Spondylometaphyseal Dysplasia with Corneal Dystrophy

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Recessive HP:0000007

SMDCD is autosomal recessive. Both affected cousins are homozygous for PLCB3 c.2632G>T; all four parents and all healthy siblings are heterozygous, and homozygosity mapping under a recessive model with complete penetrance is what localised the locus to 11q12.1-q13.1.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Only the patients (IV-1 and IV-3) were found to be homozygous for these variants, while all healthy individuals were heterozygous"

Segregation consistent with autosomal recessive inheritance in an extended consanguineous pedigree.

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Discussions and Knowledge Gaps

2

Is SMDCD an established gene-disease relationship, given that it rests on one homozygous missense allele in two cousins from a single family?

KNOWLEDGE GAP OPEN smdcd_single_family_evidence_base

Attached to

disease#Spondylometaphyseal Dysplasia with Corneal Dystrophy

Every clinical and molecular statement about this disorder comes from one report of one consanguineous pedigree. The linkage interval spanned 19.3 Mb and 487 genes, and four homozygous candidate variants survived filtering; PLCB3 was selected partly on the prior that phospholipid-metabolism genes such as PLCB4 and PCYT1A cause bone dysplasia, and the three competitors were excluded by functional assays rather than by independent genetic replication. The functional work is good, but no second family has been published, so the relationship has not been replicated in the way a gene-disease assertion normally requires. The ISDS nosology nonetheless lists it as a distinct entity, which this entry follows while recording the limitation.

Proposed experiments

Seek independent PLCB3 families through matchmaking

exp_smdcd_independent_replication

Submit the PLCB3 phenotype to GeneMatcher and equivalent matchmaking services and to skeletal dysplasia consortia, and reanalyse unsolved neonatal corneal-clouding-plus-skeletal-dysplasia exomes for biallelic PLCB3 variants.

Would support

pathophysiology#Homozygous PLCB3 p.Ala878Ser

Would refute

pathophysiology#Homozygous PLCB3 p.Ala878Ser

Supporting outcome

A second unrelated family with biallelic PLCB3 variants and a matching phenotype would convert the assertion from single-family to replicated.

Refuting outcome

Identification of a pathogenic variant in one of the other candidate genes in the interval in a second family with the same phenotype would reopen the gene assignment.

Show evidence (2 references)

PMID:29122926 SUPPORT Human Clinical

"Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ~490 genes."

The size of the linkage interval is what makes independent replication, rather than functional exclusion of competitors, the missing evidence.

PMID:29122926 SUPPORT INDIRECT Human Clinical

"Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate."

Candidate selection was partly driven by a pathway prior, which is a legitimate heuristic but not independent evidence.

How does a fibroblast actin phenotype account for a growth-plate dysplasia, a corneal opacity, and severe developmental delay?

KNOWLEDGE GAP OPEN smdcd_actin_to_organ_lesion_gap

Attached to

pathophysiology#F-Actin Cytoskeletal Disorganisation

The mechanism is demonstrated as far as the fibroblast and stops there. Three distinct organ lesions are attributed to it, in tissues that were never assayed. Zebrafish plcb3 nulls give some support for the skeletal branch, but mouse Plcb3 disruption is embryonic lethal and further knockout models gave discordant results that the authors attribute to how the gene was disrupted — so there is no settled animal model either. The corneal branch is the weakest: nothing connects phosphoinositide signalling to corneal stromal transparency, and the opacity is present within days of birth, implying a developmental rather than a degenerative process.

Proposed experiments

Hypomorphic Plcb3 knock-in and human tissue-specific models

exp_smdcd_hypomorphic_knockin_and_tissue_models

Generate a knock-in carrying the human p.A878S hypomorph rather than a null, so that animals survive, and phenotype the growth plate, cornea, and brain. Complement with patient iPSC-derived chondrocytes and corneal keratocytes assayed for PIP2, actin organisation, and tissue-specific differentiation.

Would support

pathophysiology#Corneal Dystrophy

Would refute

pathophysiology#F-Actin Cytoskeletal Disorganisation

Supporting outcome

Corneal opacity and a spondylometaphyseal skeletal phenotype in hypomorphic animals would establish that the single allele accounts for the organ lesions.

Refuting outcome

Normal actin organisation in patient-derived chondrocytes and keratocytes despite the skeletal and corneal phenotypes would show the fibroblast actin finding is not the operative mechanism in the affected tissues.

Show evidence (2 references)

PMID:29122926 SUPPORT INDIRECT Model Organism

"In mice, targeted disruption of plcb3 results in embryonic lethality."

The lethality of the mouse null is why no mammalian model of the organ lesions exists.

PMID:29122926 SUPPORT INDIRECT Model Organism

"However, further Plcb3 knockout models showed discordant results."

Discordance between knockout models means the existing animal evidence cannot arbitrate the organ mechanisms.

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Pathophysiology

6

Homozygous PLCB3 p.Ala878Ser

A conserved alanine in the Ha2' element of the proximal C-terminal domain is replaced by serine. The Ha2' element normally docks onto the catalytic core; the substitution disrupts that interaction.

PLCB3 hgnc:9056

Downstream

Destabilised Phospholipase C Beta 3 with Reduced Activity Loss of the Ha2'-to-catalytic-core interaction destabilises the protein and reduces its enzymatic activity. The allele is hypomorphic rather than null, which matters because targeted disruption of Plcb3 in mouse is embryonic lethal.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain."

The initiating molecular lesion.

Destabilised Phospholipase C Beta 3 with Reduced Activity

PLCB3 catalyses production of diacylglycerol and inositol 1,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate, and is activated by G-protein alpha-q and alpha-11 subunits and by beta-gamma subunits. The p.A878S protein is destabilised and hypomorphic, so signalling downstream of Gq-coupled receptors is attenuated and the substrate is not consumed.

phospholipase C activity GO:0004629 ↓ DECREASED

Downstream

Accumulation of Phosphatidylinositol 4,5-Bisphosphate With the hydrolysing enzyme impaired, its substrate builds up. This was measured directly in patient fibroblasts by anti-PtdIns(4,5)P2 immunofluorescence.

Show evidence (1 reference)

PMID:29122926 SUPPORT In Vitro

"the identified PLCB3:NM_000932:c.2632G>T variant destabilises the protein and reduces its enzymatic activity, leading to PIP2 accumulation"

Links the destabilisation directly to reduced catalysis and to substrate accumulation.

Accumulation of Phosphatidylinositol 4,5-Bisphosphate

PIP2 is elevated in patient fibroblasts. PIP2 is not merely a signalling precursor but a direct regulator of actin-binding proteins at the plasma membrane, which is the route by which a signalling-enzyme defect becomes a structural cytoskeletal defect.

phosphatidylinositol-mediated signaling GO:0048015 ↓ DECREASED

Downstream

F-Actin Cytoskeletal Disorganisation Excess PIP2 disorganises the actin cytoskeleton. The phenotype is the same one seen in Lowe syndrome fibroblasts, where the defect is in a different phosphoinositide-metabolising enzyme, which is the convergence argument that makes the link mechanistic rather than incidental.

Show evidence (1 reference)

PMID:29122926 SUPPORT In Vitro

"Here we show that this hypomorphic variant leads to elevated levels of PIP2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton."

Measures the substrate accumulation in patient material.

F-Actin Cytoskeletal Disorganisation

Patient fibroblasts are significantly larger than controls, with a weaker F-actin network and a more punctate appearance, scored blind to genotype using an established four-pattern classification of stress-fibre number and length. How this cellular phenotype produces a growth-plate lesion, a corneal opacity, and developmental delay is not established.

fibroblast CL:0000057

actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

actin filament GO:0005884

Experimental models

SMDCD patient-derived dermal fibroblasts PRIMARY CELL CULTURE The patient fibroblast is the only human cellular system reported for this disorder and carries both the substrate-accumulation and the cytoskeletal findings.

Downstream

Spondylometaphyseal Skeletal Dysplasia The skeletal lesion is attributed to disturbed phosphoinositide signalling during skeletal development, supported by expression of Plcb3 in bone, cartilage, and neural crest in zebrafish and by abnormal skeletal patterning with malformed facial and thoracic bones in zebrafish plcb3 null mutants. The intervening steps in human cartilage have not been demonstrated.

Severe Developmental Delay Severe global developmental delay is part of the syndrome and PLCB3 is most highly expressed in brain, but no step between the phosphoinositide defect and the neurodevelopmental phenotype has been demonstrated. Prematurity and chronic respiratory failure are uncontrolled confounders in both reported children.

Hypertelorism with Depressed Nasal Bridge A consistent facial gestalt across both affected cousins. Facial morphogenesis is neural-crest-dependent and zebrafish plcb3 is expressed in neural crest, but the connection is an inference from expression rather than a demonstrated mechanism.

Patent Ductus Arteriosus A large patent ductus arteriosus occurred in both affected children. Both were also born preterm — at 29 and 27 weeks — and prematurity alone is a sufficient explanation for a persistent duct, so this edge is left with directness UNKNOWN rather than asserted as part of the syndrome.

Corneal Dystrophy The corneal opacity is present within days of birth and is confined to the cornea, with normal retinas, optic nerves, vitreous, and posterior lens on ophthalmological and B-scan assessment. No mechanism connecting the phosphoinositide defect to corneal stromal transparency has been proposed.

Show evidence (1 reference)

PMID:29122926 SUPPORT In Vitro

"Patient fibroblasts are significantly larger with a weaker F-actin network and more punctuate appearance."

The measured cellular phenotype in patient-derived cells.

Spondylometaphyseal Skeletal Dysplasia

Profound limb shortening involving both proximal and distal segments, with short fingers and toes and a narrow chest. Radiographs show short long bones with wide metaphyses and coarse metaphyseal trabeculae, cupping of the distal radius and ulna, uncalcified distal femoral and proximal tibial epiphyses in the neonate, short ribs with a wide anterior aspect, anterior beaking of the lumbar and thoracic vertebrae with wide intervertebral spaces, and almost square, short iliac bones with medial projections. The iliac shape was close enough to Schneckenbecken dysplasia that SLC35D1 was sequenced and excluded before the locus was mapped.

Downstream

Profound Limb Shortening Micromelia involving both proximal and distal segments, detectable on prenatal ultrasound.

Metaphyseal Widening Wide metaphyses with coarse trabeculae and distal forearm cupping.

Anterior Vertebral Beaking Anterior beaks on the lumbar and thoracic bodies with wide intervertebral spaces.

Severe Postnatal Growth Deficiency Growth deficiency that is postnatal in onset: birth weight was above the 25th centile in the proband, while weight and height were both far below the third by four years.

Narrow Chest with Pulmonary Hypoplasia Short, anteriorly wide ribs give a narrow thorax that constrains lung growth. This is the feature that dominates the natural history and determines survival.

Show evidence (2 references)

PMID:29122926 SUPPORT Human Clinical

"Skeletal survey (figure 1B) showed short long bones with wide metaphyses and some coarse trabecule at the metaphyses."

The primary radiographic description of the skeletal lesion.

PMID:29122926 SUPPORT Human Clinical

"The lumbar and thoracic vertebrae had beaks at their anterior aspects, and the intervertebral spaces were wide."

The vertebral component that makes this a spondylometaphyseal rather than a purely metaphyseal dysplasia.

Corneal Dystrophy

Bilateral corneal clouding evident within the first days of life. In the second cousin the corneas showed vascularised opacities with central thickened white cream-coloured tissue and a thinner greyish periphery over an epithelialised surface. Both children underwent corneal grafting; one experienced graft rejection. Screening for a storage disease — white cell inclusions, urine mucopolysaccharides and oligosaccharides — was negative, which is the standard first differential for neonatal corneal clouding.

Downstream

Corneal Clouding Bilateral corneal opacity apparent within the first two weeks of life, with normal retinas behind it.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Ophthalmological evaluation showed bilateral vascularised corneal opacities with central thickened white cream-coloured tissue and thinner greyish periphery; the surface of the cornea was epithelised."

The detailed corneal description in the second affected cousin.

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Pathograph

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

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Phenotypes

9

Cardiovascular 1

Patent Ductus Arteriosus VERY_FREQUENT HP:0001643

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Echocardiography showed a large patent ductus arteriosus, which eventually required surgical correction."

Documents the cardiac lesion in the proband; both children were preterm, so prematurity is a confounder for this feature specifically.

Eye 2

Corneal Clouding OBLIGATE Corneal opacity HP:0007957

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"He was noted to have bilateral corneal clouding on day 12."

Documents the corneal opacity and its neonatal onset in the proband.

Hypertelorism with Depressed Nasal Bridge VERY_FREQUENT HP:0000316

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"There was hypertelorism, prominent eyes, depressed nasal bridge and short upturned nose."

The facial phenotype as recorded in the proband.

Limbs 2

Profound Limb Shortening OBLIGATE Micromelia HP:0002983

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"On examination, he had short limbs, with proximal and distal segments involved."

Documents the pattern of limb shortening in the proband.

Metaphyseal Widening OBLIGATE HP:0003016

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Skeletal survey (figure 1B) showed short long bones with wide metaphyses and some coarse trabecule at the metaphyses."

Documents the metaphyseal component of the radiographic phenotype.

Nervous System 1

Severe Developmental Delay OBLIGATE Global developmental delay HP:0001263

Severity: SEVERE

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Currently, he is 6 years old with severe developmental delay."

Documents the severity of the developmental phenotype at age six.

Respiratory 1

Narrow Chest with Pulmonary Hypoplasia OBLIGATE HP:0002089

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"The baby had a stormy neonatal period and was difficult to wean off the ventilator due to the narrow chest and hypoplastic lungs."

Attributes the ventilator dependence directly to the thoracic and pulmonary hypoplasia.

Growth 1

Severe Postnatal Growth Deficiency OBLIGATE Severe short stature HP:0003510

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability."

The summary clinical description, establishing postnatal growth deficiency alongside the other core features.

Other 1

Anterior Vertebral Beaking OBLIGATE Anterior beaking of lumbar vertebrae HP:0008430

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"The lumbar and thoracic vertebrae had beaks at their anterior aspects, and the intervertebral spaces were wide."

Documents the vertebral morphology.

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Genetic Associations

1

Homozygous PLCB3 c.2632G>T (p.Ala878Ser) (Causative)

Gene: PLCB3 hgnc:9056 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:29122926 SUPPORT Human Clinical

"The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain."

Names the allele and its structural location within the protein.

PMID:29122926 SUPPORT Human Clinical

"This variant affects all three different coding isoforms of PLCB3, and this position is highly conserved at the DNA and protein levels between vertebrates and mammalians"

Conservation and isoform coverage are the population-genetic arguments for pathogenicity in a single-family report.

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Medical Actions

4

Corneal Grafting

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Both affected children underwent bilateral corneal grafting — one at six months, followed by tarsorrhaphy and keratoplasty. Outcomes were mixed: the second child experienced graft rejection, and the surviving proband still had blurred vision from corneal opacities at six years.

Mechanism Target:

MODULATES Corneal Dystrophy — Grafting replaces the opacified tissue but does not address the underlying signalling defect, and the reported outcomes suggest the benefit is partial and not durable in every case.

Show evidence (1 reference)

PMID:29122926 SUPPORT INDIRECT Human Clinical

"He had corneal grafting of the right eye followed by the left eye, but he experienced graft rejection."

Graft rejection in one of the two treated children is why the effect is recorded as partial.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"The child had bilateral corneal grafting at the age of 6 months followed by tarsorrhaphy and keratoplasty."

Documents the intervention actually performed.

Respiratory Support

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Intubation and ventilation from birth, progressing to tracheostomy and continuous supplemental oxygen for chronic respiratory failure. This is the dominant care burden and the determinant of survival.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"He is developmentally delayed and has chronic lung disease with chronic respiratory failure requiring a tracheostomy and continuous oxygen supplementation."

Documents the respiratory support required in the surviving child.

Nutritional Support via Gastrostomy

Action: Nutritional Support NCIT:C15433

Gastrostomy feeding was required in the surviving child for chronic gastro-oesophageal reflux with repeated aspiration pneumonia.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"He also has a gastrostomy tube to counteract chronic gastro-oesophageal reflux and repeated aspiration pneumonia."

Documents the feeding intervention actually performed.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive inheritance in a consanguineous family carries a 25 percent recurrence risk, and the two affected children are cousins, so the risk extends across the wider pedigree. Carrier testing for the familial allele is straightforward once identified.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Here, we report a consanguineous family from UAE with a new autosomal recessive (AR) SMD associated with intellectual disability and corneal dystrophy (SMDCD) caused by a homozygous variant in PLCB3."

Establishes the consanguineous recessive family structure that makes recurrence-risk counselling and cascade carrier testing the relevant action.

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Diagnosis

2

Neonatal Corneal Clouding with a Skeletal Dysplasia

The combination that should prompt this diagnosis is neonatal corneal clouding with a spondylometaphyseal skeletal survey. Because that combination is classically a lysosomal storage disorder, storage screening comes first and was negative in both children — white cell inclusions, urine mucopolysaccharides, and urine oligosaccharides.

eye examination NCIT:C38060

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Basic screening for storage disease including white blood cell inclusions, urine mucopolysaccharides and oligosaccharides was negative."

Documents the storage-disease exclusion that precedes the genetic diagnosis.

PLCB3 Sequencing

Biallelic PLCB3 variants confirm the diagnosis. With one family reported, the evidence base for interpreting a novel PLCB3 allele is thin; the founding report reached its assignment only after excluding three other homozygous variants in the same linkage interval by functional assay, which is a reminder of how weak homozygosity mapping alone is in a single consanguineous pedigree.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Based on these experiments we considered the variants in FEN1, INCENP and PRPF19 unlikely to be the cause of our patients"

Three competing homozygous candidates in the same interval had to be excluded functionally before PLCB3 could be assigned.

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Progression

2

Neonatal

Age: Birth to 1 month

Both children were born preterm — at 29 and 27 weeks — and were floppy at birth, requiring intubation and ventilation. Prenatal ultrasound had shown short limbs and a narrow thorax in the proband. Corneal clouding was apparent within the first two weeks.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Prenatal ultrasound revealed short limbs and narrow thorax. The baby was floppy at birth and required intubation and ventilation."

Documents the prenatal detection and the neonatal respiratory course.

Infancy and childhood

Age: 1 month onward

Chronic lung disease with respiratory failure, requiring tracheostomy and continuous oxygen in the surviving child, plus gastrostomy for chronic reflux and repeated aspiration pneumonia. Corneal grafting was performed in both children. One died at eight months of septic shock with pulmonary hypertension; the other was alive at six years, wheelchair-bound with severe developmental delay.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"He died at the age of 8 months of septic shock."

Records the fatal outcome in the second affected cousin.

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Prevalence

1

Worldwide

Cases In Literature 0.0 per 100,000 Ultra Rare

Two affected first cousins from one consanguineous Emirati family constitute the entire published caseload. Skeletal dysplasias as a class are relatively common in the United Arab Emirates at 9.46 per 10,000 births, which is the ascertainment context in which this family was recognised, but no estimate exists for this disorder specifically; rate_per_100000 is recorded as 0.0 only to mark that the true rate is far below the resolution of any published survey.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins"

Establishes that the entire described cohort is two related individuals from a single family.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Spondylometaphyseal Dysplasia with Corneal Dystrophy:

Mucopolysaccharidoses and Other Lysosomal Storage Disorders

Overlapping Features Neonatal corneal clouding with a dysostotic skeletal survey is the classic presentation of a storage disorder, and both affected children were screened for one before the genetic diagnosis was reached. Anterior vertebral beaking in particular is a recognised storage-disease sign, which makes the radiographic overlap substantial.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Basic screening for storage disease including white blood cell inclusions, urine mucopolysaccharides and oligosaccharides was negative."

The storage differential was actively pursued in the reported family, which is why it belongs here.

Schneckenbecken Dysplasia

Overlapping Features The square, short iliac bones with medial projections resembled those of Schneckenbecken dysplasia closely enough that SLC35D1 was sequenced and excluded before the linkage analysis. Schneckenbecken dysplasia sits in ISDS group 14 (severe spondylodysplastic dysplasias), so this is also a differential across nosology groups.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Given that the radiological features, particularly the shape of ilium, were similar to Schneckenbecken dysplasia (OMIM 269250), we sequenced SLC35D1 but did not find any pathogenic variants"

Documents the specific radiographic mimicry and its molecular exclusion.

Spondylometaphyseal Dysplasias with Retinal Involvement

Overlapping Features Only two other spondylometaphyseal dysplasias involve the eye, and both affect the retina rather than the cornea: SMD with cone-rod dystrophy (PCYT1A) and axial SMD with retinal degeneration. An anterior-segment lesion with normal retinas therefore separates SMDCD from both at the bedside.

Show evidence (1 reference)

PMID:29122926 SUPPORT Human Clinical

"Ophthalmological abnormalities have been reported in only two types of SMDs: SMD cone rod dystrophy (SMDCRD, MIM 608940)"

Establishes that eye involvement in the SMD group was previously confined to two retinal disorders, which is what makes the corneal phenotype diagnostic.

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Experimental Models

1

SMDCD patient-derived dermal fibroblasts PRIMARY_CELL_CULTURE

Primary adherent fibroblasts from a skin biopsy of patient IV-1, assayed for PLCB3 protein level by immunoblot, for PIP2 by anti-PtdIns(4,5)P2 immunofluorescence, and for F-actin organisation by phalloidin staining scored blind to genotype against a published four-pattern classification, with cytochalasin D as a cytoskeletal control.

Cell source

Patient-derived (skin biopsy)

Culture

Two-dimensional monolayer culture on coverslips

Pathograph links

F-Actin Cytoskeletal Disorganisation recapitulates fidelity: moderate The patient fibroblast is the only human cellular system reported for this disorder and carries both the substrate-accumulation and the cytoskeletal findings.

Limitations: Dermal fibroblasts are not chondrocytes, corneal keratocytes, or neurons, and none of the three affected tissues has been modelled. The cellular phenotype is therefore a demonstration that the allele is functionally consequential rather than a model of any of the disease's organ lesions.

Readouts

Anti-PtdIns(4,5)P2 immunofluorescence

Direction: INCREASED

Interpretation: Elevated PIP2 in patient cells is the direct evidence that the variant impairs substrate turnover in vivo.

F-actin stress-fibre pattern score

Direction: ALTERED

Interpretation: Blinded scoring of stress-fibre number and length shifts towards the weaker patterns in patient cells.

Show evidence (1 reference)

PMID:29122926 SUPPORT In Vitro

"Here we show that this hypomorphic variant leads to elevated levels of PIP2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton."

States both readouts and the causal claim the model is used to support.

{ }

Source YAML

click to show

name: Spondylometaphyseal Dysplasia with Corneal Dystrophy
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Spondylometaphyseal dysplasia with corneal dystrophy (SMDCD; OMIM #618961) is an
  ultra-rare autosomal recessive skeletal dysplasia described in two Emirati first
  cousins and caused by a homozygous hypomorphic variant in PLCB3, encoding
  phospholipase C beta 3. The enzyme hydrolyses phosphatidylinositol
  4,5-bisphosphate to inositol 1,4,5-trisphosphate and diacylglycerol, so its
  impairment is a defect of phosphoinositide signalling rather than of a structural
  matrix protein. Affected infants are born preterm with profound limb shortening
  involving both proximal and distal segments, a narrow chest, and bilateral corneal
  clouding evident within days of birth; radiographs show short long bones with wide
  metaphyses, anterior vertebral beaking, and square short iliac bones. Intellectual
  disability is severe. The disease variant p.A878S sits in the Ha2' element of the
  proximal C-terminal domain, disrupts its binding to the catalytic core, and
  destabilises the protein; patient fibroblasts accumulate the substrate PIP2 and
  show a disorganised F-actin cytoskeleton strikingly similar to that of Lowe
  syndrome fibroblasts, which are also phosphoinositide-signalling mutants. SMDCD is
  one of only three spondylometaphyseal dysplasias with eye involvement, and the
  only one affecting the cornea rather than the retina.
disease_term:
  preferred_term: spondylometaphyseal dysplasia with corneal dystrophy
  term:
    id: MONDO:0030074
    label: spondylometaphyseal dysplasia with corneal dystrophy
synonyms:
- SMDCD
- PLCB3-related spondylometaphyseal dysplasia
- Spondylometaphyseal dysplasia with corneal dystrophy and developmental delay
parents:
- Skeletal Dysplasia
classifications:
  isds_skeletal_category:
  - classification_value: spondylometaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), Table 1 group 12 "Spondylometaphyseal dysplasias (SMD)",
      entry NOS 12-0050, listed as "Spondylometaphyseal dysplasia with corneal
      dystrophy, PLCB3-related" (AR, PLCB3, MIM 618961). This is one of the two
      group-12 entries absent from dismech's own prose description of the group
      before this curation, the other being NOS 12-0060 (HHAT).
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  rate_per_100000: 0.0
  notes: >-
    Two affected first cousins from one consanguineous Emirati family constitute the
    entire published caseload. Skeletal dysplasias as a class are relatively common
    in the United Arab Emirates at 9.46 per 10,000 births, which is the ascertainment
    context in which this family was recognised, but no estimate exists for this
    disorder specifically; rate_per_100000 is recorded as 0.0 only to mark that the
    true rate is far below the resolution of any published survey.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report the clinical and molecular delineation of a new form of syndromic
      autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first
      cousins
    explanation: >-
      Establishes that the entire described cohort is two related individuals from a
      single family.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    SMDCD is autosomal recessive. Both affected cousins are homozygous for
    PLCB3 c.2632G>T; all four parents and all healthy siblings are heterozygous, and
    homozygosity mapping under a recessive model with complete penetrance is what
    localised the locus to 11q12.1-q13.1.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only the patients (IV-1 and IV-3) were found to be homozygous for these
      variants, while all healthy individuals were heterozygous
    explanation: >-
      Segregation consistent with autosomal recessive inheritance in an extended
      consanguineous pedigree.
genetic:
- name: Homozygous PLCB3 c.2632G>T (p.Ala878Ser)
  gene_term:
    preferred_term: PLCB3
    term:
      id: hgnc:9056
      label: PLCB3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    A single homozygous missense allele, PLCB3 NM_000932.2:c.2632G>T (p.Ala878Ser),
    at 11q13. The substituted alanine is highly conserved at both DNA and protein
    level across vertebrates and affects all three coding isoforms of PLCB3. The
    variant is absent from 200 ethnically matched control chromosomes and from dbSNP
    and EVS, with a heterozygous minor allele frequency of 1.824e-05 in ExAC.
    Structural modelling on the Gq-alpha-PLCbeta3 complex places it in the Ha2'
    element of the proximal C-terminal domain.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identified variant (c.2632G>T) substitutes a serine for a highly conserved
      alanine within the Ha2' element of the proximal C-terminal domain.
    explanation: Names the allele and its structural location within the protein.
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant affects all three different coding isoforms of PLCB3, and this
      position is highly conserved at the DNA and protein levels between vertebrates
      and mammalians
    explanation: >-
      Conservation and isoform coverage are the population-genetic arguments for
      pathogenicity in a single-family report.
pathophysiology:
- name: Homozygous PLCB3 p.Ala878Ser
  biological_scale: MOLECULAR
  description: >-
    A conserved alanine in the Ha2' element of the proximal C-terminal domain is
    replaced by serine. The Ha2' element normally docks onto the catalytic core; the
    substitution disrupts that interaction.
  genes:
  - preferred_term: PLCB3
    term:
      id: hgnc:9056
      label: PLCB3
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identified variant (c.2632G>T) substitutes a serine for a highly conserved
      alanine within the Ha2' element of the proximal C-terminal domain.
    explanation: The initiating molecular lesion.
  downstream:
  - target: Destabilised Phospholipase C Beta 3 with Reduced Activity
    causal_link_type: DIRECT
    description: >-
      Loss of the Ha2'-to-catalytic-core interaction destabilises the protein and
      reduces its enzymatic activity. The allele is hypomorphic rather than null,
      which matters because targeted disruption of Plcb3 in mouse is embryonic
      lethal.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This disrupts binding of the Ha2' element to the catalytic core and
        destabilises PLCB3.
      explanation: >-
        Establishes protein destabilisation as the direct consequence of the
        substitution.
- name: Destabilised Phospholipase C Beta 3 with Reduced Activity
  biological_scale: MOLECULAR
  description: >-
    PLCB3 catalyses production of diacylglycerol and inositol 1,4,5-trisphosphate
    from phosphatidylinositol 4,5-bisphosphate, and is activated by G-protein
    alpha-q and alpha-11 subunits and by beta-gamma subunits. The p.A878S protein is
    destabilised and hypomorphic, so signalling downstream of Gq-coupled receptors is
    attenuated and the substrate is not consumed.
  molecular_functions:
  - preferred_term: phospholipase C activity
    modifier: DECREASED
    term:
      id: GO:0004629
      label: C-type glycerophospholipase activity
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the identified PLCB3:NM_000932:c.2632G>T variant destabilises the protein and
      reduces its enzymatic activity, leading to PIP2 accumulation
    explanation: >-
      Links the destabilisation directly to reduced catalysis and to substrate
      accumulation.
  downstream:
  - target: Accumulation of Phosphatidylinositol 4,5-Bisphosphate
    causal_link_type: DIRECT
    description: >-
      With the hydrolysing enzyme impaired, its substrate builds up. This was
      measured directly in patient fibroblasts by anti-PtdIns(4,5)P2
      immunofluorescence.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here we show that this hypomorphic variant leads to elevated levels of PIP2
        in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton.
      explanation: >-
        Substrate accumulation demonstrated in patient-derived cells, together with
        its cytoskeletal consequence.
- name: Accumulation of Phosphatidylinositol 4,5-Bisphosphate
  biological_scale: MOLECULAR
  description: >-
    PIP2 is elevated in patient fibroblasts. PIP2 is not merely a signalling
    precursor but a direct regulator of actin-binding proteins at the plasma
    membrane, which is the route by which a signalling-enzyme defect becomes a
    structural cytoskeletal defect.
  biological_processes:
  - preferred_term: phosphatidylinositol-mediated signaling
    modifier: DECREASED
    term:
      id: GO:0048015
      label: phosphatidylinositol-mediated signaling
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that this hypomorphic variant leads to elevated levels of PIP2 in
      patient fibroblasts, causing disorganisation of the F-actin cytoskeleton.
    explanation: Measures the substrate accumulation in patient material.
  downstream:
  - target: F-Actin Cytoskeletal Disorganisation
    causal_link_type: DIRECT
    description: >-
      Excess PIP2 disorganises the actin cytoskeleton. The phenotype is the same one
      seen in Lowe syndrome fibroblasts, where the defect is in a different
      phosphoinositide-metabolising enzyme, which is the convergence argument that
      makes the link mechanistic rather than incidental.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This phenotype is strikingly similar to Lowe syndrome (MIM 309000)
        fibroblasts, which also display actin abnormalities due to defects in
        phosphoinositide signalling.
      explanation: >-
        The convergence with an independent phosphoinositide disorder supports the
        causal reading of the actin phenotype.
- name: F-Actin Cytoskeletal Disorganisation
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts are significantly larger than controls, with a weaker F-actin
    network and a more punctate appearance, scored blind to genotype using an
    established four-pattern classification of stress-fibre number and length. How
    this cellular phenotype produces a growth-plate lesion, a corneal opacity, and
    developmental delay is not established.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cellular_components:
  - preferred_term: actin filament
    term:
      id: GO:0005884
      label: actin filament
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts are significantly larger with a weaker F-actin network and
      more punctuate appearance.
    explanation: The measured cellular phenotype in patient-derived cells.
  downstream:
  - target: Spondylometaphyseal Skeletal Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The skeletal lesion is attributed to disturbed phosphoinositide signalling
      during skeletal development, supported by expression of Plcb3 in bone,
      cartilage, and neural crest in zebrafish and by abnormal skeletal patterning
      with malformed facial and thoracic bones in zebrafish plcb3 null mutants. The
      intervening steps in human cartilage have not been demonstrated.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Plcb3 null mutants in zebra fish showed abnormal skeletal patterning with
        malformed facial and thoracic bones.
      explanation: >-
        A model-organism result establishing that Plcb3 loss disturbs skeletal
        patterning, without showing the mechanism in human cartilage.
  - target: Severe Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe global developmental delay is part of the syndrome and PLCB3 is most
      highly expressed in brain, but no step between the phosphoinositide defect and
      the neurodevelopmental phenotype has been demonstrated. Prematurity and chronic
      respiratory failure are uncontrolled confounders in both reported children.
  - target: Hypertelorism with Depressed Nasal Bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A consistent facial gestalt across both affected cousins. Facial morphogenesis
      is neural-crest-dependent and zebrafish plcb3 is expressed in neural crest, but
      the connection is an inference from expression rather than a demonstrated
      mechanism.
  - target: Patent Ductus Arteriosus
    causal_link_type: UNKNOWN
    description: >-
      A large patent ductus arteriosus occurred in both affected children. Both were
      also born preterm — at 29 and 27 weeks — and prematurity alone is a sufficient
      explanation for a persistent duct, so this edge is left with directness
      UNKNOWN rather than asserted as part of the syndrome.
  - target: Corneal Dystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The corneal opacity is present within days of birth and is confined to the
      cornea, with normal retinas, optic nerves, vitreous, and posterior lens on
      ophthalmological and B-scan assessment. No mechanism connecting the
      phosphoinositide defect to corneal stromal transparency has been proposed.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Opthalmological examination revealed bilateral corneal haziness with normal
        retinas.
      explanation: >-
        Establishes that the eye lesion is corneal and anterior-segment specific, but
        supplies no mechanism, hence the unknown-intermediates grading.
- name: Spondylometaphyseal Skeletal Dysplasia
  biological_scale: ORGANISM
  description: >-
    Profound limb shortening involving both proximal and distal segments, with short
    fingers and toes and a narrow chest. Radiographs show short long bones with wide
    metaphyses and coarse metaphyseal trabeculae, cupping of the distal radius and
    ulna, uncalcified distal femoral and proximal tibial epiphyses in the neonate,
    short ribs with a wide anterior aspect, anterior beaking of the lumbar and
    thoracic vertebrae with wide intervertebral spaces, and almost square, short iliac
    bones with medial projections. The iliac shape was close enough to Schneckenbecken
    dysplasia that SLC35D1 was sequenced and excluded before the locus was mapped.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal survey (figure 1B) showed short long bones with wide metaphyses and
      some coarse trabecule at the metaphyses.
    explanation: The primary radiographic description of the skeletal lesion.
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lumbar and thoracic vertebrae had beaks at their anterior aspects, and the
      intervertebral spaces were wide.
    explanation: >-
      The vertebral component that makes this a spondylometaphyseal rather than a
      purely metaphyseal dysplasia.
  downstream:
  - target: Profound Limb Shortening
    causal_link_type: DIRECT
    description: >-
      Micromelia involving both proximal and distal segments, detectable on prenatal
      ultrasound.
  - target: Metaphyseal Widening
    causal_link_type: DIRECT
    description: Wide metaphyses with coarse trabeculae and distal forearm cupping.
  - target: Anterior Vertebral Beaking
    causal_link_type: DIRECT
    description: >-
      Anterior beaks on the lumbar and thoracic bodies with wide intervertebral
      spaces.
  - target: Severe Postnatal Growth Deficiency
    causal_link_type: DIRECT
    description: >-
      Growth deficiency that is postnatal in onset: birth weight was above the 25th
      centile in the proband, while weight and height were both far below the third
      by four years.
  - target: Narrow Chest with Pulmonary Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Short, anteriorly wide ribs give a narrow thorax that constrains lung growth.
      This is the feature that dominates the natural history and determines survival.
- name: Corneal Dystrophy
  biological_scale: ORGANISM
  description: >-
    Bilateral corneal clouding evident within the first days of life. In the second
    cousin the corneas showed vascularised opacities with central thickened white
    cream-coloured tissue and a thinner greyish periphery over an epithelialised
    surface. Both children underwent corneal grafting; one experienced graft
    rejection. Screening for a storage disease — white cell inclusions, urine
    mucopolysaccharides and oligosaccharides — was negative, which is the standard
    first differential for neonatal corneal clouding.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmological evaluation showed bilateral vascularised corneal opacities
      with central thickened white cream-coloured tissue and thinner greyish
      periphery; the surface of the cornea was epithelised.
    explanation: The detailed corneal description in the second affected cousin.
  downstream:
  - target: Corneal Clouding
    causal_link_type: DIRECT
    description: >-
      Bilateral corneal opacity apparent within the first two weeks of life, with
      normal retinas behind it.
phenotypes:
- category: Ophthalmologic
  name: Corneal Clouding
  frequency: OBLIGATE
  description: >-
    Bilateral corneal opacity noted within the first two weeks of life in both
    affected children, with normal retinas. Definitional for the entity, and the
    feature that distinguishes it from every other spondylometaphyseal dysplasia.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was noted to have bilateral corneal clouding on day 12.
    explanation: Documents the corneal opacity and its neonatal onset in the proband.
- category: Skeletal
  name: Profound Limb Shortening
  frequency: OBLIGATE
  description: >-
    Micromelia involving both proximal and distal segments, with short fingers and
    toes, detectable on prenatal ultrasound.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On examination, he had short limbs, with proximal and distal segments involved.
    explanation: Documents the pattern of limb shortening in the proband.
- category: Skeletal
  name: Metaphyseal Widening
  frequency: OBLIGATE
  description: >-
    Wide metaphyses with coarse trabeculae and cupping of the distal radius and ulna.
  phenotype_term:
    preferred_term: Metaphyseal widening
    term:
      id: HP:0003016
      label: Metaphyseal widening
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal survey (figure 1B) showed short long bones with wide metaphyses and
      some coarse trabecule at the metaphyses.
    explanation: Documents the metaphyseal component of the radiographic phenotype.
- category: Skeletal
  name: Anterior Vertebral Beaking
  frequency: OBLIGATE
  description: >-
    Anterior beaks on the lumbar and thoracic vertebral bodies with wide
    intervertebral spaces — the vertebral component of the dysplasia.
  phenotype_term:
    preferred_term: Anterior beaking of lumbar vertebrae
    term:
      id: HP:0008430
      label: Anterior beaking of lumbar vertebrae
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lumbar and thoracic vertebrae had beaks at their anterior aspects, and the
      intervertebral spaces were wide.
    explanation: Documents the vertebral morphology.
- category: Respiratory
  name: Narrow Chest with Pulmonary Hypoplasia
  frequency: OBLIGATE
  description: >-
    A narrow thorax with short, anteriorly wide ribs. Both children were floppy at
    birth, required intubation and ventilation, and developed chronic lung disease;
    one needed a tracheostomy and continuous oxygen, the other had pulmonary
    hypertension and died at eight months of septic shock. The respiratory
    consequence of the thoracic dysplasia dominates the natural history.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The baby had a stormy neonatal period and was difficult to wean off the
      ventilator due to the narrow chest and hypoplastic lungs.
    explanation: >-
      Attributes the ventilator dependence directly to the thoracic and pulmonary
      hypoplasia.
- category: Neurologic
  name: Severe Developmental Delay
  frequency: OBLIGATE
  description: >-
    Severe global developmental delay. At six years the surviving proband could roll
    over and sit unsupported but not bear weight, was wheelchair-bound, and had no
    speech or meaningful babbling despite being able to hear and understand words.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    severity: SEVERE
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, he is 6 years old with severe developmental delay.
    explanation: Documents the severity of the developmental phenotype at age six.
- category: Cardiovascular
  name: Patent Ductus Arteriosus
  frequency: VERY_FREQUENT
  description: >-
    A large patent ductus arteriosus in both affected children, requiring surgical
    correction in one and producing a left-to-right shunt in the other.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Echocardiography showed a large patent ductus arteriosus, which eventually
      required surgical correction.
    explanation: >-
      Documents the cardiac lesion in the proband; both children were preterm, so
      prematurity is a confounder for this feature specifically.
- category: Craniofacial
  name: Hypertelorism with Depressed Nasal Bridge
  frequency: VERY_FREQUENT
  description: >-
    Hypertelorism, prominent eyes, a depressed nasal bridge, and a short upturned
    nose in both affected children.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was hypertelorism, prominent eyes, depressed nasal bridge and short
      upturned nose.
    explanation: The facial phenotype as recorded in the proband.
- category: Growth
  name: Severe Postnatal Growth Deficiency
  frequency: OBLIGATE
  description: >-
    Postnatal growth deficiency. At four years the proband weighed 14 kg and measured
    85 cm, both well below the third centile, despite a birth weight above the 25th.
  phenotype_term:
    preferred_term: Severe short stature
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They displayed postnatal growth deficiency causing profound limb shortening
      with proximal and distal segments involvement, narrow chest, radiological
      abnormalities involving the spine, pelvis and metaphyses, corneal clouding and
      intellectual disability.
    explanation: >-
      The summary clinical description, establishing postnatal growth deficiency
      alongside the other core features.
progression:
- phase: Neonatal
  age_range: Birth to 1 month
  notes: >-
    Both children were born preterm — at 29 and 27 weeks — and were floppy at birth,
    requiring intubation and ventilation. Prenatal ultrasound had shown short limbs
    and a narrow thorax in the proband. Corneal clouding was apparent within the
    first two weeks.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal ultrasound revealed short limbs and narrow thorax. The baby was floppy
      at birth and required intubation and ventilation.
    explanation: Documents the prenatal detection and the neonatal respiratory course.
- phase: Infancy and childhood
  age_range: 1 month onward
  notes: >-
    Chronic lung disease with respiratory failure, requiring tracheostomy and
    continuous oxygen in the surviving child, plus gastrostomy for chronic reflux and
    repeated aspiration pneumonia. Corneal grafting was performed in both children.
    One died at eight months of septic shock with pulmonary hypertension; the other
    was alive at six years, wheelchair-bound with severe developmental delay.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He died at the age of 8 months of septic shock.
    explanation: Records the fatal outcome in the second affected cousin.
diagnosis:
- name: Neonatal Corneal Clouding with a Skeletal Dysplasia
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  description: >-
    The combination that should prompt this diagnosis is neonatal corneal clouding
    with a spondylometaphyseal skeletal survey. Because that combination is
    classically a lysosomal storage disorder, storage screening comes first and was
    negative in both children — white cell inclusions, urine mucopolysaccharides, and
    urine oligosaccharides.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basic screening for storage disease including white blood cell inclusions,
      urine mucopolysaccharides and oligosaccharides was negative.
    explanation: Documents the storage-disease exclusion that precedes the genetic diagnosis.
- name: PLCB3 Sequencing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Biallelic PLCB3 variants confirm the diagnosis. With one family reported, the
    evidence base for interpreting a novel PLCB3 allele is thin; the founding report
    reached its assignment only after excluding three other homozygous variants in
    the same linkage interval by functional assay, which is a reminder of how weak
    homozygosity mapping alone is in a single consanguineous pedigree.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on these experiments we considered the variants in FEN1, INCENP and
      PRPF19 unlikely to be the cause of our patients
    explanation: >-
      Three competing homozygous candidates in the same interval had to be excluded
      functionally before PLCB3 could be assigned.
differential_diagnoses:
- name: Mucopolysaccharidoses and Other Lysosomal Storage Disorders
  description: >-
    Neonatal corneal clouding with a dysostotic skeletal survey is the classic
    presentation of a storage disorder, and both affected children were screened for
    one before the genetic diagnosis was reached. Anterior vertebral beaking in
    particular is a recognised storage-disease sign, which makes the radiographic
    overlap substantial.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basic screening for storage disease including white blood cell inclusions,
      urine mucopolysaccharides and oligosaccharides was negative.
    explanation: >-
      The storage differential was actively pursued in the reported family, which is
      why it belongs here.
- name: Schneckenbecken Dysplasia
  description: >-
    The square, short iliac bones with medial projections resembled those of
    Schneckenbecken dysplasia closely enough that SLC35D1 was sequenced and excluded
    before the linkage analysis. Schneckenbecken dysplasia sits in ISDS group 14
    (severe spondylodysplastic dysplasias), so this is also a differential across
    nosology groups.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given that the radiological features, particularly the shape of ilium, were
      similar to Schneckenbecken dysplasia (OMIM 269250), we sequenced SLC35D1 but
      did not find any pathogenic variants
    explanation: Documents the specific radiographic mimicry and its molecular exclusion.
- name: Spondylometaphyseal Dysplasias with Retinal Involvement
  description: >-
    Only two other spondylometaphyseal dysplasias involve the eye, and both affect
    the retina rather than the cornea: SMD with cone-rod dystrophy (PCYT1A) and axial
    SMD with retinal degeneration. An anterior-segment lesion with normal retinas
    therefore separates SMDCD from both at the bedside.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmological abnormalities have been reported in only two types of SMDs:
      SMD cone rod dystrophy (SMDCRD, MIM 608940)
    explanation: >-
      Establishes that eye involvement in the SMD group was previously confined to
      two retinal disorders, which is what makes the corneal phenotype diagnostic.
treatments:
- name: Corneal Grafting
  description: >-
    Both affected children underwent bilateral corneal grafting — one at six months,
    followed by tarsorrhaphy and keratoplasty. Outcomes were mixed: the second child
    experienced graft rejection, and the surviving proband still had blurred vision
    from corneal opacities at six years.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Corneal Dystrophy
    treatment_effect: MODULATES
    description: >-
      Grafting replaces the opacified tissue but does not address the underlying
      signalling defect, and the reported outcomes suggest the benefit is partial and
      not durable in every case.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He had corneal grafting of the right eye followed by the left eye, but he
        experienced graft rejection.
      explanation: >-
        Graft rejection in one of the two treated children is why the effect is
        recorded as partial.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The child had bilateral corneal grafting at the age of 6 months followed by
      tarsorrhaphy and keratoplasty.
    explanation: Documents the intervention actually performed.
- name: Respiratory Support
  description: >-
    Intubation and ventilation from birth, progressing to tracheostomy and continuous
    supplemental oxygen for chronic respiratory failure. This is the dominant care
    burden and the determinant of survival.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: DEVICE
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He is developmentally delayed and has chronic lung disease with chronic
      respiratory failure requiring a tracheostomy and continuous oxygen
      supplementation.
    explanation: Documents the respiratory support required in the surviving child.
- name: Nutritional Support via Gastrostomy
  description: >-
    Gastrostomy feeding was required in the surviving child for chronic
    gastro-oesophageal reflux with repeated aspiration pneumonia.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  therapeutic_modality: DEVICE
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also has a gastrostomy tube to counteract chronic gastro-oesophageal reflux
      and repeated aspiration pneumonia.
    explanation: Documents the feeding intervention actually performed.
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance in a consanguineous family carries a 25 percent
    recurrence risk, and the two affected children are cousins, so the risk extends
    across the wider pedigree. Carrier testing for the familial allele is
    straightforward once identified.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a consanguineous family from UAE with a new autosomal recessive
      (AR) SMD associated with intellectual disability and corneal dystrophy (SMDCD)
      caused by a homozygous variant in PLCB3.
    explanation: >-
      Establishes the consanguineous recessive family structure that makes
      recurrence-risk counselling and cascade carrier testing the relevant action.
experimental_models:
- name: SMDCD patient-derived dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary adherent fibroblasts from a skin biopsy of patient IV-1, assayed for
    PLCB3 protein level by immunoblot, for PIP2 by anti-PtdIns(4,5)P2
    immunofluorescence, and for F-actin organisation by phalloidin staining scored
    blind to genotype against a published four-pattern classification, with
    cytochalasin D as a cytoskeletal control.
  cell_source: Patient-derived (skin biopsy)
  culture_system: Two-dimensional monolayer culture on coverslips
  modeled_mechanisms:
  - target: F-Actin Cytoskeletal Disorganisation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The patient fibroblast is the only human cellular system reported for this
      disorder and carries both the substrate-accumulation and the cytoskeletal
      findings.
    limitations: >-
      Dermal fibroblasts are not chondrocytes, corneal keratocytes, or neurons, and
      none of the three affected tissues has been modelled. The cellular phenotype is
      therefore a demonstration that the allele is functionally consequential rather
      than a model of any of the disease's organ lesions.
    readouts:
    - name: Anti-PtdIns(4,5)P2 immunofluorescence
      target: F-Actin Cytoskeletal Disorganisation
      direction: INCREASED
      interpretation: >-
        Elevated PIP2 in patient cells is the direct evidence that the variant
        impairs substrate turnover in vivo.
    - name: F-actin stress-fibre pattern score
      target: F-Actin Cytoskeletal Disorganisation
      direction: ALTERED
      interpretation: >-
        Blinded scoring of stress-fibre number and length shifts towards the weaker
        patterns in patient cells.
    evidence:
    - reference: PMID:29122926
      reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here we show that this hypomorphic variant leads to elevated levels of PIP2
        in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton.
      explanation: >-
        States both readouts and the causal claim the model is used to support.
discussions:
- discussion_id: smdcd_single_family_evidence_base
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#Spondylometaphyseal Dysplasia with Corneal Dystrophy
  prompt: >-
    Is SMDCD an established gene-disease relationship, given that it rests on one
    homozygous missense allele in two cousins from a single family?
  rationale: >-
    Every clinical and molecular statement about this disorder comes from one report
    of one consanguineous pedigree. The linkage interval spanned 19.3 Mb and 487
    genes, and four homozygous candidate variants survived filtering; PLCB3 was
    selected partly on the prior that phospholipid-metabolism genes such as PLCB4 and
    PCYT1A cause bone dysplasia, and the three competitors were excluded by functional
    assays rather than by independent genetic replication. The functional work is
    good, but no second family has been published, so the relationship has not been
    replicated in the way a gene-disease assertion normally requires. The ISDS
    nosology nonetheless lists it as a distinct entity, which this entry follows while
    recording the limitation.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1,
      a region spanning 19.32 Mb with ~490 genes.
    explanation: >-
      The size of the linkage interval is what makes independent replication, rather
      than functional exclusion of competitors, the missing evidence.
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4
      and PCYT1A, are known to cause bone dysplasia with or without eye anomalies,
      which led us to select PLCB3 as a strong candidate.
    explanation: >-
      Candidate selection was partly driven by a pathway prior, which is a legitimate
      heuristic but not independent evidence.
  proposed_experiments:
  - experiment_id: exp_smdcd_independent_replication
    name: Seek independent PLCB3 families through matchmaking
    description: >-
      Submit the PLCB3 phenotype to GeneMatcher and equivalent matchmaking services
      and to skeletal dysplasia consortia, and reanalyse unsolved neonatal
      corneal-clouding-plus-skeletal-dysplasia exomes for biallelic PLCB3 variants.
    would_support:
    - pathophysiology#Homozygous PLCB3 p.Ala878Ser
    supporting_outcome:
    - >-
      A second unrelated family with biallelic PLCB3 variants and a matching
      phenotype would convert the assertion from single-family to replicated.
    would_refute:
    - pathophysiology#Homozygous PLCB3 p.Ala878Ser
    refuting_outcome:
    - >-
      Identification of a pathogenic variant in one of the other candidate genes in
      the interval in a second family with the same phenotype would reopen the gene
      assignment.
- discussion_id: smdcd_actin_to_organ_lesion_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#F-Actin Cytoskeletal Disorganisation
  prompt: >-
    How does a fibroblast actin phenotype account for a growth-plate dysplasia, a
    corneal opacity, and severe developmental delay?
  rationale: >-
    The mechanism is demonstrated as far as the fibroblast and stops there. Three
    distinct organ lesions are attributed to it, in tissues that were never assayed.
    Zebrafish plcb3 nulls give some support for the skeletal branch, but mouse Plcb3
    disruption is embryonic lethal and further knockout models gave discordant
    results that the authors attribute to how the gene was disrupted — so there is no
    settled animal model either. The corneal branch is the weakest: nothing connects
    phosphoinositide signalling to corneal stromal transparency, and the opacity is
    present within days of birth, implying a developmental rather than a degenerative
    process.
  evidence:
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, targeted disruption of plcb3 results in embryonic lethality.
    explanation: >-
      The lethality of the mouse null is why no mammalian model of the organ lesions
      exists.
  - reference: PMID:29122926
    reference_title: Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, further Plcb3 knockout models showed discordant results.
    explanation: >-
      Discordance between knockout models means the existing animal evidence cannot
      arbitrate the organ mechanisms.
  proposed_experiments:
  - experiment_id: exp_smdcd_hypomorphic_knockin_and_tissue_models
    name: Hypomorphic Plcb3 knock-in and human tissue-specific models
    description: >-
      Generate a knock-in carrying the human p.A878S hypomorph rather than a null, so
      that animals survive, and phenotype the growth plate, cornea, and brain.
      Complement with patient iPSC-derived chondrocytes and corneal keratocytes
      assayed for PIP2, actin organisation, and tissue-specific differentiation.
    would_support:
    - pathophysiology#Corneal Dystrophy
    supporting_outcome:
    - >-
      Corneal opacity and a spondylometaphyseal skeletal phenotype in hypomorphic
      animals would establish that the single allele accounts for the organ lesions.
    would_refute:
    - pathophysiology#F-Actin Cytoskeletal Disorganisation
    refuting_outcome:
    - >-
      Normal actin organisation in patient-derived chondrocytes and keratocytes
      despite the skeletal and corneal phenotypes would show the fibroblast actin
      finding is not the operative mechanism in the affected tissues.
references:
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
  findings: []
clinical_trials: []
datasets: []
notes: >-
  Curated as part of filling ISDS Nosology group 12 (Spondylometaphyseal
  dysplasias), which was unpopulated when this work began. SMDCD is NOS 12-0050 in the 2023
  revision and was one of the two group-12 members that the schema's own
  description of the group did not name before this curation. The whole entry rests on a single family, which is
  recorded explicitly as an open discussion rather than being smoothed over: the
  functional work in patient fibroblasts is solid, but the gene-disease relationship
  has not been independently replicated. Downstream edges from the cellular node to
  the three organ lesions are graded INDIRECT_UNKNOWN_INTERMEDIATES for the same
  reason.

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PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

Spondylometaphyseal Dysplasia with Corneal Dystrophy

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