Muggenthaler-Chowdhury-Chioza Syndrome

Mendelian MONDO:0976127 Pathograph 18 Show in embeddings browser Syndromic disease Hereditary disease

Muggenthaler-Chowdhury-Chioza syndrome (HYAL2 deficiency) is an ultra-rare autosomal recessive multiple congenital anomaly disorder caused by biallelic loss-of-function variants in HYAL2, which encodes hyaluronidase 2, a GPI-anchored cell-surface enzyme that degrades the extracellular glycosaminoglycan hyaluronan. Hyaluronan is a critical, transient component of the developing heart and palatal shelf matrix, and its regulated turnover is required for normal craniofacial and cardiac morphogenesis. Loss of HYAL2 activity therefore produces a recognizable syndrome dominated by orofacial clefting (unilateral or bilateral cleft lip and palate), a characteristic craniofacial dysmorphism, and congenital cardiac anomalies, most distinctively cor triatriatum sinister - of which HYAL2 deficiency is the first defined molecular cause. More variable features include myopia (sometimes severe, with increased risk of retinal detachment), typically conductive hearing loss, and skeletal findings such as pectus excavatum and digital anomalies; intellect is usually normal. The condition is distinct from HYAL1 deficiency (mucopolysaccharidosis type IX), which affects the other major somatic hyaluronidase and presents as a mild joint-centred phenotype. First delineated by Muggenthaler and colleagues in 2017, only a handful of families have been reported.

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1
Mappings
1
Inheritance
3
Pathophys.
12
Phenotypes
18
Pathograph
1
Genes
3
Medical Actions
1
Models
1
References
🔗

Mappings

MONDO
MONDO:0976127 Muggenthaler-Chowdhury-Chioza syndrome
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
HYAL2 deficiency is inherited in an autosomal recessive manner; affected individuals carry biallelic (homozygous or compound heterozygous) pathogenic HYAL2 variants, and heterozygous carriers are unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"HYAL2 deficiency is inherited in an autosomal recessive manner."
The GeneReviews clinical synopsis states the autosomal recessive mode of inheritance for HYAL2 deficiency.
⚙

Pathophysiology

3
HYAL2 hyaluronidase 2 deficiency
Biallelic loss-of-function variants in HYAL2 destabilize the hyaluronidase 2 protein, dramatically reducing its levels and causing an absence of the GPI-anchored enzyme from the cell surface. HYAL2 normally degrades extracellular high-molecular-weight hyaluronan, acting alongside HYAL1 as one of the two major mammalian somatic hyaluronidases.
HYAL2 hgnc:5321 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HYAL2 (hgnc:5321). hgnc:5321 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context functional_impact_category: LOSS_OF_FUNCTION
Biallelic HYAL2 missense and truncating variants destabilize the protein and abolish its cell-surface presentation, producing a loss of hyaluronidase 2 function. Nonsense alleles yield no detectable protein and missense alleles are degraded or fail GPI-anchored surface localization.
hyaluronidase 2 activity GO:0004415 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased hyaluronidase 2 activity, annotated with hyalurononglucosaminidase activity (GO:0004415). GO:0004415 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired extracellular hyaluronan degradation Loss of the cell-surface hyaluronidase 2 enzyme removes a major route for degrading extracellular hyaluronan.
Show evidence (2 references)
PMID:28081210 SUPPORT In Vitro
"Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels."
Establishes that the pathogenic HYAL2 variants act by destabilizing the protein and reducing its levels, i.e. loss of function.
PMID:34906488 SUPPORT In Vitro
"functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein."
Independent functional studies confirm that pathogenic missense variants cause HYAL2 protein instability and loss of the cell-surface enzyme.
Impaired extracellular hyaluronan degradation
With HYAL2 activity lost, high-molecular-weight extracellular hyaluronan is not properly degraded. Because hyaluronan is a critical, developmentally regulated component of the extracellular matrix of the developing heart and palatal shelves, its dysregulated turnover disrupts the matrix remodeling required for normal morphogenesis of these structures.
hyaluronan catabolic process GO:0030214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hyaluronan catabolic process (GO:0030214). GO:0030214 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted hyaluronan-dependent developmental morphogenesis Failure to remodel the hyaluronan-rich matrix of the developing heart and palatal shelves disrupts their morphogenesis.
Show evidence (1 reference)
PMID:34906488 SUPPORT Other
"catalyzing the degradation of the high molecular weight glycosaminoglycan polymer hyaluronan."
Confirms that HYAL2 catalyzes degradation of high-molecular-weight hyaluronan, the reaction that fails in HYAL2 deficiency. This is a background enzymology statement in the Fasham introduction, not a human clinical observation, so it is graded OTHER.
Disrupted hyaluronan-dependent developmental morphogenesis
Dysregulated hyaluronan turnover during embryonic development disrupts morphogenesis of the tissues in which hyaluronan is a critical, transient matrix constituent - the craniofacial structures (palatal shelves, lip), the heart, the vitreous of the eye, and the skeleton - producing the orofacial clefting, cardiac malformations, myopia, and skeletal findings that define the syndrome. Mechanistically, failure to clear high-molecular-weight hyaluronan drives excess epithelial-to-mesenchymal transition and decreased differentiation in the affected cushions and shelves. The Hyal2-/- mouse recapitulates these developmental abnormalities, supporting a causal, conserved role for HYAL2 in this process.
Animal models
Hyal2-/- knockout mouse Mouse partially recapitulates The Hyal2-null mouse reproduces the core craniofacial and cardiac developmental defects of the human syndrome, establishing HYAL2 loss as a conserved cause of the disrupted hyaluronan-dependent morphogenesis.
Downstream
Cleft lip Disrupted palatal shelf and lip morphogenesis produces cleft lip.
Cleft palate Disrupted palatal shelf morphogenesis produces cleft palate.
Congenital cardiac anomalies Disrupted cardiac cushion morphogenesis produces the congenital cardiac anomalies.
Cor triatriatum sinister Disrupted cardiac morphogenesis produces cor triatriatum sinister.
Facial dysmorphism Disrupted craniofacial morphogenesis produces the characteristic facial dysmorphism.
Myopia Dysregulated hyaluronan turnover in the vitreous, of which hyaluronan is the major macromolecule, disrupts ocular development and produces myopia.
Cataract Disrupted hyaluronan-dependent ocular development contributes to the cataract seen in some individuals.
Conductive hearing impairment Disrupted craniofacial and middle-ear development, associated with the palatal clefting, produces the conductive hearing impairment.
Sensorineural hearing loss Disrupted hyaluronan-dependent otic development is the proposed basis for the sensorineural hearing loss identified in a minority of individuals.
Pectus excavatum Disrupted hyaluronan-dependent skeletal development produces pectus excavatum.
Digital anomalies Disrupted hyaluronan-dependent skeletal development produces the digital anomalies.
Show evidence (1 reference)
PMID:28081210 SUPPORT Model Organism
"investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate."
Hyal2-null mice develop craniofacial abnormalities including cleft palate, demonstrating that loss of HYAL2 disrupts craniofacial morphogenesis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Muggenthaler-Chowdhury-Chioza Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Cardiovascular 2
Cor triatriatum sinister HP:0031134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cor triatriatum sinister (HP:0031134). HP:0031134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28081210 SUPPORT Human Clinical
"cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans."
Documents cor triatriatum sinister as an incompletely penetrant feature of HYAL2 deficiency in affected humans.
Congenital cardiac anomalies Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital cardiac anomalies, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37733894 SUPPORT Human Clinical
"HYAL2 deficiency is characterized by cardiac anomalies"
GeneReviews names cardiac anomalies first among the defining clinical characteristics of HYAL2 deficiency.
PMID:34906488 SUPPORT Human Clinical
"Congenital cardiac anomalies, identified in most new cases, comprise an important component of the disease phenotype"
The expanded Fasham cohort finds congenital cardiac anomalies in most new cases, establishing them as a consistent component of the phenotype.
Ear 2
Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"hearing loss (typically conductive), and skeletal findings (including pectus excavatum and digital anomalies)"
GeneReviews specifies that the hearing loss in HYAL2 deficiency is typically conductive (quoted within the clinical-characteristics sentence).
Sensorineural hearing loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28081210 SUPPORT Human Clinical
"one affected individual was found to have profound sensorineural hearing loss."
Documents profound sensorineural hearing loss in an affected individual, distinct from the usual conductive hearing impairment.
Eye 3
Myopia HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Sequelae: Staphyloma
Show evidence (3 references)
PMID:37733894 SUPPORT Human Clinical
"ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment)"
GeneReviews documents mild-to-severe myopia, with increased retinal detachment risk, as an ophthalmic manifestation.
PMID:34906488 SUPPORT Human Clinical
"confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition."
Independently lists myopia among the most consistent manifestations of the condition.
PMID:34906488 SUPPORT Other
"The human vitreous is a specialized extracellular matrix composed of hyaluronan, the major macromolecule, interwoven with chondroitin sulfate proteoglycans (including versican and collagen IX) and other collagen fibrils."
Background statement that hyaluronan is the major macromolecule of the vitreous, providing the mechanistic rationale for why impaired hyaluronan turnover produces the ocular (myopic) phenotype.
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34906488 SUPPORT Human Clinical
"along with more variable features, including congenital cardiac anomalies (cor triatriatum sinister), myopia with staphyloma, cataract, conductive/sensorineural hearing loss, pectus excavatum, and single palmar creases."
Fasham et al. list cataract among the variable clinical features of HYAL2 deficiency.
Staphyloma Posterior staphyloma HP:0030856 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Staphyloma, annotated with Posterior staphyloma (HP:0030856). HP:0030856 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34906488 SUPPORT Human Clinical
"along with more variable features, including congenital cardiac anomalies (cor triatriatum sinister), myopia with staphyloma, cataract, conductive/sensorineural hearing loss, pectus excavatum, and single palmar creases."
Fasham et al. list staphyloma (with myopia) among the variable ocular features of HYAL2 deficiency.
Head and Neck 3
Cleft lip HP:0410030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip (HP:0410030). HP:0410030 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28081210 SUPPORT Human Clinical
"Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting."
Identifies syndromic orofacial clefting as the defining presentation of HYAL2 mutations.
PMID:37733894 SUPPORT Human Clinical
"cleft lip and palate (unilateral or bilateral)"
GeneReviews lists unilateral or bilateral cleft lip and palate as a core manifestation.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"cleft lip and palate (unilateral or bilateral)"
GeneReviews documents cleft palate as part of the core craniofacial manifestation of HYAL2 deficiency.
Facial dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recognizable craniofacial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34906488 SUPPORT Human Clinical
"confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition."
Documents a recognizable craniofacial phenotype as a consistent manifestation of the syndrome.
Limbs 1
Digital anomalies Abnormal digit morphology HP:0011297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Digital anomalies, annotated with Abnormal digit morphology (HP:0011297). HP:0011297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"skeletal findings (including pectus excavatum and digital anomalies)"
GeneReviews lists digital anomalies among the skeletal findings of HYAL2 deficiency.
Musculoskeletal 1
Pectus excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"skeletal findings (including pectus excavatum and digital anomalies)"
GeneReviews lists pectus excavatum among the skeletal findings of HYAL2 deficiency.
🧬

Genetic Associations

1
HYAL2 pathogenic variants (Causative)
Gene: HYAL2 hgnc:5321 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HYAL2 (hgnc:5321). hgnc:5321 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:34906488 SUPPORT Human Clinical
"Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants."
Expands the HYAL2 mutational spectrum with nine additional pathogenic variants across ten newly identified individuals.
PMID:34906488 SUPPORT Computational
"In silico modeling of missense variants identified likely deleterious effects on protein folding."
In silico modeling supports a protein-folding/destabilization mechanism for the missense variants.
💊

Medical Actions

3
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
Platform: Other
There is no cure for HYAL2 deficiency. Management is supportive, coordinated by a multidisciplinary team (pediatric cardiology and cardiac surgery for cardiac anomalies, a craniofacial team for the clefting, and audiology and speech-language pathology for hearing and communication) to maximize function and reduce complications.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"There is no cure for HYAL2 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
GeneReviews states that management is supportive, with no curative therapy.
Surgical repair of cleft and cardiac anomalies
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical management is directed at the structural anomalies - staged craniofacial/cleft repair and cardiac surgery for the congenital cardiac anomalies (including cor triatriatum sinister when hemodynamically significant).
Mechanism Target:
RESTORES Cleft lip — Staged craniofacial/cleft surgery repairs the orofacial cleft, restoring the lip anatomy; symptomatic correction of the structural malformation rather than modification of the underlying developmental mechanism.
RESTORES Cleft palate — Cleft palate repair restores palatal continuity for feeding and speech.
RESTORES Congenital cardiac anomalies — Cardiac surgery corrects the congenital cardiac anomalies (including lesions requiring intervention in the first year of life).
RESTORES Cor triatriatum sinister — Surgical resection of the dividing left-atrial membrane corrects cor triatriatum sinister when hemodynamically significant.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"care by specialists in pediatric cardiology and cardiac surgery and a multidisciplinary craniofacial team to coordinate timing and type of surgical interventions"
GeneReviews describes cardiac surgery and coordinated craniofacial surgical interventions as part of management.
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
Platform: Other
Because HYAL2 deficiency is autosomal recessive, genetic counseling informs families of the 25% recurrence risk for sibs and the availability of carrier, prenatal, and preimplantation genetic testing once the familial variants are known.
Show evidence (2 references)
PMID:37733894 SUPPORT Human Clinical
"Once the HYAL2 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk and prenatal and preimplantation genetic testing are possible."
GeneReviews documents the genetic counseling and testing options that follow from recessive inheritance.
PMID:37733894 SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews states the 25% sib recurrence risk that the genetic-counseling description reports.
🔬

Diagnosis

1
Molecular genetic testing for biallelic HYAL2 variants
The diagnosis is established in a proband with the suggestive craniofacial, cardiac, ophthalmic, otologic, and skeletal findings by identifying biallelic (homozygous or compound heterozygous) pathogenic HYAL2 variants on molecular genetic testing (exome or genome sequencing). There is no biochemical or functional assay in routine clinical use; molecular confirmation is the basis of diagnosis, and it also enables the carrier, prenatal, and preimplantation testing offered in genetic counseling.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"The diagnosis of HYAL2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in HYAL2 identified by molecular genetic testing."
GeneReviews states the diagnostic criterion - suggestive findings plus biallelic pathogenic HYAL2 variants on molecular genetic testing.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare; GeneReviews (2023) summarizes 17 individuals from seven families reported to date.
Show evidence (1 reference)
PMID:37733894 SUPPORT Human Clinical
"To date, 17 individuals from seven families have been reported with HYAL2 deficiency."
Directly supports the ultra-rare, cases-in-literature occurrence of HYAL2 deficiency.
🐁

Animal Models

1
Hyal2-/- knockout mouse
Constitutive Hyal2-null mice were used to establish the causal, conserved role of HYAL2 in the disorder. They universally show facial dysmorphism, underdevelopment of the viscerocranium, submucosal cleft palate (in ~83% of nulls), and cardiac valve thickening; cor triatriatum sinister (~50%) and hearing loss are found in a proportion of animals, paralleling the incompletely penetrant features seen in affected humans. Because the null allele abolishes HYAL2 entirely - whereas the human missense alleles retain residual protein - the mouse also develops circulating hyaluronan accumulation and cardiopulmonary complications not seen in the described human patients.
Species
Mouse
Genotype
Hyal2 homozygous null (Hyal2-/-)
Publication
PMID:28081210
Pathograph links
Disrupted hyaluronan-dependent developmental morphogenesis partially recapitulates fidelity: high The Hyal2-null mouse reproduces the core craniofacial and cardiac developmental defects of the human syndrome, establishing HYAL2 loss as a conserved cause of the disrupted hyaluronan-dependent morphogenesis.
Limitations: Only a proportion of null mice manifest cor triatriatum sinister (~50%) and hearing loss, mirroring the incomplete penetrance of these features in humans; and the complete null abolishes HYAL2 (versus residual protein from human missense alleles), so nulls additionally develop circulating hyaluronan accumulation and cardiopulmonary disease absent in the described human patients.
Readouts
Craniofacial morphogenesis (submucosal cleft palate)
Gross and micro-CT examination of the craniofacial skeleton and palate of Hyal2-/- versus littermate control mice.
Direction: INCREASED
Interpretation: Craniofacial abnormalities including submucosal cleft palate in null mice are the structural correlate of the disrupted morphogenesis node.
Show evidence (1 reference)
PMID:28081210 SUPPORT Model Organism
"investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate."
Reports the craniofacial and palatal malformations measured in the null mouse that ground this readout.
Show evidence (1 reference)
PMID:28081210 SUPPORT Model Organism
"Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate."
Establishes that the null mouse recapitulates the craniofacial developmental defects seen in affected individuals, making it informative for the disrupted-morphogenesis node. Cor triatriatum sinister and hearing loss are only partially penetrant in the mouse (see limitations).
{ }

Source YAML

click to show 
name: Muggenthaler-Chowdhury-Chioza Syndrome
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
description: >-
  Muggenthaler-Chowdhury-Chioza syndrome (HYAL2 deficiency) is an ultra-rare
  autosomal recessive multiple congenital anomaly disorder caused by biallelic
  loss-of-function variants in HYAL2, which encodes hyaluronidase 2, a
  GPI-anchored cell-surface enzyme that degrades the extracellular
  glycosaminoglycan hyaluronan. Hyaluronan is a critical, transient component of
  the developing heart and palatal shelf matrix, and its regulated turnover is
  required for normal craniofacial and cardiac morphogenesis. Loss of HYAL2
  activity therefore produces a recognizable syndrome dominated by orofacial
  clefting (unilateral or bilateral cleft lip and palate), a characteristic
  craniofacial dysmorphism, and congenital cardiac anomalies, most distinctively
  cor triatriatum sinister - of which HYAL2 deficiency is the first defined
  molecular cause. More variable features include myopia (sometimes severe, with
  increased risk of retinal detachment), typically conductive hearing loss, and
  skeletal findings such as pectus excavatum and digital anomalies; intellect is
  usually normal. The condition is distinct from HYAL1 deficiency
  (mucopolysaccharidosis type IX), which affects the other major somatic
  hyaluronidase and presents as a mild joint-centred phenotype. First delineated
  by Muggenthaler and colleagues in 2017, only a handful of families have been
  reported.
disease_term:
  preferred_term: Muggenthaler-Chowdhury-Chioza syndrome
  term:
    id: MONDO:0976127
    label: Muggenthaler-Chowdhury-Chioza syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0976127
      label: Muggenthaler-Chowdhury-Chioza syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Syndromic disease
- Hereditary disease
synonyms:
- HYAL2 deficiency
- HYAL2-related syndromic orofacial clefting
notes: >-
  Muggenthaler-Chowdhury-Chioza syndrome is the HYAL2 counterpart of HYAL1
  deficiency (mucopolysaccharidosis type IX). Both disrupt somatic hyaluronan
  turnover, but they are clinically and biochemically distinct: HYAL1 loss
  produces a mild, joint-centred lysosomal storage phenotype, whereas HYAL2 loss
  produces a developmental multiple-congenital-anomaly syndrome of orofacial
  clefting, cor triatriatum sinister, and craniofacial dysmorphism, reflecting
  the role of HYAL2 in degrading hyaluronan in the developing heart and palatal
  shelf matrix. The disorder is ultra-rare; the reported case series remain
  small (17 individuals from seven families summarized in GeneReviews as of the
  2023 review), so several well-documented features are described conservatively
  in prose rather than over-annotated. Cor triatriatum sinister and hearing loss
  are incompletely penetrant, having been identified in only a proportion of
  affected humans and Hyal2-/- mice.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    HYAL2 deficiency is inherited in an autosomal recessive manner; affected
    individuals carry biallelic (homozygous or compound heterozygous) pathogenic
    HYAL2 variants, and heterozygous carriers are unaffected.
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HYAL2 deficiency is inherited in an autosomal recessive manner."
    explanation: >-
      The GeneReviews clinical synopsis states the autosomal recessive mode of
      inheritance for HYAL2 deficiency.
pathophysiology:
- name: HYAL2 hyaluronidase 2 deficiency
  description: >-
    Biallelic loss-of-function variants in HYAL2 destabilize the hyaluronidase 2
    protein, dramatically reducing its levels and causing an absence of the
    GPI-anchored enzyme from the cell surface. HYAL2 normally degrades
    extracellular high-molecular-weight hyaluronan, acting alongside HYAL1 as one
    of the two major mammalian somatic hyaluronidases.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HYAL2
    term:
      id: hgnc:5321
      label: HYAL2
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic HYAL2 missense and truncating variants destabilize the protein
      and abolish its cell-surface presentation, producing a loss of
      hyaluronidase 2 function. Nonsense alleles yield no detectable protein and
      missense alleles are degraded or fail GPI-anchored surface localization.
  molecular_functions:
  - preferred_term: hyaluronidase 2 activity
    modifier: DECREASED
    term:
      id: GO:0004415
      label: hyalurononglucosaminidase activity
  evidence:
  - reference: PMID:28081210
    reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels."
    explanation: >-
      Establishes that the pathogenic HYAL2 variants act by destabilizing the
      protein and reducing its levels, i.e. loss of function.
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein."
    explanation: >-
      Independent functional studies confirm that pathogenic missense variants
      cause HYAL2 protein instability and loss of the cell-surface enzyme.
  downstream:
  - target: Impaired extracellular hyaluronan degradation
    causal_link_type: DIRECT
    description: >-
      Loss of the cell-surface hyaluronidase 2 enzyme removes a major route for
      degrading extracellular hyaluronan.
    evidence:
    - reference: PMID:28081210
      reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix."
      explanation: >-
        Identifies extracellular hyaluronan degradation as the function of
        HYAL2, whose loss leaves that substrate incompletely turned over. This
        is a background statement of HYAL2 enzymology, not a human clinical
        observation, so it is graded OTHER.
- name: Impaired extracellular hyaluronan degradation
  description: >-
    With HYAL2 activity lost, high-molecular-weight extracellular hyaluronan is
    not properly degraded. Because hyaluronan is a critical, developmentally
    regulated component of the extracellular matrix of the developing heart and
    palatal shelves, its dysregulated turnover disrupts the matrix remodeling
    required for normal morphogenesis of these structures.
  biological_scale: MOLECULAR
  chemical_entities:
  - preferred_term: hyaluronan
    modifier: INCREASED
    term:
      id: CHEBI:16336
      label: hyaluronic acid
  biological_processes:
  - preferred_term: hyaluronan catabolic process
    modifier: DECREASED
    term:
      id: GO:0030214
      label: hyaluronan catabolic process
  evidence:
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "catalyzing the degradation of the high molecular weight glycosaminoglycan polymer hyaluronan."
    explanation: >-
      Confirms that HYAL2 catalyzes degradation of high-molecular-weight
      hyaluronan, the reaction that fails in HYAL2 deficiency. This is a
      background enzymology statement in the Fasham introduction, not a human
      clinical observation, so it is graded OTHER.
  downstream:
  - target: Disrupted hyaluronan-dependent developmental morphogenesis
    causal_link_type: DIRECT
    description: >-
      Failure to remodel the hyaluronan-rich matrix of the developing heart and
      palatal shelves disrupts their morphogenesis.
    evidence:
    - reference: PMID:28081210
      reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix."
      explanation: >-
        Ties impaired hyaluronan turnover to the developing heart and palatal
        shelf matrix, the substrates of the affected morphogenesis. This is a
        background statement of HYAL2 enzymology, not a human clinical
        observation, so it is graded OTHER.
- name: Disrupted hyaluronan-dependent developmental morphogenesis
  description: >-
    Dysregulated hyaluronan turnover during embryonic development disrupts
    morphogenesis of the tissues in which hyaluronan is a critical, transient
    matrix constituent - the craniofacial structures (palatal shelves, lip), the
    heart, the vitreous of the eye, and the skeleton - producing the orofacial
    clefting, cardiac malformations, myopia, and skeletal findings that define
    the syndrome. Mechanistically, failure to clear high-molecular-weight
    hyaluronan drives excess epithelial-to-mesenchymal transition and decreased
    differentiation in the affected cushions and shelves. The Hyal2-/- mouse
    recapitulates these developmental abnormalities, supporting a causal,
    conserved role for HYAL2 in this process.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:28081210
    reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate."
    explanation: >-
      Hyal2-null mice develop craniofacial abnormalities including cleft palate,
      demonstrating that loss of HYAL2 disrupts craniofacial morphogenesis.
  downstream:
  - target: Cleft lip
    causal_link_type: DIRECT
    description: Disrupted palatal shelf and lip morphogenesis produces cleft lip.
  - target: Cleft palate
    causal_link_type: DIRECT
    description: Disrupted palatal shelf morphogenesis produces cleft palate.
  - target: Congenital cardiac anomalies
    causal_link_type: DIRECT
    description: Disrupted cardiac cushion morphogenesis produces the congenital cardiac anomalies.
  - target: Cor triatriatum sinister
    causal_link_type: DIRECT
    description: Disrupted cardiac morphogenesis produces cor triatriatum sinister.
  - target: Facial dysmorphism
    causal_link_type: DIRECT
    description: Disrupted craniofacial morphogenesis produces the characteristic facial dysmorphism.
  - target: Myopia
    causal_link_type: DIRECT
    description: >-
      Dysregulated hyaluronan turnover in the vitreous, of which hyaluronan is
      the major macromolecule, disrupts ocular development and produces myopia.
  - target: Cataract
    causal_link_type: DIRECT
    description: Disrupted hyaluronan-dependent ocular development contributes to the cataract seen in some individuals.
  - target: Conductive hearing impairment
    causal_link_type: DIRECT
    description: >-
      Disrupted craniofacial and middle-ear development, associated with the
      palatal clefting, produces the conductive hearing impairment.
  - target: Sensorineural hearing loss
    causal_link_type: DIRECT
    description: >-
      Disrupted hyaluronan-dependent otic development is the proposed basis for
      the sensorineural hearing loss identified in a minority of individuals.
  - target: Pectus excavatum
    causal_link_type: DIRECT
    description: Disrupted hyaluronan-dependent skeletal development produces pectus excavatum.
  - target: Digital anomalies
    causal_link_type: DIRECT
    description: Disrupted hyaluronan-dependent skeletal development produces the digital anomalies.
phenotypes:
- name: Cleft lip
  category: Craniofacial
  description: >-
    Unilateral or bilateral cleft lip, part of the orofacial clefting (cleft lip
    and palate) that is a core - though, in the expanded cohort, variable -
    feature of HYAL2 deficiency and the presentation through which the syndrome
    was first recognized. The companion cleft palate is modelled as a separate
    phenotype node.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:28081210
    reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting."
    explanation: >-
      Identifies syndromic orofacial clefting as the defining presentation of
      HYAL2 mutations.
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft lip and palate (unilateral or bilateral)"
    explanation: >-
      GeneReviews lists unilateral or bilateral cleft lip and palate as a core
      manifestation.
- name: Cleft palate
  category: Craniofacial
  description: >-
    Cleft palate accompanies the cleft lip as part of the orofacial clefting;
    Hyal2-/- mice show a submucosal cleft palate.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft lip and palate (unilateral or bilateral)"
    explanation: >-
      GeneReviews documents cleft palate as part of the core craniofacial
      manifestation of HYAL2 deficiency.
- name: Cor triatriatum sinister
  category: Cardiovascular
  description: >-
    Cor triatriatum sinister, a congenital cardiac anomaly in which a fibromuscular
    membrane subdivides the left atrium, is an incompletely penetrant but
    characteristic feature. HYAL2 deficiency is the first defined molecular cause
    of human cor triatriatum sinister.
  phenotype_term:
    preferred_term: Cor triatriatum sinister
    term:
      id: HP:0031134
      label: Cor triatriatum sinister
  evidence:
  - reference: PMID:28081210
    reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans."
    explanation: >-
      Documents cor triatriatum sinister as an incompletely penetrant feature of
      HYAL2 deficiency in affected humans.
- name: Myopia
  category: Ophthalmologic
  description: >-
    Myopia, which can range from mild to severe (up to about -16.75 diopters),
    occurs in HYAL2 deficiency and carries an increased risk of retinal
    detachment. Hyaluronan is a major constituent of the vitreous humor.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment)"
    explanation: >-
      GeneReviews documents mild-to-severe myopia, with increased retinal
      detachment risk, as an ophthalmic manifestation.
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition."
    explanation: >-
      Independently lists myopia among the most consistent manifestations of the
      condition.
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The human vitreous is a specialized extracellular matrix composed of hyaluronan, the major macromolecule, interwoven with chondroitin sulfate proteoglycans (including versican and collagen IX) and other collagen fibrils."
    explanation: >-
      Background statement that hyaluronan is the major macromolecule of the
      vitreous, providing the mechanistic rationale for why impaired hyaluronan
      turnover produces the ocular (myopic) phenotype.
  sequelae:
  - target: Staphyloma
    description: >-
      Progressive high myopia leads to posterior scleral ectasia (staphyloma),
      reported in several affected individuals.
- name: Conductive hearing impairment
  category: Otologic
  description: >-
    Hearing loss, typically conductive, occurs in HYAL2 deficiency and was an
    incompletely penetrant feature in both affected humans and Hyal2-/- mice.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hearing loss (typically conductive), and skeletal findings (including pectus excavatum and digital anomalies)"
    explanation: >-
      GeneReviews specifies that the hearing loss in HYAL2 deficiency is
      typically conductive (quoted within the clinical-characteristics sentence).
- name: Facial dysmorphism
  category: Craniofacial
  description: >-
    Affected individuals share a recognizable craniofacial dysmorphism beyond the
    clefting, allowing clinical recognition of the syndrome.
  phenotype_term:
    preferred_term: Recognizable craniofacial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition."
    explanation: >-
      Documents a recognizable craniofacial phenotype as a consistent
      manifestation of the syndrome.
- name: Pectus excavatum
  category: Skeletal
  description: >-
    Skeletal findings in HYAL2 deficiency include pectus excavatum and digital
    anomalies.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal findings (including pectus excavatum and digital anomalies)"
    explanation: >-
      GeneReviews lists pectus excavatum among the skeletal findings of HYAL2
      deficiency.
- name: Congenital cardiac anomalies
  category: Cardiovascular
  description: >-
    Congenital cardiac anomalies are a core, high-incidence feature of HYAL2
    deficiency and comprise a spectrum beyond the distinctive cor triatriatum
    sinister - valvular anomalies, atrial/ventricular septal defects, and, in the
    expanded cohort, clinically significant lesions requiring early surgery
    (coarctation of the aorta, mitral valve atresia, hypoplastic left ventricle,
    pulmonary valve atresia, tetralogy of Fallot). Unlike the incompletely
    penetrant cor triatriatum sinister, cardiac anomalies as a class are a
    defining manifestation of the syndrome.
  phenotype_term:
    preferred_term: Congenital cardiac anomalies
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HYAL2 deficiency is characterized by cardiac anomalies"
    explanation: >-
      GeneReviews names cardiac anomalies first among the defining clinical
      characteristics of HYAL2 deficiency.
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital cardiac anomalies, identified in most new cases, comprise an important component of the disease phenotype"
    explanation: >-
      The expanded Fasham cohort finds congenital cardiac anomalies in most new
      cases, establishing them as a consistent component of the phenotype.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Lens opacities / cataract are reported among the ocular findings, part of a
    broader hyaluronan-dependent ocular (vitreoretinal) phenotype.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with more variable features, including congenital cardiac anomalies (cor triatriatum sinister), myopia with staphyloma, cataract, conductive/sensorineural hearing loss, pectus excavatum, and single palmar creases."
    explanation: >-
      Fasham et al. list cataract among the variable clinical features of HYAL2
      deficiency.
- name: Staphyloma
  category: Ophthalmologic
  description: >-
    Posterior staphyloma, associated with the high myopia, was reported in
    several affected individuals.
  phenotype_term:
    preferred_term: Staphyloma
    term:
      id: HP:0030856
      label: Posterior staphyloma
  evidence:
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with more variable features, including congenital cardiac anomalies (cor triatriatum sinister), myopia with staphyloma, cataract, conductive/sensorineural hearing loss, pectus excavatum, and single palmar creases."
    explanation: >-
      Fasham et al. list staphyloma (with myopia) among the variable ocular
      features of HYAL2 deficiency.
- name: Sensorineural hearing loss
  category: Otologic
  description: >-
    Although hearing loss in HYAL2 deficiency is typically conductive, profound
    sensorineural hearing loss was identified in an affected individual,
    indicating the otologic involvement is not exclusively conductive.
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:28081210
    reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one affected individual was found to have profound sensorineural hearing loss."
    explanation: >-
      Documents profound sensorineural hearing loss in an affected individual,
      distinct from the usual conductive hearing impairment.
- name: Digital anomalies
  category: Skeletal
  description: >-
    Digital anomalies (including toe syndactyly and single palmar creases) are
    reported among the skeletal findings of HYAL2 deficiency.
  phenotype_term:
    preferred_term: Digital anomalies
    term:
      id: HP:0011297
      label: Abnormal digit morphology
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal findings (including pectus excavatum and digital anomalies)"
    explanation: >-
      GeneReviews lists digital anomalies among the skeletal findings of HYAL2
      deficiency.
genetic:
- name: HYAL2 pathogenic variants
  gene_term:
    preferred_term: HYAL2
    term:
      id: hgnc:5321
      label: HYAL2
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    description: >-
      Disease results from biallelic (homozygous or compound heterozygous)
      loss-of-function HYAL2 variants.
    evidence:
    - reference: PMID:37733894
      reference_title: HYAL2 Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "biallelic pathogenic variants in HYAL2 identified by molecular genetic testing."
      explanation: >-
        GeneReviews establishes the diagnosis on biallelic pathogenic HYAL2
        variants, consistent with recessive inheritance.
  features: >-
    Muggenthaler-Chowdhury-Chioza syndrome is caused by biallelic
    loss-of-function variants in HYAL2, which encodes the GPI-anchored
    cell-surface hyaluronidase 2. The originally reported Amish and Saudi Arabian
    families carried homozygous missense variants, and a later series identified
    additional novel missense and small-deletion variants. Functional and in
    silico studies indicate that the missense variants cluster around the
    predicted enzymatic active site and destabilize protein folding, causing
    protein instability and loss of the enzyme from the cell surface.
  evidence:
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants."
    explanation: >-
      Expands the HYAL2 mutational spectrum with nine additional pathogenic
      variants across ten newly identified individuals.
  - reference: PMID:34906488
    reference_title: Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In silico modeling of missense variants identified likely deleterious effects on protein folding."
    explanation: >-
      In silico modeling supports a protein-folding/destabilization mechanism for
      the missense variants.
animal_models:
- name: Hyal2-/- knockout mouse
  species: Mouse
  genotype: Hyal2 homozygous null (Hyal2-/-)
  publication: PMID:28081210
  description: >-
    Constitutive Hyal2-null mice were used to establish the causal, conserved
    role of HYAL2 in the disorder. They universally show facial dysmorphism,
    underdevelopment of the viscerocranium, submucosal cleft palate (in ~83% of
    nulls), and cardiac valve thickening; cor triatriatum sinister (~50%) and
    hearing loss are found in a proportion of animals, paralleling the
    incompletely penetrant features seen in affected humans. Because the null
    allele abolishes HYAL2 entirely - whereas the human missense alleles retain
    residual protein - the mouse also develops circulating hyaluronan
    accumulation and cardiopulmonary complications not seen in the described
    human patients.
  modeled_mechanisms:
  - target: Disrupted hyaluronan-dependent developmental morphogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    description: >-
      The Hyal2-null mouse reproduces the core craniofacial and cardiac
      developmental defects of the human syndrome, establishing HYAL2 loss as a
      conserved cause of the disrupted hyaluronan-dependent morphogenesis.
    limitations: >-
      Only a proportion of null mice manifest cor triatriatum sinister (~50%)
      and hearing loss, mirroring the incomplete penetrance of these features in
      humans; and the complete null abolishes HYAL2 (versus residual protein
      from human missense alleles), so nulls additionally develop circulating
      hyaluronan accumulation and cardiopulmonary disease absent in the described
      human patients.
    readouts:
    - name: Craniofacial morphogenesis (submucosal cleft palate)
      target: Disrupted hyaluronan-dependent developmental morphogenesis
      description: >-
        Gross and micro-CT examination of the craniofacial skeleton and palate
        of Hyal2-/- versus littermate control mice.
      direction: INCREASED
      interpretation: >-
        Craniofacial abnormalities including submucosal cleft palate in null
        mice are the structural correlate of the disrupted morphogenesis node.
      evidence:
      - reference: PMID:28081210
        reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate."
        explanation: >-
          Reports the craniofacial and palatal malformations measured in the
          null mouse that ground this readout.
    evidence:
    - reference: PMID:28081210
      reference_title: "Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate."
      explanation: >-
        Establishes that the null mouse recapitulates the craniofacial
        developmental defects seen in affected individuals, making it informative
        for the disrupted-morphogenesis node. Cor triatriatum sinister and
        hearing loss are only partially penetrant in the mouse (see limitations).
treatments:
- name: Supportive and multidisciplinary care
  description: >-
    There is no cure for HYAL2 deficiency. Management is supportive, coordinated
    by a multidisciplinary team (pediatric cardiology and cardiac surgery for
    cardiac anomalies, a craniofacial team for the clefting, and audiology and
    speech-language pathology for hearing and communication) to maximize function
    and reduce complications.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no cure for HYAL2 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
    explanation: >-
      GeneReviews states that management is supportive, with no curative therapy.
- name: Surgical repair of cleft and cardiac anomalies
  description: >-
    Surgical management is directed at the structural anomalies - staged
    craniofacial/cleft repair and cardiac surgery for the congenital cardiac
    anomalies (including cor triatriatum sinister when hemodynamically
    significant).
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "care by specialists in pediatric cardiology and cardiac surgery and a multidisciplinary craniofacial team to coordinate timing and type of surgical interventions"
    explanation: >-
      GeneReviews describes cardiac surgery and coordinated craniofacial surgical
      interventions as part of management.
  target_mechanisms:
  - target: Cleft lip
    treatment_effect: RESTORES
    description: >-
      Staged craniofacial/cleft surgery repairs the orofacial cleft, restoring
      the lip anatomy; symptomatic correction of the structural malformation
      rather than modification of the underlying developmental mechanism.
  - target: Cleft palate
    treatment_effect: RESTORES
    description: Cleft palate repair restores palatal continuity for feeding and speech.
  - target: Congenital cardiac anomalies
    treatment_effect: RESTORES
    description: >-
      Cardiac surgery corrects the congenital cardiac anomalies (including
      lesions requiring intervention in the first year of life).
  - target: Cor triatriatum sinister
    treatment_effect: RESTORES
    description: >-
      Surgical resection of the dividing left-atrial membrane corrects cor
      triatriatum sinister when hemodynamically significant.
- name: Genetic counseling
  description: >-
    Because HYAL2 deficiency is autosomal recessive, genetic counseling informs
    families of the 25% recurrence risk for sibs and the availability of carrier,
    prenatal, and preimplantation genetic testing once the familial variants are
    known.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the HYAL2 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk and prenatal and preimplantation genetic testing are possible."
    explanation: >-
      GeneReviews documents the genetic counseling and testing options that
      follow from recessive inheritance.
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews states the 25% sib recurrence risk that the genetic-counseling
      description reports.
diagnosis:
- name: Molecular genetic testing for biallelic HYAL2 variants
  description: >-
    The diagnosis is established in a proband with the suggestive craniofacial,
    cardiac, ophthalmic, otologic, and skeletal findings by identifying biallelic
    (homozygous or compound heterozygous) pathogenic HYAL2 variants on molecular
    genetic testing (exome or genome sequencing). There is no biochemical or
    functional assay in routine clinical use; molecular confirmation is the basis
    of diagnosis, and it also enables the carrier, prenatal, and preimplantation
    testing offered in genetic counseling.
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of HYAL2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in HYAL2 identified by molecular genetic testing."
    explanation: >-
      GeneReviews states the diagnostic criterion - suggestive findings plus
      biallelic pathogenic HYAL2 variants on molecular genetic testing.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare; GeneReviews (2023) summarizes 17 individuals from seven families
    reported to date.
  evidence:
  - reference: PMID:37733894
    reference_title: HYAL2 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 17 individuals from seven families have been reported with HYAL2 deficiency."
    explanation: >-
      Directly supports the ultra-rare, cases-in-literature occurrence of HYAL2
      deficiency.
references:
- reference: PMID:37733894
  title: HYAL2 Deficiency.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:37733894
HYAL2 Deficiency.
No top-level findings curated for this source.