleting the ligand endothelin 3 (ET3/EDN3)"
        explanation: Reports the Edn3-deletion rescue result.
    evidence:
    - reference: PMID:36637912
      reference_title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation"
      explanation: >-
        Establishes that both MFDA alleles produce the transformation in vivo.
discussions:
- discussion_id: mismatch_mfda_mouse_nonskeletal_features
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does a mouse carrying the exact homologous Ednra Y129F substitution
    reproduce the entire craniofacial and ossicular phenotype but not the
    scalp-patterned alopecia that names the human syndrome?
  attaches_to:
  - phenotypes#Alopecia
  - phenotypes#Cleft Palate
  - pathophysiology#Multi-Element First and Second Arch Malformation
  rationale: >
    This is a model-fidelity question rather than an absence of evidence: the
    knock-in carries the identical residue change, was phenotyped through a
    standardized pipeline, and positively reproduces the skeletal arm — so the
    negative result on alopecia is informative rather than uninformative. It is
    also the one non-skeletal negative that holds across both independently
    generated models, which is why the mismatch is framed on alopecia alone.
    Two readings are open. Either endothelin signalling has a role in human hair
    follicle development that the mouse does not share, in which case the model is
    simply silent on the human syndrome's most diagnostic feature; or the relevant
    murine tissue is not sensitised under standard husbandry — murine hair cycling
    is synchronised and stage-dependent, so a follicular defect could be masked by
    the sampling stage. The distinction determines whether this mouse can be used
    at all for preclinical work on the alopecia, which is the feature patients
    present with.

    Deliberately excluded from the mismatch: eyelid defects. The ENU Y129F line was
    reported free of them, but the CRISPR knock-ins of both MFDA alleles show open
    eyelids at birth and periocular skin erosion, so there is no cross-model murine
    negative to set against the human lower eyelid coloboma. The two reports may
    genuinely disagree, or the lines may differ in background or construction;
    either way a blanket "the mouse has no eyelid phenotype" is not supportable and
    is not asserted here. Cleft palate is retained in attaches_to on its own
    footing: the human phenotype now has a primary clinical source, and the ENU
    Y129F line is explicitly reported free of cleft palate, so this is a genuine
    cross-species negative rather than a placeholder for a missing citation. It
    is not folded into the framing above because it rests on the single ENU
    report, whereas the alopecia negative holds across both models.
  proposed_experiments:
  - experiment_id: exp_mfda_mouse_hair_cycle_staged_phenotyping
    name: Hair-cycle-staged and tissue-conditional phenotyping of Ednra Y129F mice
    description: >
      Re-phenotype the Ednra Y129F mouse for follicular morphology across defined
      anagen/catagen/telogen stages rather than at a single timepoint, and in
      parallel generate a skin-restricted conditional allele to test whether local
      expression is sufficient. Map Edn3 availability in murine versus human scalp
      dermis at the corresponding stage. A staged defect would rescue the model
      for preclinical use; a flat negative across all stages with confirmed local
      expression would establish a genuine species difference and redirect work to
      human follicle systems.
- discussion_id: gap_mfda_alopecia_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does an EDNRA gain-of-function variant cause scalp alopecia,
    a phenotype outside the pharyngeal arch skeleton and absent from the knock-in
    mouse?
  attaches_to:
  - phenotypes#Alopecia
  - phenotypes#Generalized Hypopigmentation
  - pathophysiology#Multi-Element First and Second Arch Malformation
  rationale: >
    Alopecia is the feature that names the syndrome and distinguishes it from
    auriculocondylar syndrome and oro-oto-cardiac syndrome, yet it has no
    mechanistic account. Hair follicles are not pharyngeal arch derivatives, so
    the serial-homology module that explains the craniofacial phenotype does not
    reach it. The Ednra Y129F mouse reproduces the entire skeletal phenotype but
    shows no alopecia, and neither does the E303K knock-in, so the models offer no
    route in. Two possibilities are open: the endothelin axis has a direct role in
    human hair follicle or follicular neural-crest-derived melanocyte biology that
    the mouse does not share, or the alopecia is secondary to a shared upstream
    neural crest defect that the skeletal readout happens to capture more
    sensitively. Nothing in the current literature distinguishes them, but the
    generalized hypopigmentation curated in the p.Glu303Lys patient is the one
    observation that bears on the choice: a pigmentary phenotype in the same
    patient is what the melanocyte-lineage reading predicts, and it is a reason to
    look at follicular melanocytes rather than at receptor pharmacology alone.
  proposed_experiments:
  - experiment_id: exp_mfda_ednra_scalp_follicle_expression_and_signalling
    name: EDNRA/EDN3 expression and signalling in human scalp follicle at the relevant developmental stage
    description: >
      Map EDNRA and EDN3 expression across human embryonic and fetal scalp,
      distinguishing follicular epithelium, dermal papilla and
      neural-crest-derived follicular melanocytes, and test whether the MFDA
      variants alter endothelin-3-driven signalling in follicle-derived cells
      using the same BRET and pharmacological assays already applied to the
      craniofacial phenotype. A positive result would place alopecia on a direct
      EDNRA arm; a negative result would redirect attention to a shared upstream
      neural crest defect and would specifically motivate lineage tracing rather
      than further receptor pharmacology.
notes: >
  Scope and boundary caveats a curator should preserve:

  Direction of effect is the whole point. MFDA is EDNRA GAIN of function; the
  clinically adjacent auriculocondylar syndrome arises from LOSS of signalling in
  the same axis (EDN1 loss of function, or dominant negative PLCB4/GNAI3), and
  biallelic EDNRA loss of function gives a third entity, oro-oto-cardiac
  syndrome. The homeotic transformations run in opposite directions —
  maxillary-to-mandibular in MFDA, mandibular-to-maxillary in the loss-of-function
  disorders. This is why MFDA is curated as a separate Disease rather than as a
  has_subtypes entry on Auriculocondylar_Syndrome, and why the two entries'
  conforms_to edges attach to the same module nodes without the entries being
  redundant: the module is about the arch-patterning axis, and these are its two
  poles. Do not merge them, and do not describe MFDA as an
  "EDNRA-related craniofacial disorder" without stating the direction.

  Not a pure gain of function in every territory. The functional consequences are
  complex and context-dependent: the upper jaw shows aberrant ETAR signalling
  while the lower jaw appears to show disrupted signalling, which is why patients
  have micrognathia rather than a duplicated mandible. The in vitro and in vivo
  assays in the founding report were explicit that the effects were complex and
  context-dependent, and that qualification should not be dropped when
  summarizing the entry as "gain of function".

  Cardiovascular development is spared. Unlike Ednra-null mice, MFDA patients
  have no cardiovascular malformations. This is evidence that substantial EDNRA
  signalling is retained, and it is a real constraint on any model of the
  disorder — a proposed mechanism that abolishes EDNRA signalling would predict
  cardiac defects that patients do not have.

  Alopecia is unexplained and is recorded as an open KNOWLEDGE_GAP above rather
  than being given a plausible-sounding mechanism in the pathograph.

  Johnson-McMillin syndrome. The somatic mosaic p.Glu303Lys individual had
  previously been described under that diagnosis. Whether Johnson-McMillin
  syndrome as a whole is subsumed by MFDA is not established by that single case
  and is deliberately not asserted here.
references:
- reference: PMID:25772936
  title: "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia."
- reference: PMID:36637912
  title: "Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding."
- reference: PMID:27671791
  title: "Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation."
- reference: PMID:32133772
  title: "Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome."
- reference: PMID:15110048
  title: "Endothelin-1 regulates the dorsoventral branchial arch patterning in mice."
- reference: PMID:20583178
  title: "Mandibulofacial dysostosis, severe lower eyelid coloboma, cleft palate, and alopecia: A new distinct form of mandibulofacial dysostosis or a severe form of Johnson-McMillin syndrome?"

📚

References & Deep Research

References

6

PMID:25772936

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia.

No top-level findings curated for this source.

PMID:36637912

Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding.

No top-level findings curated for this source.

PMID:27671791

Viable Ednra (Y129F) mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation.

No top-level findings curated for this source.

PMID:32133772

Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome.

No top-level findings curated for this source.

PMID:15110048

Endothelin-1 regulates the dorsoventral branchial arch patterning in mice.

No top-level findings curated for this source.

PMID:20583178

Mandibulofacial dysostosis, severe lower eyelid coloboma, cleft palate, and alopecia: A new distinct form of mandibulofacial dysostosis or a severe form of Johnson-McMillin syndrome?

No top-level findings curated for this source.

Mandibulofacial Dysostosis with Alopecia

Ask OpenScientist

OpenScientist Report

Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Prevalence

Animal Models

Source YAML

References & Deep Research

References