Colobomatous Microphthalmia-Rhizomelic Dysplasia Syndrome

Mendelian MONDO:0014380 Pathograph 10 Show in embeddings browser Skeletal Dysplasia Syndromic microphthalmia

A recognizable syndrome combining severe structural eye malformation — anophthalmia, microphthalmia, or coloboma — with a skeletal dysplasia characterized by rhizomelic (proximal-segment) limb shortening and abnormal joint formation, and with intellectual disability. It is caused by heterozygous MAB21L2 variants; the recurrent de novo p.Arg51Cys substitution is the allele associated with the skeletal phenotype. MAB21L2 variants also cause isolated eye malformations without skeletal involvement, so this entry is scoped to the syndromic oculo-skeletal presentation rather than to the gene. Conditional deletion in the mouse limb bud delays endochondral ossification and reduces chondrocyte proliferation in the prospective humerus during a narrow window, which matches the proximal-segment distribution of the human phenotype.

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1
Inheritance
4
Pathophys.
4
Phenotypes
2
Gaps
10
Pathograph
1
Genes
2
Differentials
1
Models
2
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ISDS Skeletal Nosology
mesomelic and rhizomesomelic dysplasias
👪

Inheritance

1
Autosomal dominant, de novo HP:0000006
The skeletal-syndromic presentation arises from a heterozygous de novo MAB21L2 variant. Biallelic MAB21L2 variants have been reported in two brothers with ocular but no skeletal involvement, so allele dosage and zygosity do not map simply onto phenotype severity at this locus.
Autosomal dominant inheritance De novo rate: both delineating cases
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2."
Establishes heterozygous de novo inheritance for the syndromic presentation.
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Discussions and Knowledge Gaps

2
Why does p.Arg51Cys produce a skeletal dysplasia when other MAB21L2 alleles, including biallelic ones, produce eye malformation alone?
KNOWLEDGE GAP mab21l2_allele_specificity_of_skeletal_phenotype
Attached to
pathophysiology#MAB21L2 p.Arg51Cys Substitution
The nosology records biallelic MAB21L2 cases with ocular but no skeletal involvement, which is the opposite of what a simple dosage model predicts: two defective alleles giving less phenotype than one particular heterozygous substitution. That pattern points at a non-loss-of-function mechanism for the R51C allele specifically, but the available model is a conditional null, which cannot distinguish the two. A knockin of the human substitution, compared against the conditional null in the same limb driver, is the experiment.
What is the signal by which Mab21l2, expressed in distal limb-bud mesenchyme, controls proliferation in the proximal (stylopod) region?
KNOWLEDGE GAP mab21l2_non_autonomous_limb_action
Attached to
pathophysiology#Reduced Chondrocyte Proliferation in the Proximal Limb Bud
The expression domain and the affected structure do not coincide, and the authors conclude the gene acts non-autonomously. That is an unusual and informative arrangement — it means the phenotype is a signalling failure across the proximodistal axis rather than a cell-intrinsic defect — but the intermediary is unidentified, which is why the downstream edge in this entry stops at the proliferation node rather than naming a pathway.
⚙

Pathophysiology

4
MAB21L2 p.Arg51Cys Substitution
A specific recurrent substitution, not a generic MAB21L2 loss. The same residue change recurs in unrelated individuals with the oculo-skeletal phenotype, while other MAB21L2 alleles produce eye malformation without skeletal involvement — an allele-specific association that argues the skeletal phenotype is not simply the severe end of a dosage series. The same substitution modelled in transgenic mice reproduces severe appendicular skeletal anomalies.
MAB21L2 hgnc:6758 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAB21L2 (hgnc:6758). hgnc:6758 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context MAB21L2 hgnc:6758 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MAB21L2 (hgnc:6758). hgnc:6758 is a gene from the HUGO Gene Nomenclature Committee. allele_type: recurrent missense c.151C>T (p.Arg51Cys) variant_origin: DE_NOVO zygosity: HETEROZYGOUS
Downstream
Reduced Chondrocyte Proliferation in the Proximal Limb Bud Loss of MAB21L2 function in the early limb bud reduces proliferation in the prospective stylopod.
Disrupted Optic Cup and Fissure Morphogenesis The same allele acts on the eye, which is the organ MAB21L2 is best established to pattern.
Intellectual Disability Intellectual disability is a defining component of this syndrome and is not a feature of isolated MAB21L2-related eye disease, so it belongs to this allele rather than to the gene generally. No neurodevelopmental mechanism has been described, and the limb-restricted mouse model cannot address it.
Show evidence (2 references)
PMID:26116559 SUPPORT Human Clinical
"Recent exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma."
Places the syndromic presentation inside the MAB21L2 spectrum whose other end is isolated eye malformation.
PMID:40054064 SUPPORT Model Organism
"Human patients and transgenic mice with MAB21L2(R51C) mutation have severe skeletal anomalies in their appendicular skeleton."
States that the same specific allele produces appendicular skeletal anomalies in both species, supporting the allele-specific claim.
Disrupted Optic Cup and Fissure Morphogenesis
MAB21L2 is required for eye development, and its variants produce a graded range of structural eye malformation — coloboma where the optic fissure fails to close, microphthalmia where the optic cup is undergrown, anophthalmia at the severe end. This node records that the ocular and skeletal components of the syndrome are parallel consequences of the same allele rather than one causing the other. The cellular lesion in the eye has not been resolved to the same depth as the limb one.
MAB21L2 hgnc:6758 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAB21L2 (hgnc:6758). hgnc:6758 is a gene from the HUGO Gene Nomenclature Committee.
eye morphogenesis GO:0048592 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased eye morphogenesis (GO:0048592). GO:0048592 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Anophthalmia The severe end of the optic-cup phenotype, and what the two delineating individuals had.
Microphthalmia and Coloboma The milder expressions of the same morphogenetic failure; coloboma specifically reflects failed optic fissure closure.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma"
Establishes the range of structural eye malformation MAB21L2 variants produce, which is what this node represents.
Reduced Chondrocyte Proliferation in the Proximal Limb Bud
Conditional deletion of Mab21l2 in the mouse limb bud malforms the stylopods. The defect is developmentally narrow and specific: reduced chondrocyte proliferation in the prospective humerus region at E10.5, a critical window confined to E9.5-10.5, a smaller cartilage template by E13.5, a three-day delay in endochondral ossification, and humerus shortening at birth. Mab21l2 is expressed in the distal mesenchyme during that window while the affected structure is proximal, so the authors conclude it acts non-autonomously — the gene is not where the damage is.
limb bud chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves limb bud chondrocyte, annotated with chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
chondrocyte proliferation GO:0035988 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chondrocyte proliferation (GO:0035988). GO:0035988 is a biological process from the Gene Ontology. ↓ DECREASED endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Prx1-cre conditional Mab21l2 limb knockout Mouse recapitulates Deletion malforms the stylopod through reduced chondrocyte proliferation and delayed endochondral ossification.
Downstream
Shortened Proximal Limb Cartilage Template Fewer proliferating chondrocytes yield a smaller proximal cartilage template.
Show evidence (3 references)
PMID:40054064 SUPPORT Model Organism
"Reduced proliferation was noted in the chondrocytes of this perspective humerus region in Prx1-cre; Mab21l2flox/flox mice at E10.5. This defect may contribute to a smaller cartilage template found at E13.5 and the subsequent humerus shortening at birth."
Gives the measured proliferation defect and the chain from it to the shortened bone.
PMID:40054064 SUPPORT Model Organism
"Histological examination revealed a three-day delay of endochondral ossification in the Prx1-cre; Mab21l2flox/flox mice."
Quantifies the ossification delay in the conditional knockout.
PMID:40054064 SUPPORT Model Organism
"These results imply that Mab21l2 is acting non-autonomously to control stylopods development."
The non-autonomy conclusion, stated by the source as an implication rather than a demonstration.
Shortened Proximal Limb Cartilage Template
A smaller cartilage template in the prospective humerus and femur, the structural antecedent of the clinical rhizomelia. The proximal distribution is the point of correspondence with the mouse, whose conditional knockout malforms the stylopod specifically.
Downstream
Rhizomelic Limb Shortening The undersized proximal template ossifies into a short humerus and femur, with abnormal joint formation at their ends.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation."
Gives the defining radiographic phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Colobomatous Microphthalmia-Rhizomelic Dysplasia 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.
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Phenotypes

4
Eye 1
Microphthalmia and Coloboma FREQUENT HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma"
Establishes microphthalmia and coloboma as part of the MAB21L2 ocular spectrum.
Nervous System 1
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability."
Intellectual disability is one of the three defining components.
Growth 1
Rhizomelic Limb Shortening VERY_FREQUENT Rhizomelia HP:0008905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhizomelia (HP:0008905). HP:0008905 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation."
States the rhizomelic distribution and the joint abnormality.
Other 1
Anophthalmia VERY_FREQUENT HP:0000528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anophthalmia (HP:0000528). HP:0000528 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability."
Names anophthalmia as the ocular component of the delineating phenotype.
🧬

Genetic Associations

1
MAB21L2
Gene: MAB21L2 hgnc:6758 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAB21L2 (hgnc:6758). hgnc:6758 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2."
Establishes the specific recurrent allele in two unrelated individuals.
🔬

Diagnosis

2
Recognition of the Oculo-Skeletal Pattern
Suspected when a severe structural eye malformation is accompanied by rhizomelic limb shortening and intellectual disability. The eye phenotype is what usually presents; the skeletal component is what distinguishes this syndrome from the far commoner isolated MAC spectrum, so limb radiographs in a child with anophthalmia or microphthalmia are the discriminating step.
physical examination NCIT:C20989 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability."
Supports recognizability of the three-component pattern.
Molecular Confirmation
Confirmed by a heterozygous MAB21L2 variant, characteristically the recurrent p.Arg51Cys substitution. MAB21L2 is on standard MAC gene panels, so the gene is usually tested; the interpretive work is in recognizing that a particular allele carries the skeletal risk.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2."
Names the confirming allele.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Delineated on two unrelated individuals carrying the same de novo variant; further cases have been reported since within the broader MAB21L2 phenotypic spectrum. No denominator-based estimate exists, and the count here is for the syndromic oculo-skeletal presentation rather than for MAB21L2-related eye disease as a whole.
Show evidence (1 reference)
PMID:26116559 SUPPORT Human Clinical
"The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2."
Gives the size and composition of the delineating series.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Colobomatous Microphthalmia-Rhizomelic Dysplasia Syndrome:

Isolated microphthalmia with coloboma
Overlapping Features The non-syndromic MAC spectrum, curated separately in dismech and itself including MAB21L2-related cases. It shares the gene but not the skeletal dysplasia, and it is not assigned to the ISDS nosology.
🐁

Animal Models

1
Prx1-cre conditional Mab21l2 limb knockout
Limb-bud-restricted deletion, which isolates the skeletal phenotype from the ocular one and pins the requirement to a narrow developmental window.
Species
Mouse
Genotype
Prx1-cre; Mab21l2 flox/flox
Publication
PMID:40054064
Pathograph links
Reduced Chondrocyte Proliferation in the Proximal Limb Bud recapitulates fidelity: moderate Deletion malforms the stylopod through reduced chondrocyte proliferation and delayed endochondral ossification.
Limitations: This is a conditional null, whereas the human disorder is caused by a specific heterozygous missense allele; the model therefore tests what MAB21L2 does in the limb rather than what p.Arg51Cys does to it. The Prx1-cre driver also restricts deletion to limb mesenchyme, so the model says nothing about the ocular or cognitive components.
Readouts
Chondrocyte proliferation in the prospective humerus at E10.5
Direction: DECREASED
Interpretation: The proliferation deficit is the earliest measured lesion in the chain to a shortened humerus.
Show evidence (1 reference)
PMID:40054064 SUPPORT Model Organism
"Reduced proliferation was noted in the chondrocytes of this perspective humerus region in Prx1-cre; Mab21l2flox/flox mice at E10.5."
Reports the measured proliferation reduction at the stated stage.
Timing of endochondral ossification
Direction: DECREASED
Interpretation: A three-day delay, which is the histological correlate of the shortened proximal segment.
Show evidence (1 reference)
PMID:40054064 SUPPORT Model Organism
"Histological examination revealed a three-day delay of endochondral ossification in the Prx1-cre; Mab21l2flox/flox mice."
Reports the measured ossification delay.
Show evidence (1 reference)
PMID:40054064 SUPPORT Model Organism
"By conditional gene knockout model, we found that removing Mab21l2 by Prx1-cre during early limb development led to malformation of the stylopods."
Establishes that limb-restricted Mab21l2 loss is sufficient for the proximal skeletal phenotype, which is what makes this model informative for the node.
{ }

Source YAML

click to show 
name: Colobomatous Microphthalmia-Rhizomelic Dysplasia Syndrome
synonyms:
- Oculo-skeletal syndrome with rhizomelic shortening, MAB21L2-related
- microphthalmia/coloboma and skeletal dysplasia syndrome
- MAB21L2-related oculo-skeletal syndrome
- MCOPS14
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  A recognizable syndrome combining severe structural eye malformation —
  anophthalmia, microphthalmia, or coloboma — with a skeletal dysplasia
  characterized by rhizomelic (proximal-segment) limb shortening and abnormal
  joint formation, and with intellectual disability. It is caused by
  heterozygous MAB21L2 variants; the recurrent de novo p.Arg51Cys substitution
  is the allele associated with the skeletal phenotype. MAB21L2 variants also
  cause isolated eye malformations without skeletal involvement, so this entry
  is scoped to the syndromic oculo-skeletal presentation rather than to the
  gene. Conditional deletion in the mouse limb bud delays endochondral
  ossification and reduces chondrocyte proliferation in the prospective humerus
  during a narrow window, which matches the proximal-segment distribution of the
  human phenotype.
disease_term:
  preferred_term: colobomatous microphthalmia-rhizomelic dysplasia syndrome
  term:
    id: MONDO:0014380
    label: colobomatous microphthalmia-rhizomelic dysplasia syndrome
parents:
- Skeletal Dysplasia
- Syndromic microphthalmia
notes: >-
  Scope, and why it is not merged with the MAC entry. dismech separately curates
  ``Microphthalmia_with_Coloboma``, which is explicitly scoped to the isolated,
  non-syndromic MAC spectrum and carries MAB21L2 as one of its subtypes. That
  entry and this one are different concepts sharing a gene: there, MAB21L2 is
  one of many genes converging on optic-fissure closure; here, the skeletal
  dysplasia is the point, and it is the reason the ISDS Nosology lists the
  entity at all. Neither entry should take the other's classification — in
  particular, the isolated MAC entry must not be given an ISDS group-15
  assignment on the strength of this row.

  Note also that the nosology places a *rhizomelic* entity in a group defined by
  *mesomelic* shortening. The group's own name accommodates this — "mesomelic
  and rhizo-mesomelic" — but a reader scanning for mesomelia will not expect it.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian multisystem developmental disorder; tagged on the genetics
      axis.
  isds_skeletal_category:
  - classification_value: mesomelic_and_rhizomesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 15 "Mesomelic and rhizo-mesomelic dysplasias", row
      NOS 15-0170, listed as "Oculo-skeletal syndrome with rhizomelic
      shortening, MAB21L2-related" (MIM 615877, AD). The row's own comment notes
      that OMIM calls it "Microphthalmia/Coloboma and skeletal dysplasia
      syndrome", that skeletal involvement is not present in all individuals,
      and that two brothers with biallelic variants had ocular but no skeletal
      involvement. The assignment is to this syndromic oculo-skeletal entity;
      the dismech ``Microphthalmia_with_Coloboma`` entry, scoped to isolated
      non-syndromic MAC, is deliberately left unassigned. The 2019 revision
      (Mortier et al., PMID:31633310) numbered the same group 17.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Delineated on two unrelated individuals carrying the same de novo variant;
    further cases have been reported since within the broader MAB21L2 phenotypic
    spectrum. No denominator-based estimate exists, and the count here is for
    the syndromic oculo-skeletal presentation rather than for MAB21L2-related
    eye disease as a whole.
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two unrelated individuals described here in detail are heterozygous
      carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in
      MAB21L2.
    explanation: >-
      Gives the size and composition of the delineating series.
inheritance:
- name: Autosomal dominant, de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: "both delineating cases"
  description: >-
    The skeletal-syndromic presentation arises from a heterozygous de novo
    MAB21L2 variant. Biallelic MAB21L2 variants have been reported in two
    brothers with ocular but no skeletal involvement, so allele dosage and
    zygosity do not map simply onto phenotype severity at this locus.
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two unrelated individuals described here in detail are heterozygous
      carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in
      MAB21L2.
    explanation: >-
      Establishes heterozygous de novo inheritance for the syndromic
      presentation.
pathophysiology:
- name: MAB21L2 p.Arg51Cys Substitution
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
  genetic_context:
    gene:
      preferred_term: MAB21L2
      term:
        id: hgnc:6758
        label: MAB21L2
    allele_type: recurrent missense c.151C>T (p.Arg51Cys)
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
  description: >-
    A specific recurrent substitution, not a generic MAB21L2 loss. The same
    residue change recurs in unrelated individuals with the oculo-skeletal
    phenotype, while other MAB21L2 alleles produce eye malformation without
    skeletal involvement — an allele-specific association that argues the
    skeletal phenotype is not simply the severe end of a dosage series. The same
    substitution modelled in transgenic mice reproduces severe appendicular
    skeletal anomalies.
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent exome studies showed that these characteristics are part of the
      phenotypic spectrum of MAB21L2 gene mutations which cause a range of
      structural eye malformations such as microphthalmia/anophthalmia and
      ocular coloboma.
    explanation: >-
      Places the syndromic presentation inside the MAB21L2 spectrum whose other
      end is isolated eye malformation.
  - reference: PMID:40054064
    reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Human patients and transgenic mice with MAB21L2(R51C) mutation have severe
      skeletal anomalies in their appendicular skeleton.
    explanation: >-
      States that the same specific allele produces appendicular skeletal
      anomalies in both species, supporting the allele-specific claim.
  downstream:
  - target: Reduced Chondrocyte Proliferation in the Proximal Limb Bud
    causal_link_type: DIRECT
    description: >-
      Loss of MAB21L2 function in the early limb bud reduces proliferation in
      the prospective stylopod.
  - target: Disrupted Optic Cup and Fissure Morphogenesis
    causal_link_type: DIRECT
    description: >-
      The same allele acts on the eye, which is the organ MAB21L2 is best
      established to pattern.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Intellectual disability is a defining component of this syndrome and is
      not a feature of isolated MAB21L2-related eye disease, so it belongs to
      this allele rather than to the gene generally. No neurodevelopmental
      mechanism has been described, and the limb-restricted mouse model cannot
      address it.
- name: Disrupted Optic Cup and Fissure Morphogenesis
  biological_scale: TISSUE
  genes:
  - preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
  description: >-
    MAB21L2 is required for eye development, and its variants produce a graded
    range of structural eye malformation — coloboma where the optic fissure
    fails to close, microphthalmia where the optic cup is undergrown,
    anophthalmia at the severe end. This node records that the ocular and
    skeletal components of the syndrome are parallel consequences of the same
    allele rather than one causing the other. The cellular lesion in the eye has
    not been resolved to the same depth as the limb one.
  biological_processes:
  - preferred_term: eye morphogenesis
    modifier: DECREASED
    term:
      id: GO:0048592
      label: eye morphogenesis
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MAB21L2 gene mutations which cause a range of structural eye malformations
      such as microphthalmia/anophthalmia and ocular coloboma
    explanation: >-
      Establishes the range of structural eye malformation MAB21L2 variants
      produce, which is what this node represents.
  downstream:
  - target: Anophthalmia
    causal_link_type: DIRECT
    description: >-
      The severe end of the optic-cup phenotype, and what the two delineating
      individuals had.
  - target: Microphthalmia and Coloboma
    causal_link_type: DIRECT
    description: >-
      The milder expressions of the same morphogenetic failure; coloboma
      specifically reflects failed optic fissure closure.
- name: Reduced Chondrocyte Proliferation in the Proximal Limb Bud
  biological_scale: CELLULAR
  description: >-
    Conditional deletion of Mab21l2 in the mouse limb bud malforms the
    stylopods. The defect is developmentally narrow and specific: reduced
    chondrocyte proliferation in the prospective humerus region at E10.5, a
    critical window confined to E9.5-10.5, a smaller cartilage template by
    E13.5, a three-day delay in endochondral ossification, and humerus
    shortening at birth. Mab21l2 is expressed in the distal mesenchyme during
    that window while the affected structure is proximal, so the authors conclude
    it acts non-autonomously — the gene is not where the damage is.
  cell_types:
  - preferred_term: limb bud chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte proliferation
    modifier: DECREASED
    term:
      id: GO:0035988
      label: chondrocyte proliferation
  - preferred_term: endochondral ossification
    modifier: DECREASED
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:40054064
    reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reduced proliferation was noted in the chondrocytes of this perspective
      humerus region in Prx1-cre; Mab21l2flox/flox mice at E10.5. This defect
      may contribute to a smaller cartilage template found at E13.5 and the
      subsequent humerus shortening at birth.
    explanation: >-
      Gives the measured proliferation defect and the chain from it to the
      shortened bone.
  - reference: PMID:40054064
    reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histological examination revealed a three-day delay of endochondral
      ossification in the Prx1-cre; Mab21l2flox/flox mice.
    explanation: >-
      Quantifies the ossification delay in the conditional knockout.
  - reference: PMID:40054064
    reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results imply that Mab21l2 is acting non-autonomously to control
      stylopods development.
    explanation: >-
      The non-autonomy conclusion, stated by the source as an implication rather
      than a demonstration.
  downstream:
  - target: Shortened Proximal Limb Cartilage Template
    causal_link_type: DIRECT
    description: >-
      Fewer proliferating chondrocytes yield a smaller proximal cartilage
      template.
- name: Shortened Proximal Limb Cartilage Template
  biological_scale: TISSUE
  description: >-
    A smaller cartilage template in the prospective humerus and femur, the
    structural antecedent of the clinical rhizomelia. The proximal distribution
    is the point of correspondence with the mouse, whose conditional knockout
    malforms the stylopod specifically.
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic anomalies include severe rhizomelic shortness of the limbs
      and abnormal joint formation.
    explanation: >-
      Gives the defining radiographic phenotype.
  downstream:
  - target: Rhizomelic Limb Shortening
    causal_link_type: DIRECT
    description: >-
      The undersized proximal template ossifies into a short humerus and femur,
      with abnormal joint formation at their ends.
phenotypes:
- category: Skeletal
  name: Rhizomelic Limb Shortening
  description: >-
    Severe shortening of the proximal limb segments with abnormal joint
    formation. Skeletal involvement is not universal in MAB21L2-related disease
    — the nosology records biallelic cases with ocular but no skeletal
    phenotype — so its absence does not exclude a MAB21L2 diagnosis, only this
    syndromic presentation.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic anomalies include severe rhizomelic shortness of the limbs
      and abnormal joint formation.
    explanation: >-
      States the rhizomelic distribution and the joint abnormality.
- category: Ocular
  name: Anophthalmia
  description: >-
    The delineating cases had anophthalmia; microphthalmia and coloboma occupy
    the same MAB21L2 spectrum and may appear instead.
  phenotype_term:
    preferred_term: Anophthalmia
    term:
      id: HP:0000528
      label: Anophthalmia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel recognizable phenotype characterized by anophthalmia,
      a distinctive skeletal dysplasia and intellectual disability.
    explanation: >-
      Names anophthalmia as the ocular component of the delineating phenotype.
- category: Ocular
  name: Microphthalmia and Coloboma
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  frequency: FREQUENT
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MAB21L2 gene mutations which cause a range of structural eye malformations
      such as microphthalmia/anophthalmia and ocular coloboma
    explanation: >-
      Establishes microphthalmia and coloboma as part of the MAB21L2 ocular
      spectrum.
- category: Neurologic
  name: Intellectual Disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel recognizable phenotype characterized by anophthalmia,
      a distinctive skeletal dysplasia and intellectual disability.
    explanation: >-
      Intellectual disability is one of the three defining components.
genetic:
- name: MAB21L2
  gene_term:
    preferred_term: MAB21L2
    term:
      id: hgnc:6758
      label: MAB21L2
  relationship_type: CAUSATIVE
  notes: >-
    A male abnormal 21 like 2 family member, required for eye and limb
    development. The oculo-skeletal presentation is associated specifically with
    the recurrent p.Arg51Cys substitution; other MAB21L2 alleles give eye
    malformation without a skeletal phenotype, and biallelic alleles have been
    reported with ocular involvement only. Reporting a MAB21L2 variant as causal
    for this syndrome therefore requires attention to which allele it is, not
    only to which gene.
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two unrelated individuals described here in detail are heterozygous
      carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in
      MAB21L2.
    explanation: >-
      Establishes the specific recurrent allele in two unrelated individuals.
animal_models:
- name: Prx1-cre conditional Mab21l2 limb knockout
  species: Mouse
  genotype: Prx1-cre; Mab21l2 flox/flox
  publication: PMID:40054064
  description: >-
    Limb-bud-restricted deletion, which isolates the skeletal phenotype from the
    ocular one and pins the requirement to a narrow developmental window.
  modeled_mechanisms:
  - target: Reduced Chondrocyte Proliferation in the Proximal Limb Bud
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Deletion malforms the stylopod through reduced chondrocyte proliferation
      and delayed endochondral ossification.
    limitations: >-
      This is a conditional null, whereas the human disorder is caused by a
      specific heterozygous missense allele; the model therefore tests what
      MAB21L2 does in the limb rather than what p.Arg51Cys does to it. The
      Prx1-cre driver also restricts deletion to limb mesenchyme, so the model
      says nothing about the ocular or cognitive components.
    readouts:
    - name: Chondrocyte proliferation in the prospective humerus at E10.5
      target: Reduced Chondrocyte Proliferation in the Proximal Limb Bud
      direction: DECREASED
      interpretation: >-
        The proliferation deficit is the earliest measured lesion in the chain
        to a shortened humerus.
      evidence:
      - reference: PMID:40054064
        reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Reduced proliferation was noted in the chondrocytes of this
          perspective humerus region in Prx1-cre; Mab21l2flox/flox mice at
          E10.5.
        explanation: >-
          Reports the measured proliferation reduction at the stated stage.
    - name: Timing of endochondral ossification
      target: Reduced Chondrocyte Proliferation in the Proximal Limb Bud
      direction: DECREASED
      interpretation: >-
        A three-day delay, which is the histological correlate of the shortened
        proximal segment.
      evidence:
      - reference: PMID:40054064
        reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Histological examination revealed a three-day delay of endochondral
          ossification in the Prx1-cre; Mab21l2flox/flox mice.
        explanation: >-
          Reports the measured ossification delay.
    evidence:
    - reference: PMID:40054064
      reference_title: "Mab21l2 is required to promote cell proliferation in stylopods during early limb development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        By conditional gene knockout model, we found that removing Mab21l2 by
        Prx1-cre during early limb development led to malformation of the
        stylopods.
      explanation: >-
        Establishes that limb-restricted Mab21l2 loss is sufficient for the
        proximal skeletal phenotype, which is what makes this model informative
        for the node.
diagnosis:
- name: Recognition of the Oculo-Skeletal Pattern
  description: >-
    Suspected when a severe structural eye malformation is accompanied by
    rhizomelic limb shortening and intellectual disability. The eye phenotype is
    what usually presents; the skeletal component is what distinguishes this
    syndrome from the far commoner isolated MAC spectrum, so limb radiographs in
    a child with anophthalmia or microphthalmia are the discriminating step.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel recognizable phenotype characterized by anophthalmia,
      a distinctive skeletal dysplasia and intellectual disability.
    explanation: >-
      Supports recognizability of the three-component pattern.
- name: Molecular Confirmation
  description: >-
    Confirmed by a heterozygous MAB21L2 variant, characteristically the
    recurrent p.Arg51Cys substitution. MAB21L2 is on standard MAC gene panels,
    so the gene is usually tested; the interpretive work is in recognizing that
    a particular allele carries the skeletal risk.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:26116559
    reference_title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two unrelated individuals described here in detail are heterozygous
      carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in
      MAB21L2.
    explanation: >-
      Names the confirming allele.
differential_diagnoses:
- name: Isolated microphthalmia with coloboma
  description: >-
    The non-syndromic MAC spectrum, curated separately in dismech and itself
    including MAB21L2-related cases. It shares the gene but not the skeletal
    dysplasia, and it is not assigned to the ISDS nosology.
- name: Matthew-Wood syndrome (STRA6-related)
  description: >-
    Another syndromic microphthalmia with extraocular malformations, but with
    pulmonary and diaphragmatic rather than rhizomelic skeletal involvement.
discussions:
- discussion_id: mab21l2_allele_specificity_of_skeletal_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does p.Arg51Cys produce a skeletal dysplasia when other MAB21L2 alleles,
    including biallelic ones, produce eye malformation alone?
  attaches_to:
  - pathophysiology#MAB21L2 p.Arg51Cys Substitution
  rationale: >-
    The nosology records biallelic MAB21L2 cases with ocular but no skeletal
    involvement, which is the opposite of what a simple dosage model predicts:
    two defective alleles giving less phenotype than one particular
    heterozygous substitution. That pattern points at a non-loss-of-function
    mechanism for the R51C allele specifically, but the available model is a
    conditional null, which cannot distinguish the two. A knockin of the human
    substitution, compared against the conditional null in the same limb driver,
    is the experiment.
- discussion_id: mab21l2_non_autonomous_limb_action
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the signal by which Mab21l2, expressed in distal limb-bud
    mesenchyme, controls proliferation in the proximal (stylopod) region?
  attaches_to:
  - pathophysiology#Reduced Chondrocyte Proliferation in the Proximal Limb Bud
  rationale: >-
    The expression domain and the affected structure do not coincide, and the
    authors conclude the gene acts non-autonomously. That is an unusual and
    informative arrangement — it means the phenotype is a signalling failure
    across the proximodistal axis rather than a cell-intrinsic defect — but the
    intermediary is unidentified, which is why the downstream edge in this entry
    stops at the proliferation node rather than naming a pathway.
references:
- reference: PMID:26116559
  title: "A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation."
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
📚

References & Deep Research

References

2
PMID:26116559
A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation.
No top-level findings curated for this source.
PMID:36779427
Nosology of genetic skeletal disorders: 2023 revision.
No top-level findings curated for this source.