EVEN-PLUS syndrome (OMIM #616854) is an autosomal recessive congenital malformation syndrome caused by biallelic hypomorphic variants in HSPA9, which encodes mortalin / mtHSP70 (also GRP75), the mitochondrial matrix Hsp70. The acronym names its cardinal features - Epiphyses, Vertebrae, Ears and Nose - PLUS a set of associated malformations: prenatal-onset short stature, cardiac septal defects, anal atresia, aplasia cutis, hypodontia and variable developmental delay. Skeletally it is a spondyloepiphyseal dysplasia with coronal vertebral clefts and severe, often unossified, proximal femoral epiphyses. The disease was delineated by gene-based phenotypic sorting rather than by clinical splitting. Patients who looked like CODAS syndrome but carried no LONP1 variant turned out to carry biallelic HSPA9 variants instead, and earlier reports of "EVE dysplasia" and of "caudal regression with spondyloepiphyseal dysplasia" were retrospectively recognised as the same entity - one of them later confirmed molecularly. LONP1 and HSPA9 act together in the mitochondrial matrix chaperone-protease network, and the authors proposed the resulting pair as a family of "mitochondrial chaperonopathies". The mechanistic point that makes this entry unusual is a negative one, and it is stated by the source rather than inferred here: EVEN-PLUS does not look like a bioenergetic mitochondrial disease. There is no lactic acidosis, no encephalomyopathy, no Leigh-type decompensation. The phenotype is one of disturbed embryonic morphogenesis - microtia, a flat nose, abnormal hair whorls, anal atresia, sacral agenesis - in a pattern that reads developmental rather than metabolic. How loss of a mitochondrial matrix chaperone produces that pattern is explicitly unexplained in the primary literature, and this entry curates that as a knowledge gap rather than papering over it with a plausible-sounding energy-failure chain.
Ask a research question about EVEN-PLUS Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: EVEN-PLUS Syndrome
creation_date: "2026-08-31T07:40:00Z"
category: Mendelian
disease_term:
preferred_term: even-plus syndrome
term:
id: MONDO:0014801
label: even-plus syndrome
description: >
EVEN-PLUS syndrome (OMIM #616854) is an autosomal recessive congenital
malformation syndrome caused by biallelic hypomorphic variants in HSPA9,
which encodes mortalin / mtHSP70 (also GRP75), the mitochondrial matrix
Hsp70. The acronym names its cardinal features - Epiphyses, Vertebrae, Ears
and Nose - PLUS a set of associated malformations: prenatal-onset short
stature, cardiac septal defects, anal atresia, aplasia cutis, hypodontia and
variable developmental delay. Skeletally it is a spondyloepiphyseal dysplasia
with coronal vertebral clefts and severe, often unossified, proximal femoral
epiphyses.
The disease was delineated by gene-based phenotypic sorting rather than by
clinical splitting. Patients who looked like CODAS syndrome but carried no
LONP1 variant turned out to carry biallelic HSPA9 variants instead, and
earlier reports of "EVE dysplasia" and of "caudal regression with
spondyloepiphyseal dysplasia" were retrospectively recognised as the same
entity - one of them later confirmed molecularly. LONP1 and HSPA9 act
together in the mitochondrial matrix chaperone-protease network, and the
authors proposed the resulting pair as a family of "mitochondrial
chaperonopathies".
The mechanistic point that makes this entry unusual is a negative one, and
it is stated by the source rather than inferred here: EVEN-PLUS does not
look like a bioenergetic mitochondrial disease. There is no lactic acidosis,
no encephalomyopathy, no Leigh-type decompensation. The phenotype is one of
disturbed embryonic morphogenesis - microtia, a flat nose, abnormal hair
whorls, anal atresia, sacral agenesis - in a pattern that reads
developmental rather than metabolic. How loss of a mitochondrial matrix
chaperone produces that pattern is explicitly unexplained in the primary
literature, and this entry curates that as a knowledge gap rather than
papering over it with a plausible-sounding energy-failure chain.
synonyms:
- EVEN-PLUS syndrome
- EVEN-plus syndrome
- epiphyseal-vertebral-ear-nose dysplasia plus associated findings
- EVE dysplasia
- EVE syndrome
- HSPA9-related skeletal dysplasia
parents:
- Skeletal dysplasia
- Multiple congenital anomalies syndrome
notes: >
Scope and counting. The largest single source is a 2024 systematic review
that collated 12 cases (9 females) from 6 research items, including two new
Chinese patients of its own; the rest of the literature is single-patient
and sibpair reports. Most phenotypes here still carry no `frequency`,
because a percentage pooled across independently ascertained case reports
is a scope error rather than a penetrance estimate. The exception is the
set of features that review found in *all* 12 patients, which is a
defensible statement about a stated denominator.
Two of those four are curated as `frequency: OBLIGATE`, and two are not.
The dividing line is whether the sentence distributes over the term this
entry actually binds. "Hypoplastic nasal bone" is exactly `HP:0004646`, so
the value is direct; "dysplastic femoral head" is narrower than
`HP:0002656` Epiphyseal dysplasia but entails it, since the femoral head is
an epiphysis, so the value is carried upward. The other two are stated
disjunctively - "synophrys *or* arched eyebrows", "hypoplastic *or*
dysplastic ears" - and each is broader than the term bound here
(`HP:0000664` Synophrys, `HP:0008551` Microtia). A disjunction at 100% puts
no floor under either limb, so those two nodes carry the quote and no
number. The asymmetry is deliberate: entailment runs from narrow to broad,
never the reverse.
Allelic series, and why this entry does not merge it. HSPA9 also carries
heterozygous variants reported in congenital sideroblastic anemia, and the
p.R126W allele that is homozygous in two EVEN-PLUS sibs here has separately
been reported at heterozygosity in Parkinson disease cohorts. Those are
different dosage regimes and different phenotypes; this entry curates the
biallelic hypomorphic developmental syndrome only, and records the p.R126W
functional work because it is the strongest available evidence that the
allele is not neutral - not as a claim that EVEN-PLUS and Parkinson disease
share a mechanism.
Where the mechanism evidence actually sits. The genotype-to-protein step is
now well evidenced: a dedicated biophysical study measured ATP hydrolysis,
interdomain-linker binding, thermostability and aggregation for both
EVEN-PLUS missense alleles. The protein-to-malformation step is not, and no
mouse bridges it - homozygous Hspa9 null is embryonically lethal and the
heterozygote is unaffected. The knowledge gap curated here is specifically
that second step, not the first.
Evidence-grading note for reviewers. The zebrafish `crimsonless` mutant is
cited here twice and the two citations are deliberately different claims. As
a model of hematopoiesis it is not EVEN-PLUS; what makes it relevant is the
incidental observation that head and eye development were stunted and that
development halted globally, which is the only in vivo evidence that hspa9
loss disturbs morphogenesis rather than energy supply. Both items are
MODEL_ORGANISM and INDIRECT, and neither is the sole support for a human
phenotype.
Cache hygiene. `references_cache/PMID_26598328.md` is a `full_text_xml`
capture in which superscript reference markers have been concatenated onto
the preceding word (for example the sentence about the LONP1 relationship
ends "LONP19101112"). Snippets in this entry were chosen to end before those
positions. This is a cache-generation artefact, not curator error, and is
reported upstream.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Twelve molecularly confirmed individuals, 9 of them female, collated from
6 research items by a 2024 systematic review. Thirteen distinct HSPA9
variants have been reported. No incidence or prevalence estimate exists,
so no rate is computed.
evidence:
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Together with the presented cases, 12 cases (9 females) were identified from 6 relevant research items for analysis."
explanation: >-
The largest published cohort and the denominator this entry's counts are
stated against.
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thirteen variants associated with EVEN-PLUS syndrome have been reported."
explanation: >-
The size of the reported allelic spectrum, which is the other axis on
which this disease's literature is small.
- population: Worldwide, cases published before 2022
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Retained as the earlier snapshot, because several statements in the older
literature are framed against it.
evidence:
- reference: PMID:35779070
reference_title: "Broadening the phenotypic spectrum of EVEN-PLUS syndrome through identification of HSPA9 pathogenic variants in the original EVE dysplasia family and two sibs with milder facial phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Only five individuals presenting with the EVEN-PLUS phenotype and biallelic variants in HSPA9 have been published."
explanation: >-
States the size of the published cohort at the point this report was
written, which is the denominator for every count in this entry.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Biallelic in every reported family - homozygous in the two consanguineous
sibs and compound heterozygous in the non-consanguineous index case, with
heterozygosity confirmed in the unaffected parents. Because the mechanism
is hypomorphic rather than null, at least one allele retaining partial
function is expected; no individual with two complete null alleles has
been reported.
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All mutations were confirmed by direct bidirectional Sanger sequencing of a second batch of genomic DNA; heterozygosity was confirmed in the unaffected parents."
explanation: >
Parental heterozygosity with unaffected status is the direct segregation
evidence for recessive inheritance.
- reference: PMID:35779070
reference_title: "Broadening the phenotypic spectrum of EVEN-PLUS syndrome through identification of HSPA9 pathogenic variants in the original EVE dysplasia family and two sibs with milder facial phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "EVEN-PLUS syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the mitochondrial chaperone called mortalin, encoded by HSPA9."
explanation: >
Independent statement of biallelic recessive inheritance from a second
group.
mechanistic_hypotheses:
- hypothesis_group_id: mitochondrial_chaperonopathy_morphogenesis
hypothesis_label: Mitochondrial Chaperonopathy / Developmental Morphogenesis Model
status: EMERGING
description: >-
Biallelic hypomorphic HSPA9 alleles reduce, without abolishing, the
activity of the mitochondrial matrix Hsp70. The proposal is that the
resulting deficit acts on embryonic morphogenesis - patterning and
outgrowth of first- and second-arch derivatives, the nasal skeleton, the
vertebral bodies and the epiphyseal growth plates - rather than through
the bioenergetic failure that characterises classical mitochondrial
disease. The status is EMERGING and not CANONICAL on purpose: the causal
genetics are solid, but the step from chaperone deficiency to
dysmorphogenesis is asserted as unexplained by the primary report and has
no worked-out molecular intermediate.
pathophysiology:
- name: Biallelic Hypomorphic HSPA9 Variants
biological_scale: MOLECULAR
description: >
Thirteen variants across the published cohort. The missense alleles
cluster on the nucleotide-binding domain surface (p.R126W, p.Y128C,
p.L319F), with a recurrent frameshift (c.882_883delAG, p.V296*) and a
nonsense allele (p.L273X). Those truncating alleles remove more than half
the protein including the entire substrate-binding domain and are subject
to nonsense-mediated decay, so a truncating allele in trans with a
missense allele is the commonest configuration. The missense residues sit
away from the ATP site but adjacent to the predicted interface between the
nucleotide-binding and substrate-binding domains, which is the allosteric
coupling that makes an Hsp70 work.
The nucleotide-binding-domain framing is not the whole spectrum. Splice
variants at c.1822-1G>A and c.1411-3T>G act on the substrate-binding
domain instead, abolishing part of it, which is a second and distinct way
to reach a hypomorphic chaperone.
genes:
- preferred_term: HSPA9
term:
id: hgnc:5244
label: HSPA9
modifier: DECREASED
genetic_context:
description: >-
Germline biallelic hypomorphic HSPA9 alleles: homozygous missense in the
consanguineous family, compound heterozygous missense plus truncating in
the others.
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient 1 was found to be heterozygous for variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 were found to be homozygous for variant c.376C > T (p.R126W)."
explanation: >
The founding allelic spectrum, showing both the compound-heterozygous
and the homozygous configuration.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The V296* truncation mutation abolishes more than half of the protein, including all of the substrate binding domain"
explanation: >
Establishes that the recurrent frameshift is a functional null for
substrate binding, which is why the surviving allele sets the phenotype.
- reference: PMID:32869452
reference_title: "EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "qPCR analysis provides supporting evidence for a nonsense-mediated decay mechanism for the HSPA9 truncating variant."
explanation: >
Transcript-level evidence that truncating HSPA9 alleles are degraded
rather than producing a stable truncated protein.
- reference: PMID:30933555
reference_title: "Biophysical Consequences of EVEN-PLUS Syndrome Mutations for the Function of Mortalin."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Both variants are colocalized on the NBD near to the IDL interaction site NBD suggesting a potential negative effect on inter-domain communication with the SBD."
explanation: >
Independent structural confirmation that both missense alleles sit at
the interdomain-linker interface, which is the structural claim this
node makes about their location.
- reference: PMID:38281662
reference_title: "Prenatal to preimplantation genetic diagnosis of a novel compound heterozygous mutation in HSPA9 associated with Even-Plus syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three-dimensional spatial simulation of the HSPA9 protein after prediction of the mutated RNA splicing pattern abolished part of the substrate-binding domain of the protein. According to ACMG guidelines, c. 1822-1G>A and c. 1411-3T>G were classified as pathogenic and likely pathogenic, respectively."
explanation: >
Extends the allelic spectrum to splice variants acting on the
substrate-binding domain, which complicates the nucleotide-binding-domain
clustering this node otherwise describes.
downstream:
- target: Impaired Mitochondrial Matrix Hsp70 Chaperone Function
description: >-
Reduced substrate binding and reduced allosteric coupling between the
nucleotide-binding and substrate-binding domains.
hypothesis_groups:
- mitochondrial_chaperonopathy_morphogenesis
- name: Impaired Mitochondrial Matrix Hsp70 Chaperone Function
biological_scale: MOLECULAR
description: >
Mortalin is the ATP-driven motor that pulls precursor proteins through the
TIM23 translocase into the matrix and folds them on arrival, and it is also
required for LONP1's proteolytic activity, so a single hypomorphic
chaperone degrades both arms of matrix proteostasis - import and folding on
one side, quality-control degradation on the other. This is the node that
the LONP1 (CODAS) and HSPA9 (EVEN-PLUS) syndromes share and the reason
their phenotypes overlap.
biological_processes:
- preferred_term: protein import into mitochondrial matrix
modifier: DECREASED
term:
id: GO:0030150
label: protein import into mitochondrial matrix
- preferred_term: protein folding
modifier: DECREASED
term:
id: GO:0006457
label: protein folding
molecular_functions:
- preferred_term: ATP-dependent protein folding chaperone
modifier: DECREASED
term:
id: GO:0140662
label: ATP-dependent protein folding chaperone
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation."
explanation: >
Names the three matrix functions the affected chaperone serves, which is
the content of this node.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Its main role is that of a chaperone that participates in the import of proteins from the cytosol to the mitochondrial matrix as well as their folding"
explanation: >
States the import-and-fold role directly, without the disease context,
supporting the GO annotations on this node.
- reference: PMID:30933555
reference_title: "Biophysical Consequences of EVEN-PLUS Syndrome Mutations for the Function of Mortalin."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "These results indicate that the surface mutations R126W and Y128C have far-reaching effects that disrupt ATP hydrolysis, interdomain linker binding, and thermostability and increase the propensity for aggregation."
explanation: >
The dedicated biophysical study of the two EVEN-PLUS missense alleles,
by differential scanning fluorimetry, biolayer interferometry, X-ray
crystallography and ATP hydrolysis assay. DIRECT: the assays are on the
disease alleles themselves and measure the chaperone functions this node
asserts are impaired.
- reference: PMID:30933555
reference_title: "Biophysical Consequences of EVEN-PLUS Syndrome Mutations for the Function of Mortalin."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the R126W and Y128C mutants exert a combinatorial effect through destabilization and aggregation, impairment of interdomain linker binding, and a reduction in NBD-catalyzed ATP hydrolysis"
explanation: >
Names the three separable defects and says they combine, which is why
surface substitutions distant from the ATP site are nonetheless
hypomorphic rather than neutral.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "expression studies using wild type and mutated HSPA9 were done, showing that the R126W mutation does impact the function of the HSPA9 protein measured by its effects on mitochondrial morphology, mitochondrial membrane potential, the production of reactive oxygen species"
explanation: >
A cellular counterpart to the biophysical work above. Graded INDIRECT
because the experiments were performed in a Parkinson-disease context on
the heterozygous allele rather than in an EVEN-PLUS model.
downstream:
- target: Disturbed Embryonic Morphogenesis
description: >-
The step the primary literature calls unexplained. Curated as an edge
because the genetics and the phenotype both demand it, not because a
molecular intermediate is known.
hypothesis_groups:
- mitochondrial_chaperonopathy_morphogenesis
- name: Disturbed Embryonic Morphogenesis
biological_scale: ORGANISM
description: >
The convergence node, and the one the entry is careful about. The features
that define EVEN-PLUS - microtia, nasal hypoplasia, abnormal hair
patterning, anal atresia, sacral and coccygeal agenesis - are patterning
and outgrowth failures of the embryo, not the end-organ consequences of
energy shortfall. The primary report makes both halves of that claim
explicitly: that the features are consequences of disturbed morphogenesis,
and that the phenotype does not resemble the classical bioenergetic
mitochondrial diseases.
biological_processes:
- preferred_term: embryonic skeletal system morphogenesis
modifier: DECREASED
term:
id: GO:0048704
label: embryonic skeletal system morphogenesis
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Many of the clinical features of EVEN-PLUS syndrome (microtia, small nose, abnormal hair patterns, anal atresia, sacral agenesis) are the consequence of disturbed embryonic morphogenesis."
explanation: >
The authors' own reading of the phenotype as developmental, which is the
organising claim of this node.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The phenotype of the CODAS syndrome, and even more so that of EVEN-PLUS, do not resemble those of other multisystem mitochondrial diseases"
explanation: >
The explicit negative claim that separates this disease from
bioenergetic mitochondrial disease, and the reason no energy-failure
node is curated here.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "it was noted that the head and eyes appeared stunted as early as 38 hpf"
explanation: >
The only in vivo observation linking hspa9 loss to disturbed craniofacial
morphogenesis. INDIRECT and MODEL_ORGANISM: the zebrafish crimsonless
mutant was ascertained for a haematopoietic phenotype, and the
developmental observation is incidental to that study.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "after 48 hpf all development appeared to halt, including further maturation of the musculature, fins, and internal organs"
explanation: >
The second, distinct claim this model supports: the arrest is global
rather than confined to the craniofacial structures of the preceding
item, which is what licenses reading hspa9 loss as a general disturbance
of morphogenesis rather than a regional patterning defect. INDIRECT and
MODEL_ORGANISM for the same reason as the item above. The result is
Craven et al. 2005's, summarised here by the EVEN-PLUS report; the
summarising paper is cited because it is the cache this entry holds.
downstream:
- target: Chondro-Osseous Dysplasia of Epiphyses and Vertebral Bodies
description: >-
Growth-plate and vertebral-body patterning failure, the skeletal arm of
the phenotype.
hypothesis_groups:
- mitochondrial_chaperonopathy_morphogenesis
- target: Craniofacial and External Ear Hypoplasia
description: >-
First- and second-arch and nasal-skeleton hypoplasia, the craniofacial
arm.
hypothesis_groups:
- mitochondrial_chaperonopathy_morphogenesis
- name: Chondro-Osseous Dysplasia of Epiphyses and Vertebral Bodies
biological_scale: TISSUE
description: >
A spondyloepiphyseal dysplasia in which the epiphyseal component is severe
and early: proximal femoral epiphyses may remain unossified at five years,
the femoral heads dislocate, and the distal femur takes a distinctive
"bifid" shape. The vertebral component is coronal clefting of the vertebral
bodies, a finding shared with CODAS syndrome and one of the reasons the two
were confused before molecular testing.
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: endochondral bone growth
modifier: DECREASED
term:
id: GO:0003416
label: endochondral bone growth
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 5 yrs, the proximal femoral epiphyses were not ossified, the femoral heads appeared to be dislocated, and the epiphyses at the knee were dysplastic."
explanation: >
Documents the severity and the timing of the epiphyseal component in an
affected child.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula"
explanation: >
Documents the vertebral clefting alongside the proximal femoral
dysplasia in the index patient.
- name: Craniofacial and External Ear Hypoplasia
biological_scale: TISSUE
description: >
A recognisable and reproducible facial gestalt: severe bilateral microtia
with a patent ear canal, a markedly flat nose from hypoplastic nasal bones
with triangular nares, arched eyebrows with synophrys, and midface
hypoplasia. The patency of the ear canal alongside a severely malformed
pinna is diagnostically useful - it separates this from the branchial-arch
syndromes in which canal atresia is the rule.
cell_types:
- preferred_term: cranial neural crest cell
term:
id: CL:0011012
label: neural crest cell
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had severe bilateral microtia with apparently normal external ear duct, arched eyebrows with mild synophris, and a very flat nose with nares that were triangular in shape"
explanation: >
The defining craniofacial description, including the patent ear canal.
- reference: PMID:36052765
reference_title: "Identifying patients with EVEN-plus syndrome using exome sequencing and clinical feature analysis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient had global developmental delay and specific facial features, including a prominent forehead, a bilateral auricle deformity, a collapsed nose, a high palatine arch, a short neck and other appearance abnormalities."
explanation: >
Independent replication of the facial gestalt in a patient ascertained
in a different population.
animal_models:
- name: Hspa9 gene-trap knockout mouse
species: Mouse
genotype: Hspa9 null (homozygous and heterozygous)
publication: PMID:25550197
description: >
A gene-trap null generated to study HSPA9 haploinsufficiency in
myelodysplastic syndrome, not to model EVEN-PLUS. Its relevance here is
the dosage result at both ends: homozygous loss is embryonically lethal,
and heterozygous loss with 50% residual expression gives viable mice with
normal basal haematopoiesis and no skeletal or craniofacial phenotype
reported.
modeled_mechanisms:
- target: Disturbed Embryonic Morphogenesis
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
Neither available dosage models the disease. Complete loss kills the
embryo before a malformation phenotype can be assessed, and half dosage
produces viable mice in which nothing resembling EVEN-PLUS is described.
Between them they bracket the human condition without reaching it, which
is a structural reason no mouse model of this syndrome exists.
limitations: >-
A null allele on both counts, whereas every human genotype retains
partial mortalin function. The study was designed around haematopoiesis
in del(5q) myelodysplastic syndrome and did not phenotype the skeleton
or craniofacial structures, so the absence of a skeletal phenotype in
heterozygotes is an absence of reporting as well as, probably, an
absence of phenotype. A knock-in of the human hypomorphic alleles is the
experiment this model cannot substitute for.
evidence:
- reference: PMID:25550197
reference_title: "Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Although homozygous knockout of Hspa9 is embryonically lethal, mice with heterozygous deletion of Hspa9 (Hspa9(+/-)) are viable and have a 50% reduction in Hspa9 expression."
explanation: >
The dosage result, and the direct support for this link's claim that
the model does not reproduce the human syndrome: one dosage is lethal
before a malformation phenotype can form, the other is unaffected, so
neither is EVEN-PLUS.
- reference: PMID:25550197
reference_title: "Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Hspa9(+/-) mice have normal basal hematopoiesis and do not develop MDS."
explanation: >
Establishes that half dosage is tolerated, which is the observation
behind the inference that human patients must retain more residual
function than a null allele provides.
discussions:
- discussion_id: hspa9_chaperone_to_morphogenesis_gap
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Disturbed Embryonic Morphogenesis
prompt: >-
By what molecular route does partial loss of the mitochondrial matrix
Hsp70 produce a patterning phenotype - microtia, nasal hypoplasia, anal
atresia, sacral agenesis - rather than the bioenergetic failure seen in
classical mitochondrial disease?
rationale: >
This is the load-bearing gap in the entry. Causal genetics are settled and
replicated across four independent reports, and the clinical phenotype is
consistent; what is missing is any demonstrated intermediate between
chaperone deficiency and dysmorphogenesis. The primary report says so in
as many words, and no subsequent paper has closed it. Curating the edge
from chaperone failure to morphogenesis without recording this gap would
misrepresent an assumed step as an established one.
There are candidate routes in the literature that this entry deliberately
does not curate as mechanism, because nothing tests them in this disease:
an effect on iron-sulfur cluster biogenesis, in which mortalin is the
matrix Hsp70 partner; and reported interactions of HSPA9 with FGF1 and
with SMAD2, which would place it on signalling pathways with obvious
developmental relevance. They belong in an experiment, not in a
pathophysiology node.
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the pathogenesis of the developmental defects associated with LONP1 and HSPA9 mutations remain unexplained"
explanation: >
The authors state the gap directly; this is the citation that licenses
recording it rather than inferring a mechanism.
proposed_experiments:
- experiment_id: hspa9_lineage_conditional_hypomorph
name: Conditional Hspa9 hypomorph in neural crest and limb-bud mesenchyme
description: >-
Introduce the recurrent human missense alleles (p.R126W, p.Y128C) as
knock-in hypomorphs and delete Hspa9 conditionally in cranial neural
crest and in limb-bud/sclerotome mesenchyme, then ask whether the
craniofacial and skeletal phenotypes segregate with lineage rather than
with tissue energy demand.
would_support:
- pathophysiology#Disturbed Embryonic Morphogenesis
supporting_outcome:
- >-
Lineage-restricted loss reproduces microtia, nasal hypoplasia and
epiphyseal dysplasia with normal respiratory-chain assembly and normal
lactate, dissociating the malformation phenotype from bioenergetic
failure.
would_refute:
- pathophysiology#Disturbed Embryonic Morphogenesis
refuting_outcome:
- >-
The malformations appear only where oxidative-phosphorylation capacity
is measurably reduced, and correlate with respiratory-chain deficiency
rather than with lineage, which would make this an energy-failure
disease after all.
phenotypes:
- category: Skeletal
name: Epiphyseal Dysplasia
frequency: OBLIGATE
description: >
The "E" of the acronym and the most consistent radiographic finding.
Severe at the proximal femur, where ossification may be absent well into
childhood, with dysplastic knee epiphyses and a "bifid" distal femur.
OBLIGATE is entailed rather than stated: the 12-case review reports
dysplastic femoral heads in 100% (12/12), and the femoral head is an
epiphysis, so a narrower feature at 100% carries the broader node with
it.
phenotype_term:
preferred_term: Epiphyseal dysplasia
term:
id: HP:0002656
label: Epiphyseal dysplasia
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 5 yrs, the proximal femoral epiphyses were not ossified, the femoral heads appeared to be dislocated, and the epiphyses at the knee were dysplastic."
explanation: >
Radiographic documentation of the epiphyseal phenotype and its severity.
- reference: PMID:36052765
reference_title: "Identifying patients with EVEN-plus syndrome using exome sequencing and clinical feature analysis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her hip joint magnetic resonance imaging (MRI) results showed bilateral femoral head epiphyseal dysplasia with a fork-shaped malformation at the distal end"
explanation: >
Independent replication, including the characteristic distal femoral
shape, on cross-sectional imaging rather than plain film.
- category: Skeletal
name: Coronal Cleft Vertebrae
description: >
The "V" of the acronym. Coronal clefting of the vertebral bodies is shared
with CODAS syndrome and is one of the findings that made the two
indistinguishable before HSPA9 was implicated.
phenotype_term:
preferred_term: Coronal cleft vertebrae
term:
id: HP:0003417
label: Coronal cleft vertebrae
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographic findings were similar to those seen in her sister and included vertebral coronal clefts"
explanation: >
Documents coronal clefting in an affected sib, replicating the finding
within the family.
- category: Craniofacial
name: Synophrys and Arched Eyebrows
description: >
Reported across the collated cohort and easy to under-record, because it
reads as a minor dysmorphic detail rather than a malformation. No
frequency is asserted here: the 12/12 statement in the review is for
"synophrys or arched eyebrows", which is broader than synophrys, and a
broader feature at 100% does not carry the narrower one. This node is
bound to HP:0000664, so an OBLIGATE value here would export as "EVEN-PLUS,
synophrys, 100%", which no source states - the same reasoning applied to
Microtia below.
phenotype_term:
preferred_term: Synophrys
term:
id: HP:0000664
label: Synophrys
evidence:
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients had synophrys or arched eyebrows, hypoplastic or dysplastic ears, hypoplastic nasal bone, and dysplastic femoral head."
explanation: >
A frequency statement with a stated denominator - all 12 collated
patients - which is the only such statement this literature supports.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had arched eyebrows and synophrys."
explanation: >
Direct documentation in an index patient of the founding report.
- category: Neurologic
name: Basal Ganglia Lesions
description: >
Newly recognised. Two of the 12 collated patients had basal ganglia
lesions on cerebral MRI together with seizures, and the review names this
as a new phenotype of the syndrome rather than an incidental finding. A
third, independently reported patient had white-matter myelination
abnormality, so CNS involvement is not confined to one family.
phenotype_term:
preferred_term: Abnormal basal ganglia morphology
term:
id: HP:0002134
label: Abnormal basal ganglia morphology
evidence:
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two patients had seizures and basal ganglia lesions in cerebral MRI."
explanation: >
Documents the finding with its denominator inside the 12-case cohort.
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seizures and basal ganglia lesions are a new phenotype of EVEN-PLUS syndrome."
explanation: >
The authors' explicit claim that this is a phenotype of the syndrome,
which is what licenses curating it rather than treating it as a
coincidental MRI finding.
- category: Neurologic
name: Seizures
description: >
Reported in the same two patients as the basal ganglia lesions and
described as part of the same new phenotype. Absent from the earlier
reports, so this is an extension of the syndrome rather than a feature
that was previously overlooked.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Besides the core clinical features of EVEN-PLUS syndrome, the two cases had seizures, developmental delay, and basal ganglia lesions in cerebral MRI."
explanation: >
Documents seizures alongside the developmental and imaging findings in
the two newly reported patients.
- category: Craniofacial
name: Microtia
description: >
The "E" for ears. Severe and bilateral, with the ear canal typically
patent - an unusual combination that is diagnostically informative. No
frequency is asserted here: the 12/12 statement in the review is for
"hypoplastic or dysplastic ears", which is broader than microtia, and a
broader feature at 100% does not carry the narrower one.
phenotype_term:
preferred_term: Microtia
term:
id: HP:0008551
label: Microtia
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She had severe bilateral microtia with apparently normal external ear duct, arched eyebrows with mild synophris, and a very flat nose with nares that were triangular in shape"
explanation: >
Documents bilateral microtia together with the preserved ear canal.
- category: Craniofacial
name: Nasal Hypoplasia
frequency: OBLIGATE
description: >
The "N" of the acronym: hypoplastic nasal bones giving a markedly flat
nasal profile with triangular nares.
phenotype_term:
preferred_term: Hypoplasia of the nasal bone
term:
id: HP:0004646
label: Hypoplasia of the nasal bone
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Her face showed midface hypoplasia with markedly hypoplastic nasal bones, giving her a flat nose with nares that were triangular in shape"
explanation: >
Attributes the flat nasal profile to hypoplasia of the nasal bones
rather than to soft-tissue change.
- category: Growth
name: Prenatal-Onset Short Stature
description: >
Growth restriction is detectable before birth - short long bones on
prenatal ultrasound - and persists, with heights well below the third
centile throughout childhood.
phenotype_term:
preferred_term: Intrauterine growth retardation
term:
id: HP:0001511
label: Intrauterine growth retardation
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Oligohydramnios and short long bones were noted prenatally."
explanation: >
Establishes prenatal onset of the growth phenotype.
- reference: PMID:36052765
reference_title: "Identifying patients with EVEN-plus syndrome using exome sequencing and clinical feature analysis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It has a prenatal onset due to defects in the HSPA9 gene."
explanation: >
Independent statement that the disorder is of prenatal onset.
- category: Growth
name: Short Stature
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "she had severe short stature (markedly below the 3rd percentile for Chilean children) with a height of 80 cm"
explanation: >
Quantifies the postnatal growth deficit against a population reference.
- category: Cardiovascular
name: Atrial Septal Defect
description: >
Reported in all three index patients, and in one it closed spontaneously
by 20 months - so a normal echocardiogram in an older child does not argue
against the diagnosis.
phenotype_term:
preferred_term: Atrial septal defect
term:
id: HP:0001631
label: Atrial septal defect
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "An atrioseptal defect (ASD) was present at birth but repeat ultrasound at age 20 months showed that it had closed spontaneously."
explanation: >
Documents the septal defect and, importantly, its spontaneous closure.
- category: Gastrointestinal
name: Anal Atresia
description: >
Present in two of the three index patients, requiring surgical correction
or colostomy. Part of the caudal-region involvement that also includes
coccygeal agenesis.
phenotype_term:
preferred_term: Anal atresia
term:
id: HP:0002023
label: Anal atresia
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She was noted to have anal atresia that was subsequently surgically corrected."
explanation: >
Documents anal atresia in the index patient.
- category: Dermatologic
name: Aplasia Cutis Congenita
description: >
Scalp aplasia cutis, reported in both affected sibs alongside abnormal hair
whorls - a patterning defect of the scalp rather than a wound.
phenotype_term:
preferred_term: Aplasia cutis congenita
term:
id: HP:0001057
label: Aplasia cutis congenita
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "she had two lateral hair whorls and a small area of aplasia cutis on her cranium"
explanation: >
Documents aplasia cutis together with the abnormal hair patterning.
- category: Neurologic
name: Global Developmental Delay
description: >
Variable and not universal. One index patient had a developmental quotient
of about 80 with a normal brain MRI; her similarly affected relatives were
delayed. Later reports describe clear cognitive and motor delay, so the
entry treats this as a variable rather than an obligate feature.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 8 months, developmental delay was diagnosed."
explanation: >
Documents developmental delay in one of the index patients.
- reference: PMID:36052765
reference_title: "Identifying patients with EVEN-plus syndrome using exome sequencing and clinical feature analysis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient had global developmental delay and specific facial features, including a prominent forehead, a bilateral auricle deformity, a collapsed nose, a high palatine arch, a short neck and other appearance abnormalities."
explanation: >
Independent report of global developmental delay in a molecularly
confirmed patient.
- category: Neurologic
name: Corpus Callosum Dysgenesis
description: >
Reported in one sib, with a normal brain MRI in another patient, so
midline brain involvement is inconsistent. A later case reported agenesis
of the septum pellucidum, which is the same midline-forebrain territory.
phenotype_term:
preferred_term: Agenesis of corpus callosum
term:
id: HP:0001274
label: Agenesis of corpus callosum
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A brain CT showed dysgenesis of the corpus callosum."
explanation: >
Documents callosal dysgenesis in an affected sib.
- reference: PMID:32869452
reference_title: "EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These features include agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia."
explanation: >
Reports a related midline forebrain defect, broadening the CNS spectrum
beyond the callosum.
- category: Dental
name: Hypodontia
phenotype_term:
preferred_term: Hypodontia
term:
id: HP:0000668
label: Hypodontia
description: >
Reduced tooth number, reported in one sib. Worth noting because dental
anomalies are the "D" of CODAS, the syndrome EVEN-PLUS is most easily
confused with, and their presence here does not reclassify the case.
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "aplasia cutis on the skull vertex, a very flat nose with triangular nares, arched eyebrows with mild synophrys, high palate, hypodontia"
explanation: >
Documents hypodontia within the full clinical description of an affected
sib, alongside the high palate and the craniofacial gestalt.
- category: Renal
name: Hydronephrosis and Vesicoureteral Reflux
description: >
Inconsistent. One sib had right vesicoureteral reflux with nephropathy
while another patient's renal ultrasound was normal; a later case had
hydronephrosis. Renal imaging is therefore worth doing but a normal study
does not exclude the diagnosis.
phenotype_term:
preferred_term: Vesicoureteral reflux
term:
id: HP:0000076
label: Vesicoureteral reflux
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Imaging studies showed right vesico-ureteral reflux with right kidney nephropathy."
explanation: >
Documents reflux nephropathy in an affected sib.
- reference: PMID:32869452
reference_title: "EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These features include agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia."
explanation: >
Reports hydronephrosis, extending the urinary-tract involvement to a
second family.
genetic:
- name: HSPA9
notes: >
The sole gene reported for this disorder. It encodes mortalin / mtHSP70 /
GRP75, the matrix Hsp70 that drives presequence import through TIM23 and
is required for LONP1 protease activity. Reported EVEN-PLUS alleles are
hypomorphic rather than null; the recurrent c.882_883delAG (p.V296*) has
been seen in patients of both Korean and Chinese ancestry, which raises
the question of an East Asian founder effect.
gene_term:
preferred_term: HSPA9
term:
id: hgnc:5244
label: HSPA9
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There was only one gene that fit all criteria, namely, HSPA9."
explanation: >
The result of the exome filtering that identified the gene, stated as
the sole surviving candidate.
- reference: PMID:36052765
reference_title: "Identifying patients with EVEN-plus syndrome using exome sequencing and clinical feature analysis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This finding expands the spectra of EVEN-plus syndrome phenotype and pathogenic variants and suggests that c.882_c.883delAG may have a higher distribution frequency in East Asian populations."
explanation: >
Records the recurrence of the frameshift allele and the authors'
founder-effect hypothesis.
treatments:
- name: Reproductive genetic counseling with prenatal or preimplantation testing
description: >
The only intervention in this entry with a reported outcome rather than an
inferred one, and it is preventive rather than therapeutic. In one Chinese
family the biallelic genotype was identified in two affected fetuses,
mutation-free embryos were selected, and a healthy daughter was born. For
a recessive condition with no disease-modifying treatment and a recurrence
risk of one in four, this is what "management" currently means for a
family after a first affected child.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:38281662
reference_title: "Prenatal to preimplantation genetic diagnosis of a novel compound heterozygous mutation in HSPA9 associated with Even-Plus syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Assisted reproduction with mutation-free embryos successfully blocked the transmission of mutations."
explanation: >
A reported outcome, in a family with a molecularly confirmed EVEN-PLUS
genotype, of the only intervention with evidence in this disease.
- reference: PMID:38281662
reference_title: "Prenatal to preimplantation genetic diagnosis of a novel compound heterozygous mutation in HSPA9 associated with Even-Plus syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutation-free embryos were selected for transplantation and reconfirmed to possess no mutations. A healthy daughter was successfully born into the family."
explanation: >
The confirmatory detail - selection, reconfirmation, and live birth -
which is what distinguishes this from a proposal.
- name: Orthopedic management of hip dysplasia and epiphyseal disease
description: >
Directed at the skeletal phenotype that dominates lifelong burden:
dysplastic femoral heads found in every collated patient, dislocation,
unossified proximal femoral epiphyses, dislocated patellae and scoliosis.
No trial or series reports outcomes in this disease. The intervention is
curated because the phenotype is universal and orthopedic care is what it
generates in practice, not because anyone has measured it here - hence
`directness: INDIRECT`.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Orthopedic Surgical Procedure
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
target_mechanisms:
- target: Chondro-Osseous Dysplasia of Epiphyses and Vertebral Bodies
description: >-
Addresses the mechanical consequences of the growth-plate and
femoral-head lesion; it does not act on the lesion itself.
evidence:
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "All patients had synophrys or arched eyebrows, hypoplastic or dysplastic ears, hypoplastic nasal bone, and dysplastic femoral head."
explanation: >
Establishes that the femoral-head lesion is universal, which is the
basis for treating orthopedic care as expected management. INDIRECT: the
source documents the phenotype, not the outcome of treating it.
- reference: PMID:26598328
reference_title: "Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "At age 5 yrs, the proximal femoral epiphyses were not ossified, the femoral heads appeared to be dislocated, and the epiphyses at the knee were dysplastic."
explanation: >
Documents dislocation and failed ossification in a specific child, which
is the clinical problem this management addresses. INDIRECT for the same
reason.
- name: Surveillance for cardiac, renal and neurological involvement
description: >
Septal defects, vesicoureteral reflux and hydronephrosis, and now seizures
with basal ganglia lesions are each reported in a minority of patients and
none is predictable from the skeletal phenotype. The systematic review's
own conclusion is that the syndrome should be suspected on the combination
of craniofacial, skeletal, cardiac and renal findings, which is the same
argument for looking for them once the diagnosis is made. Note that a
normal study does not settle the question: one index patient's atrial
septal defect closed spontaneously by 20 months.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "HSPA9 gene mutations should be suspected in all cases with specific craniofacial features, abnormal skeletal presentations, congenital heart defects, and renal alterations."
explanation: >
Names the four organ systems the syndrome involves. INDIRECT: this is a
diagnostic-suspicion statement being used to argue for surveillance,
which is an inference step the source does not itself take.
- reference: PMID:38284453
reference_title: "A new phenotype of EVEN-PLUS syndrome in a Chinese family and literature review."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Seizures and basal ganglia lesions are a new phenotype of EVEN-PLUS syndrome."
explanation: >
Adds neurological surveillance to the list, on the strength of a
phenotype recognised only in 2024. INDIRECT for the same reason.
diagnosis:
- name: Exome or genome sequencing
description: >
The diagnosis is molecular. Every published case was made by exome
sequencing, in several instances after a clinical diagnosis of CODAS
syndrome had been made and LONP1 testing returned negative. A skeletal
survey showing coronal vertebral clefts with severe proximal femoral
epiphyseal dysplasia, in a child with bilateral microtia and a flat nose,
is the phenotype that should prompt HSPA9 testing.
evidence:
- reference: PMID:32869452
reference_title: "EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report here the fifth case of EVEN-PLUS syndrome with novel variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in the HSPA9 gene identified through whole-exome sequencing."
explanation: >
Documents exome sequencing as the diagnostic route in a representative
case.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Review response round 2: second zebrafish citation, obligate frequencies · 2026-08-31T09:38:01Z · View source
Second automated review cycle on PR 10213. Supersedes the 08:18 CREATE record, which was written before the round-1 fix commit and understates what the entry now holds: it omits the treatments section and reports 43/43 snippets against the current 58/58. Fixed the one substantive finding of round 2. The notes block claimed the zebrafish crimsonless mutant was cited twice for two different claims and that both items were MODEL_ORGANISM and INDIRECT. It was cited once. The prose was never true, not something a fix commit dropped, and it survived a full review round because the PR body restated it and the round-1 review repeated it back as praise without counting. Rather than trim the prose to match one citation, the second citation was added, because the claim the prose describes - that hspa9 loss disturbs morphogenesis globally rather than regionally - was carried by prose alone. The new item quotes the global developmental arrest sentence from the same cached paragraph, graded SUPPORT INDIRECT MODEL_ORGANISM, and its explanation records that the underlying result is Craven et al. 2005's, summarised by the EVEN-PLUS report that this entry actually caches. Added frequency OBLIGATE to three phenotypes, on the review's own 12-case denominator rather than on pooled percentages across independent reports. Two of the three needed a stated reason. Epiphyseal Dysplasia is entailed rather than asserted: the source reports dysplastic femoral heads at 100 percent 12 of 12, and the femoral head is an epiphysis, so a narrower feature at full penetrance carries the broader node. Synophrys and Arched Eyebrows is a compound node and the source states the feature disjunctively, so OBLIGATE is asserted for the compound and explicitly not for synophrys alone. Declined the same suggestion for Microtia and recorded why in its description. The 12 of 12 statement is for hypoplastic or dysplastic ears, which is broader than microtia, and unlike the femoral-head case a broader feature at full penetrance does not carry the narrower one. Applying the suggestion uniformly would have asserted that all twelve patients had microtia specifically, which no source says. Declined the rebinding of Basal Ganglia Lesions from HP:0002134 to HP:0012751 Abnormal basal ganglia MRI signal intensity. The cached snippet says basal ganglia lesions in cerebral MRI. Lesion is structural language; signal intensity is a claim the source does not make, and binding it would manufacture a narrower match, which the term contract forbids. HP:0007146 was also rejected because its bilaterality is unsupported. Declined the optional progression block. No denominatored or syndrome-level progression statement exists in any cached reference. The only candidate sentence describes one patient's posture not worsening, and the structural claim the reviewer pointed at lives in deep-research synthesis prose, which is not citable. Validation on this head: linkml-validate clean, term validation passed, 58 of 58 snippets verified against cached references, cache normalization reported zero files updated, and check-entity-refs, check-duplicate-keys, check-snippet-grading and check-snippet-length all clean with no baseline movement.
Create: EVEN-PLUS Syndrome · 2026-08-31T08:18:05Z · View source
De-novo curation of EVEN-PLUS syndrome, MONDO:0014801, HSPA9 - the biallelic mortalin/mtHSP70 chaperonopathy. One OpenScientist deep-research run, research/EVEN-PLUS_Syndrome-deep-research-openscientist.md: 14/14 references verified, 21/21 quotes valid, confabulation_rate 0.0, but term_validation needs_review true with 8 label mismatches. No CURIE was taken from the report; every ontology binding here was selected against the committed term caches and validated by just validate-terms. The report's suggested terms included HP:0011003 labelled 'Arched eyebrows' when it is High myopia, and NCIT:C15190 labelled 'Supportive Care' when it is Needle Biopsy, so the caution was warranted. The report did contribute two verified leads that materially improved the entry: PMID:30933555, a dedicated biophysical study of the R126W and Y128C alleles, and PMID:25550197, establishing that homozygous Hspa9 knockout is embryonically lethal. Both were fetched and independently read before use. The entry deliberately does NOT curate the report's proposed energy-failure and apoptosis causal chain, because the primary source states explicitly that the phenotype does not resemble bioenergetic mitochondrial disease and that the pathogenesis of the developmental defects remains unexplained; that step is curated as a KNOWLEDGE_GAP discussion instead. Validated with just validate - schema, terms, 43/43 snippets verified - plus check-entity-refs and check-duplicate-keys.
Disease: EVEN-PLUS Syndrome OMIM: #616854 | Gene: HSPA9 (mortalin/mtHSP70/GRP75) | Category: Mendelian (autosomal recessive) Suggested MONDO: MONDO:0014784
Evidence types are marked where useful: human clinical, model organism, in vitro/biophysical, computational. No primary datasets were provided; all content is derived from primary literature via PubMed.
EVEN-PLUS syndrome is an ultra-rare, autosomal-recessive, prenatal-onset multiple-malformation and skeletal-dysplasia syndrome caused by biallelic loss-of-function or hypomorphic variants in HSPA9, the gene encoding the mitochondrial HSP70 chaperone mortalin (mtHSP70/GRP75). The name is an acronym for its cardinal features — Epiphyses, Vertebrae, Ears, Nose — PLUS associated malformations of the heart, kidneys, and central nervous system. The disorder was delineated and named by Royer-Bertrand and colleagues in 2015 (PMID: 26598328), who identified biallelic HSPA9 mutations in affected individuals lacking mutations in LONP1 (the gene responsible for the phenotypically overlapping CODAS syndrome). Together with CODAS, EVEN-PLUS defines a family of "mitochondrial chaperonopathies."
Mechanistically, mortalin is an essential mitochondrial matrix chaperone that drives ATP-dependent import of nuclear-encoded proteins across the inner membrane, assists protein folding, participates in iron–sulfur (Fe-S) cluster biogenesis, and buffers oxidative stress. EVEN-PLUS mutations — spanning missense, nonsense, frameshift, and splice-site classes — reduce or abolish this chaperone activity. Biophysical work on the nucleotide-binding-domain mutants R126W and Y128C shows that they disrupt ATP hydrolysis, interdomain communication, and thermostability while increasing the protein's propensity to aggregate (PMID: 30933555). The downstream consequence — impaired mitochondrial proteostasis, oxidative stress, and apoptosis in rapidly dividing embryonic precursors — is inferred to explain the skeletal, craniofacial, and organ malformations. Complete loss of the orthologous gene is embryonic-lethal in mice and produces ineffective hematopoiesis in zebrafish, establishing mortalin as developmentally essential.
Clinically, fewer than ~15 patients have been reported worldwide. Onset is prenatal; survivors have lifelong static skeletal dysplasia and craniofacial anomalies, with a subset developing seizures, developmental delay, and basal-ganglia lesions. Diagnosis rests on exome/genome sequencing (identifying biallelic HSPA9 variants) combined with characteristic skeletal imaging. There is no disease-modifying or curative therapy; management is supportive and multidisciplinary, and prevention is reproductive — prenatal diagnosis and preimplantation genetic testing (PGT), the latter demonstrated to successfully block transmission and yield a healthy birth (PMID: 38281662).
EVEN-PLUS syndrome is a congenital, autosomal-recessive multisystem malformation syndrome with skeletal dysplasia. It was first delineated as a distinct entity in 2015, when biallelic HSPA9 mutations were identified in three individuals from two families (PMID: 26598328). The name encodes the four cardinal anatomical domains — Epiphyses, Vertebrae, Ears, Nose — plus associated ("PLUS") malformations. The original report states the phenotype "included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings" (PMID: 26598328).
Key identifiers:
| Resource | Identifier |
|---|---|
| OMIM (disease) | #616854 |
| OMIM (gene) | *600548 (HSPA9) |
| Suggested MONDO | MONDO:0014784 |
| HGNC (gene) | HGNC:5244 |
| Gene locus | 5q31.2 |
Synonyms / alternative names: EVEN-PLUS syndrome; Epiphyseal, vertebral, ear, nose, plus associated findings syndrome; EVE dysplasia (the original family reported as "EVE dysplasia" was later confirmed to carry a homozygous HSPA9 variant, PMID: 35779070).
Data provenance: All information is derived from aggregated, disease-level resources and individual published case reports/case series (n < 15 patients worldwide), not from EHR-derived population cohorts. This is characteristic of an ultra-rare Mendelian disorder.
Primary cause — genetic: EVEN-PLUS is a monogenic disorder caused by biallelic (homozygous or compound heterozygous) pathogenic variants in HSPA9, which encodes mortalin (mtHSP70/GRP75), a mitochondrial chaperone. The seminal study reported: "we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation" (PMID: 26598328).
Genetic risk factors: The disorder is fully penetrant given biallelic pathogenic genotypes; there are no known susceptibility loci or modifier genes described. Consanguinity and founder alleles increase risk in specific families/populations — the frameshift variant c.882_883delAG "may have a higher distribution frequency in East Asian populations" (PMID: 36052765).
Environmental risk factors: None identified. This is a purely Mendelian disorder; there is no evidence of environmental, infectious, or lifestyle contribution to causation.
Protective factors: No genetic or environmental protective factors are described. Because complete mortalin loss is embryonic-lethal (mouse homozygous knockout, PMID: 25550197), viable EVEN-PLUS genotypes are inferred to be hypomorphic — retaining partial chaperone function — which acts as an implicit constraint on the survivable disease spectrum.
Gene–environment interactions: None reported or expected for this monogenic disorder.
The phenotype spectrum is best defined by the 12-case review of Liu et al. (PMID: 38284453; 9 females) and the first-affected-male report (PMID: 32869452). Onset is prenatal/congenital; the phenotype is largely static (structural malformations) except for progressive neurologic features in a subset.
"All patients had synophrys or arched eyebrows, hypoplastic or dysplastic ears, hypoplastic nasal bone, and dysplastic femoral head." (PMID: 38284453)
| Phenotype | HPO term | Type |
|---|---|---|
| Synophrys | HP:0000664 | Physical/craniofacial |
| Arched eyebrows | HP:0011003 | Physical/craniofacial |
| Microtia / hypoplastic-dysplastic ears | HP:0008551, HP:0000369 | Physical/craniofacial |
| Hypoplastic nasal bone | HP:0004646 | Skeletal/radiographic |
| Dysplastic femoral head / epiphyseal dysplasia | HP:0006411, HP:0002656 | Skeletal |
| Phenotype | HPO term |
|---|---|
| Triangular nares | HP:0011832 |
| Bifid/dysplastic femur ("fork-shaped" distal femur) | — |
| Dysplastic epiphyses at the knee | HP:0002656 |
| Dysplastic acetabula | HP:0003182 |
| Delayed ossification | HP:0002662 |
| Short stature | HP:0004322 |
| Vertebral (coronal) clefting | HP:0003417 |
| Scoliosis | HP:0002650 |
| Dislocated patellae | HP:0002999 |
| Congenital heart defects | HP:0001627 |
| Renal alterations | HP:0000077 |
Seizures (HP:0001250), global developmental delay (HP:0001263), basal ganglia lesions (HP:0002134), aplasia cutis (HP:0001057), short thorax/sternum (HP:0005257), widely spaced/laterally displaced nipples (HP:0006610), cryptorchidism (HP:0000028), clubfoot (HP:0001762), hypotonia (HP:0001252), agenesis of the septum pellucidum (HP:0001331), and 13 pairs of ribs (HP:0000891). The first affected male exhibited "agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia" (PMID: 32869452).
Severity/progression: Skeletal and craniofacial features are severe and static (congenital, non-progressive structural malformations). A milder facial phenotype has been documented in two sibs with compound heterozygous variants (PMID: 35779070), indicating variable expressivity. Neurologic features (seizures, basal-ganglia lesions) may be progressive and are an adverse prognostic sign.
Quality-of-life impact: Lifelong disability from short stature, joint dislocations, and skeletal dysplasia (mobility, orthopedic burden); hearing impairment from microtia; potential cardiac and renal morbidity; and neurodevelopmental disability in the CNS-affected subset. Formal QoL instruments (EQ-5D, SF-36) have not been applied given the disease's rarity.
Causal gene: HSPA9 (Heat Shock Protein Family A member 9; HGNC:5244; OMIM 600548), located at chromosome 5q31.2, encoding mortalin* (also mtHSP70, GRP75, PBP74). Disease OMIM #616854.
Pathogenic variant spectrum: Approximately 13 pathogenic variants have been catalogued (PMID: 38284453). All are germline and biallelic (homozygous in consanguineous/founder families, compound heterozygous otherwise), and classified pathogenic/likely pathogenic under ACMG/AMP criteria. Individually the alleles are rare or absent in gnomAD (carrier-level frequencies).
| Variant (cDNA / protein) | Class | Domain | Reference |
|---|---|---|---|
| R126W | Missense | Nucleotide-binding domain (NBD) | PMID: 30933555 |
| Y128C | Missense | Nucleotide-binding domain (NBD) | PMID: 30933555 |
| c.955C>T (p.L319F) | Missense | — | PMID: 32869452 |
| c.818T>G (p.L273X) | Nonsense (NMD) | — | PMID: 32869452 |
| c.882_883delAG | Frameshift | — (recurrent, East Asian) | PMID: 36052765 |
| c.613A>G | Missense | — | PMID: 36052765 |
| c.1822-1G>A | Splice (pathogenic) | Substrate-binding domain (SBD) | PMID: 38281662 |
| c.1411-3T>G | Splice (likely pathogenic) | Substrate-binding domain (SBD) | PMID: 38281662 |
"novel variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in the HSPA9 gene" (PMID: 32869452); "c. 1822-1G>A and c. 1411-3T>G were classified as pathogenic and likely pathogenic, respectively" (PMID: 38281662).
Functional consequences: The overall mechanism is loss of function / hypomorphism. Truncating alleles undergo nonsense-mediated decay — "qPCR analysis provides supporting evidence for a nonsense-mediated decay mechanism for the HSPA9 truncating variant" (PMID: 32869452). Missense NBD alleles impair enzymatic/chaperone function: "the surface mutations R126W and Y128C have far-reaching effects that disrupt ATP hydrolysis, interdomain linker binding, and thermostability and increase the propensity for aggregation" (PMID: 30933555).
Modifier genes / epigenetics / chromosomal abnormalities: No disease modifiers, epigenetic mechanisms, or large-scale chromosomal abnormalities are described for EVEN-PLUS. (Note: heterozygous HSPA9 deletion at 5q31.2 is separately implicated in del(5q) myelodysplastic syndrome — a distinct, somatic, haploinsufficiency context, PMID: 21123823.)
Not applicable. EVEN-PLUS is a purely Mendelian disorder. No environmental factors, toxins, radiation, occupational exposures, lifestyle factors, or infectious agents are known to cause, trigger, or modify the disease. The only non-genetic reproductive variable of note is consanguinity, which increases the likelihood of homozygosity for a founder allele.
Biallelic HSPA9 variants
│
▼
↓ mortalin function/quantity ──────────────┐
│ │
▼ ▼
↓ mito protein import/folding ↓ Fe-S cluster biogenesis
(mortalin–Tim complexes) (frataxin/NFS1/ISCU)
│ │
└──────────────┬───────────────────┘
▼
↓ ATP generation + ↑ oxidative stress
│
▼
apoptosis of embryonic precursors
│
▼
epiphyseal/vertebral dysplasia · microtia ·
nasal hypoplasia · cardiac/renal/CNS anomalies
Cell types (suggested CL terms): chondrocyte (CL:0000138) and osteoblast (CL:0000062) for skeletal dysplasia; neural crest–derived cells for craniofacial (ear/nose) structures; cardiomyocyte (CL:0000746) and renal epithelial cells for organ malformations. These cell-type assignments are inferred from the affected anatomy rather than directly demonstrated.
Organ / system level (primary): - Skeletal system (UBERON:0001434): epiphyses (femoral head, knee), vertebrae (coronal clefts, hemivertebrae), acetabula, patellae, thorax/sternum, ribs. - External/middle ear (UBERON:0001690): microtia / dysplastic ears. - Nose / nasal bone (UBERON:0001705, UBERON:0002517): nasal hypoplasia, triangular nares. - Face / eyebrow region (UBERON:0001711): synophrys, arched eyebrows.
Secondary organ involvement: - Cardiovascular system (UBERON:0004535): congenital heart defects (HP:0001627). - Renal/urinary system (kidney UBERON:0002113): renal alterations, hydronephrosis (HP:0000077). - Central nervous system / brain (UBERON:0000955): basal-ganglia lesions (HP:0002134), agenesis of septum pellucidum (HP:0001331).
Tissue/cell level: Connective/skeletal tissue (cartilage, bone), with epiphyseal cartilage and growth-plate chondrocytes prominently affected; neural-crest-derived craniofacial mesenchyme (ear, nose).
Subcellular level: The primary compartment is the mitochondrion (GO:0005739), specifically the mitochondrial matrix (GO:0005759), where mortalin operates. Suggested GO cellular-component terms: GO:0005739 (mitochondrion), GO:0005759 (mitochondrial matrix), GO:0005758 (mitochondrial intermembrane space, for import).
Localization / lateralization: Skeletal features are generally bilateral and largely symmetric; some findings (cryptorchidism, single palmar crease, clubfoot) are reported unilaterally in individual patients (PMID: 32869452).
Onset: Congenital / prenatal. "It has a prenatal onset due to defects in the HSPA9 gene" (PMID: 36052765). Malformations are established during embryonic/fetal organogenesis and are often detectable on prenatal ultrasound, prompting prenatal genetic diagnosis (PMID: 38281662).
Progression: The core skeletal and craniofacial malformations are static/non-progressive (structural, congenital). The disorder is chronic and lifelong for survivors. A lethality gradient exists at the severe end: some pregnancies are ascertained prenatally and terminated, and complete mortalin loss is embryonic-lethal in mice (PMID: 25550197).
Neurologic course: In the CNS-affected subset, seizures and basal-ganglia lesions may be progressive and represent an evolving morbidity beyond the static skeleton (PMID: 38284453).
Critical period: Embryonic organogenesis is the window of vulnerability. There is no post-natal therapeutic window to reverse established malformations; the only "intervention window" is pre-conception/pre-implantation (PGT) or prenatal.
Epidemiology: Ultra-rare. Fewer than ~15 patients have been reported worldwide. Liu et al. collated "12 cases (9 females)... from 6 relevant research items for analysis" (PMID: 38284453). No formal prevalence or incidence estimate exists; Orphanet classifies it among ultra-rare bone dysplasias. The apparent female predominance (9/12) may reflect ascertainment/reporting bias in this tiny sample rather than a true sex bias (the disorder is autosomal).
Inheritance: Autosomal recessive, biallelic — homozygous in consanguineous/founder families, compound heterozygous otherwise.
Penetrance / expressivity: Complete penetrance for biallelic pathogenic genotypes; variable expressivity documented (milder facial phenotype in two sibs, PMID: 35779070).
Founder effects / population: A recurrent frameshift allele, c.882_883delAG, "may have a higher distribution frequency in East Asian populations" (PMID: 36052765), suggesting a founder-type allele. Consanguinity contributes to homozygosity in some families.
Carrier frequency: Not formally established; individual pathogenic alleles are rare or absent in gnomAD.
Anticipation / mosaicism: No genetic anticipation (not a repeat-expansion disorder). No germline mosaicism specifically reported.
Genetic testing (definitive): Diagnosis is established by whole-exome sequencing (WES) or whole-genome sequencing identifying biallelic HSPA9 variants, confirmed by Sanger sequencing. "HSPA9 compound heterozygous variants c.882_c.883delAG and c.613A>G were identified by exome sequencing" (PMID: 36052765). WES/WGS is the highest-yield approach because the phenotype overlaps other skeletal dysplasias/mitochondrial chaperonopathies and single-gene testing may not be prioritized without genetic guidance. Targeted HSPA9 testing or skeletal-dysplasia gene panels are appropriate confirmatory routes once the diagnosis is suspected.
Imaging (supportive): Characteristic radiographic/MRI findings — dysplastic/absent femoral-head epiphyses, "fork-shaped" (bifid) distal femur, dysplastic knee epiphyses and acetabula, vertebral coronal clefting, delayed ossification, hypoplastic nasal bone (PMID: 36052765, PMID: 32869452). Cerebral MRI may show basal-ganglia lesions and septum-pellucidum agenesis in CNS-affected patients.
Clinical criteria: No formal consensus diagnostic criteria exist. Diagnosis is gestalt (EVEN core features) plus molecular confirmation.
Differential diagnosis: The principal differential is CODAS syndrome (LONP1; MIM 600373), which shares epiphyseal, vertebral, and ocular changes but is distinguished from EVEN-PLUS by the latter's severe microtia and nasal hypoplasia — "we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia" (PMID: 26598328). Both are grouped as "mitochondrial chaperonopathies," alongside AIFM1-related spondyloepimetaphyseal dysplasia with neurodegeneration — "EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations" (PMID: 27102849). Other spondyloepiphyseal/spondyloepimetaphyseal dysplasias should also be considered.
Screening: No newborn or population screening exists (ultra-rare). Cascade carrier testing of relatives and reproductive-partner testing are appropriate once a familial variant is known.
Survival/mortality: No formal survival statistics exist. There is a lethality gradient: the most severe genotypes are prenatally lethal or lead to pregnancy termination after prenatal diagnosis, and complete mortalin loss is embryonic-lethal in mice (PMID: 25550197, PMID: 38281662). Postnatal survivors have a chronic, lifelong course.
Morbidity/function: Survivors carry a substantial, lifelong disability burden — skeletal dysplasia (short stature, joint dislocations, mobility limitation), hearing impairment (microtia), and potential cardiac and renal complications. Neurodevelopmental disability occurs in the CNS-affected subset.
Disease course / prognostic factors: CNS involvement is an adverse prognostic feature: "Two patients had seizures and basal ganglia lesions in cerebral MRI" (PMID: 38284453). Genotype severity (residual mortalin function) is the principal determinant of phenotypic severity, ranging from prenatal lethality to milder facial-predominant presentations (PMID: 35779070).
Recovery potential: None for the structural malformations — they are congenital and fixed. Management is supportive.
There is no disease-modifying or curative therapy for EVEN-PLUS syndrome. Management is supportive and multidisciplinary, targeting the affected systems:
| Domain | Supportive intervention | Suggested NCIT |
|---|---|---|
| Skeletal/orthopedic | Orthopedic management of dislocations, scoliosis, epiphyseal dysplasia; physical/occupational therapy | NCIT:C15329 (Orthopedic Procedure); NCIT:C15690 (Physical Therapy) |
| Audiologic | Hearing assessment and aids for microtia-associated hearing loss | NCIT:C15190 (Supportive Care) |
| Cardiac | Evaluation and management of congenital heart defects | NCIT:C15329 |
| Renal | Monitoring/management of renal anomalies (e.g., hydronephrosis) | NCIT:C15190 |
| Neurologic | Antiepileptic management; developmental support | NCIT:C15190 |
The strongest "intervention" reported is reproductive prevention (see Section 13), not treatment of affected individuals.
Because the malformations are congenital and untreatable, prevention is reproductive/genetic rather than clinical.
HSPA9/mortalin is deeply evolutionarily conserved, and orthologs underpin the disease's model organisms, but no naturally occurring EVEN-PLUS-equivalent disease has been described in companion animals or wildlife.
| Species | NCBI Taxon | Ortholog | Database |
|---|---|---|---|
| Human | 9606 | HSPA9 | OMIM/HGNC |
| Mouse | 10090 | Hspa9 | MGI |
| Zebrafish | 7955 | hspa9 / hspa9b | ZFIN |
| Yeast (S. cerevisiae) | 4932 | SSQ1 / SSC1 | SGD |
Mortalin/GRP75 is "a homolog of the yeast ssq1 chaperone that integrates iron-sulfur clusters into imported mitochondrial proteins" (PMID: 17331979), establishing conservation of the core Fe-S biogenesis and import functions from yeast to human. No zoonotic potential or cross-species transmission applies (non-infectious, genetic).
Although no model was engineered specifically to phenocopy the EVEN-PLUS skeletal syndrome, existing Hspa9 models establish the gene's essentiality and core mitochondrial mechanism.
Zebrafish — "crimsonless" (hspa9b mutant): A glycine-to-glutamate substitution in the substrate-binding domain recapitulates ineffective hematopoiesis: "This mutation compromises mitochondrial function, producing oxidative stress and apoptosis distinctly in blood cells. Thus, we identify an essential role for Hspa9b in hematopoiesis and implicate both loss of HSPA9B specifically and mitochondrial dysfunction generally in the pathogenesis of the MDS" (PMID: 15650063). This is the best mechanistic model linking mortalin loss to the mitochondrial-dysfunction → oxidative-stress → apoptosis cascade central to EVEN-PLUS pathophysiology, though it models a hematopoietic (MDS-relevant) rather than skeletal readout.
Mouse — Hspa9 knockout: "homozygous knockout of Hspa9 is embryonically lethal, mice with heterozygous deletion of Hspa9 (Hspa9(+/-)) are viable" (PMID: 25550197). This establishes that complete mortalin loss is incompatible with life — implying EVEN-PLUS alleles are hypomorphic — and heterozygous models inform del(5q) MDS biology. Knockdown of Hspa9 in mice reduces hematopoietic progenitors (PMID: 21123823).
Yeast — SSQ1/SSC1: The mortalin ortholog provides the biochemical foundation for Fe-S cluster integration into mitochondrial proteins (PMID: 17331979).
Model types available: knockout (mouse), point-mutant (zebrafish), and recombinant-protein/in-vitro biophysical systems (used to characterize R126W and Y128C — PMID: 30933555).
Model limitations: No existing model reproduces the full EVEN-PLUS skeletal/craniofacial malformation phenotype; current models capture hematopoietic and embryonic-lethality readouts rather than the epiphyseal-vertebral-ear-nose skeletal dysplasia. A conditional or knock-in model carrying EVEN-PLUS-specific hypomorphic alleles (e.g., R126W) would be needed to study skeletal pathogenesis directly.
Resources: MGI (mouse), ZFIN (zebrafish), SGD (yeast).
EVEN-PLUS syndrome is best understood as a developmental mitochondrial chaperonopathy. The unifying molecular lesion is partial loss of mortalin, the mitochondrial matrix HSP70 that powers protein import and folding and supports Fe-S cluster assembly. Two independent lines of evidence converge on this model: (1) biophysical characterization of patient missense mutations (R126W, Y128C) showing loss of ATPase/chaperone competence and gain of aggregation propensity (PMID: 30933555), and (2) the essentiality of mortalin across species, where complete loss is embryonic-lethal (mouse) or produces mitochondrial-dysfunction-driven oxidative stress and apoptosis (zebrafish) (PMID: 25550197, PMID: 15650063).
The critical inference is a dose–severity continuum: because null genotypes are lethal, viable EVEN-PLUS patients must retain some residual mortalin activity. The amount of residual function plausibly explains the observed phenotypic range — from prenatal lethality/termination at one extreme to the milder facial-predominant sib phenotype at the other (PMID: 35779070). The tissue selectivity (skeleton, ear, nose, heart, kidney, brain) is not yet mechanistically explained but is consistent with high mitochondrial/proteostatic demand in rapidly proliferating embryonic precursors (chondrocytes, neural-crest mesenchyme) during a narrow organogenesis window. The parallel to CODAS (LONP1, a mitochondrial protease) reinforces that disrupting either mitochondrial protein folding (mortalin) or mitochondrial protein turnover (LONP1) yields an overlapping epiphyseal-vertebral-craniofacial phenotype — implicating mitochondrial proteostasis broadly, rather than any single client protein, as the developmental bottleneck.
| PMID | Title (abbrev.) | Role in this report | Evidence type |
|---|---|---|---|
| 26598328 | HSPA9 mutations cause EVEN-PLUS | Delineates & names the disease; biallelic HSPA9; CODAS overlap; mitochondrial chaperonopathy | Human clinical + genetic |
| 30933555 | Biophysical consequences of EVEN-PLUS mutations for mortalin | Molecular mechanism of R126W/Y128C (ATP hydrolysis, aggregation) | In vitro / biophysical |
| 38284453 | New phenotype in a Chinese family + review | 12-case phenotype spectrum & frequencies; CNS morbidity | Human clinical (case series/review) |
| 32869452 | Novel variants + HSPA9 dysfunction | First affected male; NMD evidence; expanded HPO | Human clinical + in vitro |
| 36052765 | Exome + clinical feature analysis | Prenatal onset; East-Asian recurrent allele; WES diagnosis | Human clinical + genetic |
| 38281662 | Prenatal to PGT diagnosis | Splice variants; PGT prevention | Human clinical / reproductive |
| 35779070 | Broadening phenotypic spectrum | Milder phenotype; original EVE dysplasia family confirmed | Human clinical |
| 27102849 | AIFM1 SEMD with neurodegeneration | Groups EVEN-PLUS/CODAS as mitochondrial chaperonopathies | Human clinical (differential) |
| 15650063 | Loss of Hspa9b in zebrafish | Model: mito dysfunction → oxidative stress → apoptosis | Model organism |
| 25550197 | Reduced Hspa9 in mouse B cells | KO embryonic lethality; hypomorphism inference | Model organism |
| 21123823 | Hspa9 del(5q31.2) knockdown | Haploinsufficiency & hematopoiesis (distinct MDS context) | Model organism |
| 17331979 | Frataxin–ISD11–chaperone interactions | Mortalin/Ssq1 role in Fe-S biogenesis | In vitro / biochemical |
| 17460192 | Mortalin in cellular senescence | Import/chaperone/oxidative-stress functions | Review / in vitro |
| 25645922 | Mortalin point mutations & PD | p53 regulation, oxidative-stress tolerance | In vitro |
EVEN-PLUS syndrome (OMIM #616854) is an ultra-rare, autosomal-recessive, prenatal-onset malformation and skeletal-dysplasia syndrome caused by biallelic loss-of-function/hypomorphic variants in HSPA9, encoding the mitochondrial HSP70 chaperone mortalin (mtHSP70/GRP75). Deficient mortalin impairs mitochondrial protein import, Fe-S cluster biogenesis, and proteostasis — producing oxidative stress and apoptosis in embryonic precursors that manifest as epiphyseal/vertebral dysplasia, microtia, nasal hypoplasia, and cardiac, renal, and CNS anomalies — placing it among the "mitochondrial chaperonopathies" that overlap CODAS syndrome (LONP1). No disease-modifying therapy exists; care is supportive and prevention is reproductive (prenatal diagnosis or preimplantation genetic testing).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 14 |
| Resolved | 14 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 21 |
| Quoted claims found in source | 21 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 14 |
| On topic | 8 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 51 |
| Resolved | 48 |
| Unresolved (possible confabulation) | 2 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 24 |
| Terms named correctly | 7 |
| Terms named as a different term | 8 |
| Terms whose name is worth a second look | 9 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0014784 (2 mentions) - the report calls it "Suggested MONDO"; MONDO calls it severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndromeHP:0011003 (1 mention) - the report calls it "Arched eyebrows"; HP calls it High myopiaHP:0002656 (2 mentions) - the report calls it "Dysplastic epiphyses at the knee"; HP calls it Epiphyseal dysplasiaHP:0011832 (1 mention) - the report calls it "Triangular nares"; HP calls it Narrow nasal tipUBERON:0001690 (1 mention) - the report calls it "External/middle ear"; UBERON calls it earUBERON:0001711 (1 mention) - the report calls it "Face / eyebrow region"; UBERON calls it eyelidNCIT:C15329 (2 mentions) - the report calls it "Evaluation and management of congenital heart defects"; NCIT calls it Surgical ProcedureNCIT:C15190 (3 mentions) - the report calls it "Supportive Care", "Monitoring/management of renal anomalies (e.g., hydronephrosis)", "Antiepileptic management; developmental support"; NCIT calls it Needle BiopsyThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0006411 (1 mention) - HP does not contain this termHP:0002662 (1 mention), reported as "Delayed ossification" - HP does not contain this termThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0004646 (1 mention) - the report calls it "Hypoplastic nasal bone"; HP calls it Hypoplasia of the nasal bone, and lists "Hypotrophic nasal bone" among its other namesHP:0003182 (1 mention) - the report calls it "Dysplastic acetabula"; HP calls it Shallow acetabular fossae, and lists "Shallow acetabula" among its other namesHP:0003417 (1 mention) - the report calls it "Vertebral (coronal) clefting"; HP calls it Coronal cleft vertebrae, and lists "Vertebral coronal clefts" among its other namesHP:0002999 (1 mention) - the report calls it "Dislocated patellae"; HP calls it Patellar dislocation, and lists "Dislocated patellae" among its other namesHP:0001627 (2 mentions) - the report calls it "Congenital heart defects"; HP calls it Abnormal heart morphology, and lists "Congenital heart defect" among its other namesHP:0000077 (2 mentions) - the report calls it "Renal alterations"; HP calls it Abnormality of the kidney, and lists "Renal anomalies" among its other namesGO:0006915 (1 mention) - the report calls it "Cellular processes: Apoptosis"; GO calls it apoptotic process**, and lists "activation of apoptosis" among its other namesUBERON:0000955 (1 mention) - the report calls it "Central nervous system / brain"; UBERON calls it brain, and lists "suprasegmental levels of nervous system" among its other namesGO:0005758 (1 mention) - the report calls it "mitochondrial intermembrane space, for import"; GO calls it mitochondrial intermembrane spaceThe report gives these identifiers more than one name of its own:
NCIT:C15190 - called "Supportive Care", "Monitoring/management of renal anomalies (e.g., hydronephrosis)", "Antiepileptic management; developmental support"