This entry models the autosomal recessive KIF7-related form of acrocallosal syndrome (ACLS), a rare multiple congenital anomaly disorder caused by biallelic KIF7 variants. KIF7 is the human ortholog of Drosophila Costal2 and a cilium-tip regulator of the Sonic hedgehog (SHH) pathway. It is characterized by agenesis or hypoplasia of the corpus callosum, craniofacial dysmorphism (macrocephaly, prominent forehead, hypertelorism), postaxial and/or preaxial polydactyly with duplication of the hallux, and intellectual disability. KIF7 dysfunction deregulates GLI transcription-factor output and impairs GLI3 processing, placing ACLS within the primary-cilium Hedgehog-signaling ciliopathy spectrum, with phenotypic overlap with hydrolethalus syndrome (a more severe, often lethal allelic disorder) and Joubert syndrome (shared molar tooth sign).
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Conditions with similar clinical presentations that must be differentiated from Acrocallosal Syndrome:
name: Acrocallosal Syndrome
synonyms:
- Acrocallosal syndrome, KIF7-related
creation_date: "2026-06-13T20:27:42Z"
category: Mendelian
description: >-
This entry models the autosomal recessive KIF7-related form of acrocallosal
syndrome (ACLS), a rare multiple congenital anomaly disorder caused by
biallelic KIF7 variants. KIF7 is the human ortholog of Drosophila Costal2 and
a cilium-tip regulator of the Sonic hedgehog (SHH) pathway. It is
characterized by agenesis or hypoplasia of the
corpus callosum, craniofacial dysmorphism (macrocephaly, prominent forehead,
hypertelorism), postaxial and/or preaxial polydactyly with duplication of the
hallux, and intellectual disability. KIF7 dysfunction deregulates GLI
transcription-factor output and impairs GLI3 processing, placing ACLS within
the primary-cilium Hedgehog-signaling ciliopathy spectrum, with phenotypic
overlap with hydrolethalus syndrome (a more severe, often lethal allelic
disorder) and Joubert syndrome (shared molar tooth sign).
disease_term:
preferred_term: acrocallosal syndrome
term:
id: MONDO:0008708
label: acrocallosal syndrome
parents:
- Ciliopathies
inheritance:
- name: Autosomal Recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Acrocallosal syndrome is inherited in an autosomal recessive manner and is
caused by biallelic (homozygous or compound heterozygous) pathogenic KIF7
variants. Truncating and splice-disrupting alleles are well established;
biallelic missense substitutions have also been reported with broader,
sometimes atypical phenotypes, so the allelic spectrum should not be
described as exclusively loss of function.
evidence:
- reference: PMID:26648833
reference_title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder
characterized by agenesis of the corpus callosum, facial dysmorphism,
postaxial polydactyly of the hands as well as preaxial polydactyly of the
feet, and developmental delay
explanation: >-
Establishes the autosomal recessive inheritance and the cardinal
malformation tetrad of ACLS.
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe the first four compound heterozygous cases
explanation: >-
Documents compound heterozygous KIF7 genotypes, consistent with recessive
inheritance.
- reference: PMID:26174511
reference_title: "Novel KIF7 missense substitutions in two patients presenting with multiple malformations and features of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We present two children who both had two missense mutations in the Kinesin
Family Member 7 (KIF7) gene.
explanation: >-
Documents biallelic missense substitutions and prevents over-restricting
the allelic spectrum to truncating loss-of-function variants.
classifications:
isds_skeletal_category:
- classification_value: polydactyly_syndactyly_triphalangism
notes: >-
ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019 revision
(Mortier et al., PMID:31633310), Table 1 group 41
"Polydactyly-Syndactyly-Triphalangism group"; listed as "Acrocallosal syndrome".
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
A historical case report and literature summary identified only 37
previously described cases worldwide. This is a historical literature-case
count for the clinically defined phenotype across genetic etiologies, not a
KIF7-specific or denominator-based population estimate, and the current
total is expected to be higher.
evidence:
- reference: PMID:22696705
reference_title: "Acrocallosal syndrome in a young hypertensive male."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Since Schinzel’s original description, only 37 cases of acrocallosal
syndrome have been described worldwide.
explanation: >-
Supports a historical worldwide cases-in-literature classification while
avoiding conversion of the count into an epidemiologic rate.
progression:
- phase: Congenital onset
age_range: Antenatal to neonatal
notes: >-
The structural brain, craniofacial, and limb anomalies arise prenatally and
are present at birth, although the full neurodevelopmental phenotype becomes
apparent during follow-up.
evidence:
- reference: PMID:24949054
reference_title: "The acrocallosal syndrome in a neonate with further widening of phenotypic expression."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An Indian neonate presented on day 1 of life (youngest in the literature
to be reported) with combination of abnormalities consistent with the
acrocallosal syndrome and some additional findings.
explanation: A neonatal case directly establishes congenital presentation.
- phase: Neurodevelopmental course
age_range: Childhood to adulthood
notes: >-
Developmental impairment is usually substantial but varies across the
KIF7-associated spectrum. Long-term observations include persistent
craniofacial dysmorphism and severe intellectual disability in many
KIF7-positive individuals, while milder adult cognitive outcomes have been
reported for some alleles.
evidence:
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, long-term follow-up revealed that patients with pathogenic KIF7
variants had more severe and persistent facial dysmorphism and in general
more severe ID, while in patients with (likely) pathogenic C5orf42
variants, facial dysmorphism became less prominent over time and they
could catch up and reach a level of mild to moderate ID despite initial
severe DD.
explanation: >-
Long-term comparative follow-up documents persistence and variability in
the KIF7-associated neurodevelopmental course.
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Importantly, patient 3 with homozygosity of the KIF7 splice site
pathogenic variant at position −3 could also catch up with only mild
cognitive deficits in adulthood
explanation: >-
Directly supports a milder adult cognitive outcome for one KIF7 splice
variant while avoiding a broad genotype-phenotype rule.
pathophysiology:
- name: KIF7 Cilium-Tip Dysfunction and Impaired Hedgehog Signal Transduction
conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
description: >-
KIF7, the human ortholog of Drosophila Costal2, is an immotile kinesin-4
protein that localizes to the tip of the primary cilium, where it organizes
the cilium-tip compartment and regulates the GLI transcription factors of
the Hedgehog pathway. In the absence of Hedgehog ligand KIF7 promotes
processing of GLI3 into its transcriptional repressor form; upon pathway
activation KIF7 and GLI accumulate at the cilium tip. Pathogenic KIF7
dysfunction deregulates GLI target genes and impairs GLI3 processing,
disrupting the tightly dosed Hedgehog output required for midline brain,
limb, and craniofacial patterning.
genes:
- preferred_term: KIF7
term:
id: hgnc:30497
label: KIF7
biological_processes:
- preferred_term: Smoothened (Hedgehog) Signaling
term:
id: GO:0007224
label: smoothened signaling pathway
modifier: DYSREGULATED
- preferred_term: Regulation of Hedgehog Signaling
term:
id: GO:0008589
label: regulation of smoothened signaling pathway
modifier: DYSREGULATED
cellular_components:
- preferred_term: Ciliary Tip
term:
id: GO:0097542
label: ciliary tip
- preferred_term: Primary Cilium
term:
id: GO:0005929
label: cilium
cell_types:
- preferred_term: Ciliated Cell
term:
id: CL:0000064
label: ciliated cell
downstream:
- target: Dysregulated GLI3 Repressor and FGF8 Signaling
causal_link_type: DIRECT
description: >-
KIF7 depletion impairs GLI3 processing, reduces GLI3 repressor activity,
overactivates SHH target genes, and increases FGF8 signaling.
evidence:
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In both humans and mice, KIF7 depletion leads to abnormal GLI3
processing and over-activation of SHH target genes.
explanation: >-
Directly links KIF7 depletion to the altered GLI output represented by
the downstream signaling node.
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
increased FGF8 signaling is responsible in part for CC defects
associated to KIF7 depletion
explanation: >-
Completes the edge-level evidence for the FGF8 component of the
downstream signaling node.
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
KIF7, the human ortholog of Drosophila Costal2, is a key component of the
Hedgehog signaling pathway
explanation: >-
Identifies KIF7 as a core Hedgehog pathway component (Costal2 ortholog),
establishing the molecular basis of the ACLS mechanism.
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we show deregulation of most GLI transcription factor targets and impaired
GLI3 processing in tissues from individuals with KIF7 mutations
explanation: >-
Demonstrates the downstream molecular consequence of KIF7 loss in patient
tissues: deregulated GLI targets and impaired GLI3 processing.
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our data show the role of KIF7 in human primary cilia, especially in the
Hedgehog pathway through the regulation of GLI targets, and expand the
clinical spectrum of ciliopathies
explanation: >-
Places ACLS within the primary-cilium Hedgehog-signaling ciliopathy
spectrum, supporting conformance to the ciliopathy module Hedgehog node.
- reference: PMID:34705483
reference_title: "Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7's microtubule binding."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vertebrates, Hedgehog signaling requires the primary cilium, and KIF7
and Gli transcription factors accumulate at the cilium tip in response to
Hedgehog activation
explanation: >-
Cell-based evidence that KIF7 is a cilium-tip Hedgehog regulator whose
ciliary accumulation is coupled to pathway activation.
- reference: PMID:34705483
reference_title: "Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7's microtubule binding."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we show that the immotile behavior of KIF7 is required to prevent ciliary
localization of Gli transcription factors in the absence of Hedgehog
signaling
explanation: >-
Mechanistic detail that KIF7 restrains GLI in the unstimulated state,
explaining how loss of function deregulates GLI output.
- name: Dysregulated GLI3 Repressor and FGF8 Signaling
description: >-
KIF7 depletion lowers GLI3-repressor signaling and overactivates SHH target
genes. In the Kif7-null model, restoring GLI3-repressor activity rescues the
modeled ACLS features, while increased FGF8 signaling contributes
specifically to anterior corpus-callosum defects.
biological_processes:
- preferred_term: Smoothened Signaling Pathway
term:
id: GO:0007224
label: smoothened signaling pathway
modifier: DYSREGULATED
- preferred_term: Fibroblast Growth Factor Receptor Signaling Pathway
term:
id: GO:0008543
label: fibroblast growth factor receptor signaling pathway
modifier: INCREASED
evidence:
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
decreased GLI3R signaling is fully responsible for the ACLS features in
these mice, as all phenotypes are rescued by increasing GLI3R activity.
explanation: >-
Genetic rescue in the mouse model places reduced GLI3-repressor activity
downstream of Kif7 depletion.
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
increased FGF8 signaling is responsible in part for CC defects associated
to KIF7 depletion, as modulating FGF8 signaling rescued CC formation
anteriorly in Kif7-/- mice.
explanation: >-
Functional rescue supports increased FGF8 signaling as a partial mediator
of the modeled callosal defect.
downstream:
- target: Cortical Midline Guidepost-Cell Mispatterning
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- cortical septum-boundary patterning defects
description: >-
Altered GLI3-repressor and FGF8 signaling disrupts cortical septum-boundary
patterning and the distribution of guidepost cells at the callosal
midline.
evidence:
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
CC agenesis in these mice is associated with specific patterning defects
of the cortical septum boundary leading to altered distribution of
guidepost cells required to guide the callosal axons through the
midline.
explanation: >-
The Kif7-null model directly connects signaling disruption with the
cortical-boundary and guidepost-cell defect.
- target: Cerebellar and CNS Malformation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Developmentally mis-dosed GLI signaling is consistent with the
cerebellar and broader CNS malformation spectrum, but the intervening
tissue-specific sequence has not been resolved.
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we show deregulation of most GLI transcription factor targets and
impaired GLI3 processing in tissues from individuals with KIF7
mutations
explanation: >-
Patient-tissue evidence supports the signaling lesion, but does not by
itself resolve the downstream CNS-developmental sequence.
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
overlapping features that include polydactyly, brain abnormalities and
cleft palate
explanation: >-
Human genetic evidence supports the target brain-malformation spectrum;
the edge remains explicitly indirect with unknown intermediates.
- target: Limb and Craniofacial Patterning Defect
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- reduced GLI3-repressor-dependent digit patterning
- abnormal embryonic craniofacial patterning
description: >-
Altered GLI3 output disrupts anterior-posterior digit specification and
midline craniofacial development.
evidence:
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
decreased GLI3R signaling is fully responsible for the ACLS features in
these mice, as all phenotypes are rescued by increasing GLI3R activity.
explanation: >-
Genetic restoration of GLI3-repressor activity rescued the modeled ACLS
features, including the polydactyly phenotype reported in this model.
- name: Cortical Midline Guidepost-Cell Mispatterning
description: >-
In the Kif7-null model, cortical septum-boundary patterning is abnormal and
guidepost cells required for callosal axons to cross the midline are
redistributed. This provides an experimentally resolved route to callosal
agenesis; its detailed cellular sequence remains model-organism evidence.
biological_processes:
- preferred_term: Corpus Callosum Development
term:
id: GO:0022038
label: corpus callosum development
modifier: ABNORMAL
- preferred_term: Axon Guidance
term:
id: GO:0007411
label: axon guidance
modifier: ABNORMAL
locations:
- preferred_term: Corpus Callosum
term:
id: UBERON:0002336
label: corpus callosum
evidence:
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
CC agenesis in these mice is associated with specific patterning defects
of the cortical septum boundary leading to altered distribution of
guidepost cells required to guide the callosal axons through the midline.
explanation: >-
Defines the cortical-midline cellular mechanism and its role in callosal
axon guidance.
downstream:
- target: Agenesis of Corpus Callosum
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- failed guidance of callosal axons across the cortical midline
description: >-
Mispatterned midline guidepost cells are associated with failed callosal
axon guidance and agenesis of the corpus callosum in the Kif7-null model.
evidence:
- reference: PMID:30445565
reference_title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
CC agenesis in these mice is associated with specific patterning defects
of the cortical septum boundary leading to altered distribution of
guidepost cells required to guide the callosal axons through the
midline.
explanation: >-
The model associates guidepost-cell mispatterning with callosal
agenesis and identifies failed midline axon guidance as the intervening
step.
- name: Cerebellar and CNS Malformation
conforms_to: "ciliopathy_dysfunction#Cerebellar and CNS Malformation"
description: >-
Impaired cilium-dependent Hedgehog signaling during neurodevelopment
produces the hallmark CNS malformations of ACLS: agenesis or hypoplasia of
the corpus callosum and cerebellar vermis dysgenesis. In a subset of
patients the cerebellar/brainstem malformation is severe enough to generate
the molar tooth sign on MRI, overlapping with Joubert syndrome and
reflecting the shared ciliary Hedgehog mechanism.
biological_processes:
- preferred_term: Corpus Callosum Development
term:
id: GO:0022038
label: corpus callosum development
modifier: ABNORMAL
- preferred_term: Cerebellum Development
term:
id: GO:0021549
label: cerebellum development
modifier: ABNORMAL
cell_types:
- preferred_term: Neuron
term:
id: CL:0000540
label: neuron
locations:
- preferred_term: Corpus Callosum
term:
id: UBERON:0002336
label: corpus callosum
- preferred_term: Cerebellar Vermis
term:
id: UBERON:0004720
label: cerebellar vermis
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by
corpus callosum agenesis or hypoplasia, craniofacial dysmorphism,
duplication of the hallux, postaxial polydactyly, and severe mental
retardation
explanation: >-
Establishes corpus callosum agenesis/hypoplasia as a defining CNS feature
of ACLS.
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly
indicated the diagnosis
explanation: >-
Documents cerebellar vermis dysgenesis and the molar tooth sign as
diagnostically informative CNS malformations in ACLS.
downstream:
- target: Hypoplasia of Corpus Callosum
causal_link_type: DIRECT
description: Abnormal callosal development can produce corpus-callosum hypoplasia.
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
corpus callosum agenesis or hypoplasia, craniofacial dysmorphism,
duplication of the hallux, postaxial polydactyly
explanation: >-
Clinical evidence supports hypoplasia as a direct outcome of abnormal
callosal development; the cellular route is not inferred from the
agenesis-only mouse model.
- target: Cerebellar Vermis Hypoplasia
causal_link_type: DIRECT
description: Abnormal cerebellar development produces vermis hypoplasia or dysgenesis.
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly
indicated the diagnosis
explanation: >-
Direct clinical imaging evidence links the CNS-malformation node to
vermis dysgenesis.
- target: Molar Tooth Sign
causal_link_type: DIRECT
description: Severe cerebellar and brainstem malformation can produce the molar tooth sign.
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly
indicated the diagnosis
explanation: >-
Directly documents the molar-tooth imaging configuration in the
KIF7-associated spectrum.
- target: Dandy-Walker Malformation
causal_link_type: DIRECT
description: >-
Severe cerebellar and vermian developmental disruption can produce a
Dandy-Walker malformation.
evidence:
- reference: PMID:29910499
reference_title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
showed partial callosal agenesis, pachygyria, ventriculomegaly, agenesis
of cerebellar vermis and Dandy–Walker malformation.
explanation: >-
A KIF7-confirmed infant had the Dandy-Walker configuration on MRI.
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
KIF7-associated developmental brain disruption is clinically linked to
intellectual disability, but the precise causal mediators are not
resolved and are not reduced to callosal agenesis alone.
evidence:
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients with pathogenic KIF7 variants had more severe and persistent
facial dysmorphism and in general more severe ID
explanation: >-
Supports the clinical association while the downstream cellular route
remains unresolved.
- target: Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Developmental CNS dysfunction can manifest as hypotonia, although the
responsible circuits have not been resolved.
evidence:
- reference: PMID:22696705
reference_title: "Acrocallosal syndrome in a young hypertensive male."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Except for hypotonia, rest of the central nervous system examination was
normal.
explanation: Documents hypotonia in a clinically diagnosed adult case.
- target: Seizure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Seizures occur in a subset of KIF7-positive individuals, but the exact
epileptogenic mechanism is unresolved.
evidence:
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seizure7/18 (39%)2/19 (11%)"
explanation: >-
The pooled KIF7-positive ACLS/Joubert spectrum had seizures in 7 of 18
individuals with available data.
- name: Limb and Craniofacial Patterning Defect
description: >-
KIF7-dependent Hedgehog/GLI3 signaling is required for dosed limb and
craniofacial patterning. Deregulated GLI output produces polydactyly,
hallux duplication, syndactyly, cleft palate, and the characteristic
macrocephalic craniofacial appearance.
biological_processes:
- preferred_term: limb morphogenesis
term:
id: GO:0035108
label: limb morphogenesis
modifier: ABNORMAL
- preferred_term: palate development
term:
id: GO:0060021
label: roof of mouth development
modifier: ABNORMAL
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
overlapping features that include polydactyly, brain abnormalities and
cleft palate
explanation: >-
Original KIF7 report supports limb and craniofacial malformations as
part of the KIF7 ciliopathy spectrum.
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by postaxial and/or preaxial polydactyly, cutaneous
syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the
corpus callosum, and intellectual disability
explanation: >-
Review evidence connects KIF7-associated ACLS to polydactyly,
syndactyly, macrocephaly, and hypertelorism.
downstream:
- target: Postaxial Polydactyly
causal_link_type: DIRECT
description: Abnormal limb patterning produces postaxial polydactyly.
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by postaxial and/or preaxial polydactyly, cutaneous
syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of
the corpus callosum, and intellectual disability
explanation: Supports postaxial polydactyly as an output of this patterning defect.
- target: Preaxial Polydactyly
causal_link_type: DIRECT
description: Abnormal limb patterning produces preaxial polydactyly.
evidence:
- reference: PMID:26648833
reference_title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
postaxial polydactyly of the hands as well as preaxial polydactyly of
the feet
explanation: Supports the two region-specific polydactyly outcomes.
- target: Duplication of the Hallux
causal_link_type: DIRECT
description: Preaxial foot patterning disruption produces hallux duplication.
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
corpus callosum agenesis or hypoplasia, craniofacial dysmorphism,
duplication of the hallux, postaxial polydactyly
explanation: Supports hallux duplication as a characteristic limb outcome.
- target: Cutaneous Syndactyly
causal_link_type: DIRECT
description: Digital patterning disruption produces soft-tissue syndactyly.
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by postaxial and/or preaxial polydactyly, cutaneous
syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of
the corpus callosum, and intellectual disability
explanation: Supports cutaneous syndactyly as part of the digital pattern.
- target: Cleft Palate
causal_link_type: DIRECT
description: Midline craniofacial patterning disruption produces cleft palate.
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
overlapping features that include polydactyly, brain abnormalities and
cleft palate
explanation: Supports cleft palate within the KIF7 malformation spectrum.
- target: Macrocephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: ACLS craniofacial patterning disruption contributes to macrocephaly.
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by postaxial and/or preaxial polydactyly, cutaneous
syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of
the corpus callosum, and intellectual disability
explanation: Supports macrocephaly as an associated craniofacial outcome.
- target: Hypertelorism
causal_link_type: DIRECT
description: Craniofacial patterning disruption produces hypertelorism.
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Facial dysmorphism with hypertelorism and prominent forehead in all the
cases
explanation: Supports hypertelorism as a recurring craniofacial outcome.
- target: Prominent Forehead
causal_link_type: DIRECT
description: Craniofacial patterning disruption produces a prominent forehead.
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Facial dysmorphism with hypertelorism and prominent forehead in all the
cases
explanation: Supports prominent forehead as a recurring craniofacial outcome.
phenotypes:
- name: Agenesis of Corpus Callosum
category: Neurologic
description: >-
Complete agenesis of the corpus callosum is a cardinal ACLS feature and
gives the syndrome its name; partial hypoplasia is represented separately.
phenotype_term:
preferred_term: Agenesis of corpus callosum
term:
id: HP:0001274
label: Agenesis of corpus callosum
evidence:
- reference: PMID:26648833
reference_title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder
characterized by agenesis of the corpus callosum
explanation: >-
Corpus callosum agenesis is the eponymous, defining CNS malformation of
ACLS.
- name: Hypoplasia of Corpus Callosum
category: Neurologic
description: >-
Partial underdevelopment of the corpus callosum is an alternative to
complete agenesis within the KIF7-related ACLS spectrum.
phenotype_term:
preferred_term: Hypoplasia of the corpus callosum
term:
id: HP:0002079
label: Hypoplasia of the corpus callosum
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by
corpus callosum agenesis or hypoplasia
explanation: >-
Explicitly documents hypoplasia as part of the callosal phenotype rather
than collapsing all cases into complete agenesis.
- name: Postaxial Polydactyly
category: Skeletal
description: >-
Postaxial polydactyly of the hands is one of the two cardinal limb features
of ACLS, reflecting deregulated Hedgehog/GLI3 anterior-posterior limb
patterning.
phenotype_term:
preferred_term: Postaxial hand polydactyly
term:
id: HP:0001162
label: Postaxial hand polydactyly
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Acrocallosal syndrome is a multiple congenital anomaly disorder
characterized by postaxial and/or preaxial polydactyly
explanation: >-
Postaxial polydactyly is a cardinal limb malformation of ACLS.
- name: Preaxial Polydactyly
category: Skeletal
description: >-
Preaxial polydactyly of the feet, frequently manifesting as duplication of
the hallux, is characteristic of ACLS.
phenotype_term:
preferred_term: Preaxial foot polydactyly
term:
id: HP:0001841
label: Preaxial foot polydactyly
evidence:
- reference: PMID:26648833
reference_title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
postaxial polydactyly of the hands as well as preaxial polydactyly of the
feet
explanation: >-
Preaxial polydactyly of the feet is a recognized cardinal limb feature of
ACLS.
- name: Duplication of the Hallux
category: Skeletal
description: >-
Duplication of the hallux (great toe) is a distinctive preaxial digital
malformation in ACLS.
phenotype_term:
preferred_term: Duplication of the hallux
term:
id: HP:0010066
label: Duplication of phalanx of hallux
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
corpus callosum agenesis or hypoplasia, craniofacial dysmorphism,
duplication of the hallux, postaxial polydactyly
explanation: >-
Hallux duplication is listed among the defining clinical features of ACLS.
- name: Macrocephaly
category: Craniofacial
description: >-
Macrocephaly (enlarged head) is a consistent craniofacial feature of ACLS.
phenotype_term:
preferred_term: Macrocephaly
term:
id: HP:0000256
label: Macrocephaly
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by postaxial and/or preaxial polydactyly, cutaneous
syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the
corpus callosum, and intellectual disability
explanation: >-
Macrocephaly is enumerated among the characteristic features of ACLS.
- name: Hypertelorism
category: Craniofacial
frequency: VERY_FREQUENT
description: >-
Widely spaced eyes (hypertelorism) are part of the characteristic
craniofacial dysmorphism of ACLS.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Facial dysmorphism with hypertelorism and prominent forehead in all the
cases
explanation: >-
Hypertelorism was present in all cases of this ACLS series, supporting
VERY_FREQUENT classification.
- name: Prominent Forehead
category: Craniofacial
frequency: VERY_FREQUENT
description: >-
A prominent (bossed) forehead is a consistent craniofacial feature of ACLS.
phenotype_term:
preferred_term: Prominent forehead
term:
id: HP:0011220
label: Prominent forehead
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Facial dysmorphism with hypertelorism and prominent forehead in all the
cases
explanation: >-
Prominent forehead was present in all cases of this ACLS series, supporting
VERY_FREQUENT classification.
- name: Intellectual Disability
category: Neurodevelopmental
description: >-
Intellectual disability, frequently severe, is a core neurodevelopmental
feature of ACLS.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
absence or hypoplasia of the corpus callosum, and intellectual disability
explanation: >-
Intellectual disability is a defining neurodevelopmental feature of ACLS.
- name: Hypotonia
category: Neurologic
description: >-
Reduced muscle tone is a recognized neurologic manifestation and can
compound early motor delay.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:22696705
reference_title: "Acrocallosal syndrome in a young hypertensive male."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Except for hypotonia, rest of the central nervous system examination was
normal.
explanation: Documents hypotonia in a clinically diagnosed adult case.
- name: Seizure
category: Neurologic
frequency: FREQUENT
description: >-
Seizures occur in a substantial minority of individuals across the
KIF7-positive ACLS/Joubert-spectrum literature.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seizure7/18 (39%)2/19 (11%)"
explanation: >-
The KIF7-positive ACLS/Joubert spectrum had seizures in 7 of 18
individuals with available data, supporting the FREQUENT band.
- name: Cerebellar Vermis Hypoplasia
category: Neurologic
description: >-
Cerebellar vermis dysgenesis/hypoplasia, sometimes severe enough to produce
the molar tooth sign, occurs in ACLS and overlaps with Joubert syndrome.
phenotype_term:
preferred_term: Cerebellar vermis hypoplasia
term:
id: HP:0001320
label: Cerebellar vermis hypoplasia
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly
indicated the diagnosis
explanation: >-
Cerebellar vermis dysgenesis is a CNS malformation supporting the
diagnosis of ACLS.
- name: Molar Tooth Sign
category: Neurologic
description: >-
The molar tooth sign on MRI (deepened interpeduncular fossa with elongated,
thickened superior cerebellar peduncles) can occur in ACLS, reflecting the
shared ciliary Hedgehog mechanism with Joubert syndrome.
phenotype_term:
preferred_term: Molar tooth sign on MRI
term:
id: HP:0002419
label: Molar tooth sign on MRI
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They present with features like molar tooth sign and hyperventilation
that are not very typical in ACLS, but do occur in other ciliopathies
explanation: >-
The molar tooth sign is described as "not very typical" in ACLS, supporting
its presence in a variable subset without assigning a frequency from
qualitative wording.
- name: Dandy-Walker Malformation
category: Neurologic
description: >-
Dandy-Walker malformation is a variable cerebellar/posterior-fossa feature
documented in the KIF7-related ACLS spectrum; it is not present in every
affected individual.
phenotype_term:
preferred_term: Dandy-Walker malformation
term:
id: HP:0001305
label: Dandy-Walker malformation
evidence:
- reference: PMID:29910499
reference_title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
showed partial callosal agenesis, pachygyria, ventriculomegaly, agenesis
of cerebellar vermis and Dandy–Walker malformation.
explanation: >-
A KIF7-confirmed infant had Dandy-Walker malformation on MRI, supporting
inclusion without assigning a population frequency.
- name: Cleft Palate
category: Craniofacial
description: >-
Cleft palate occurs in a subset of ACLS cases and is also a feature of the
allelic hydrolethalus syndrome, reflecting shared deregulation of midline
craniofacial Hedgehog patterning.
phenotype_term:
preferred_term: Cleft palate
term:
id: HP:0000175
label: Cleft palate
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
polydactyly, brain abnormalities and cleft palate
explanation: >-
Cleft palate is listed among the overlapping malformation features of
hydrolethalus and acrocallosal syndromes in the original KIF7 discovery paper.
- name: Cutaneous Syndactyly
category: Skeletal
description: >-
Cutaneous (soft-tissue) syndactyly of the digits is a recognized digital
malformation in ACLS, co-occurring with polydactyly.
phenotype_term:
preferred_term: Cutaneous syndactyly
term:
id: HP:0012725
label: Cutaneous syndactyly
evidence:
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by postaxial and/or preaxial polydactyly, cutaneous
syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the
corpus callosum, and intellectual disability
explanation: >-
Cutaneous syndactyly is enumerated among the characteristic limb features
of ACLS in this KIF7 syndromology review.
imaging_findings:
- name: Corpus Callosum Agenesis or Hypoplasia on MRI
modality: MRI
imaging_finding_term:
preferred_term: Abnormal corpus callosum morphology
term:
id: HP:0001273
label: Abnormal corpus callosum morphology
phenotype_term:
preferred_term: Abnormal corpus callosum morphology
term:
id: HP:0001273
label: Abnormal corpus callosum morphology
located_in:
preferred_term: Corpus Callosum
term:
id: UBERON:0002336
label: corpus callosum
description: >-
Brain MRI demonstrates complete agenesis or partial hypoplasia of the
corpus callosum. This is a cardinal diagnostic component of the syndrome,
although molecular confirmation is required for KIF7-specific diagnosis.
diagnostic: true
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
corpus callosum agenesis or hypoplasia, craniofacial dysmorphism,
duplication of the hallux, postaxial polydactyly
explanation: >-
Establishes callosal agenesis or hypoplasia as a defining structural
neuroimaging finding.
- reference: PMID:29910499
reference_title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Magnetic resonance imaging (MRI) of the brain
explanation: >-
Establishes MRI as the modality used for the structural brain findings in
this KIF7-confirmed case.
- reference: PMID:29910499
reference_title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
showed partial callosal agenesis, pachygyria, ventriculomegaly, agenesis
of cerebellar vermis and Dandy–Walker malformation.
explanation: >-
The same MRI sentence documents partial callosal agenesis in a
KIF7-confirmed case.
- name: Molar Tooth Sign on MRI
modality: MRI
imaging_finding_term:
preferred_term: Molar tooth sign on MRI
term:
id: HP:0002419
label: Molar tooth sign on MRI
phenotype_term:
preferred_term: Molar tooth sign on MRI
term:
id: HP:0002419
label: Molar tooth sign on MRI
located_in:
preferred_term: Brainstem
term:
id: UBERON:0002298
label: brainstem
description: >-
Vermis dysgenesis with associated brainstem configuration can create the
molar tooth sign. It occurs in a variable subset and signals overlap with
the KIF7-related Joubert spectrum rather than defining every ACLS case.
diagnostic: false
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly
indicated the diagnosis
explanation: Documents the molar tooth configuration on brain imaging.
- name: Olfactory Bulb and Tract Abnormalities on Neuroimaging
located_in:
preferred_term: Olfactory Bulb
term:
id: UBERON:0002264
label: olfactory bulb
description: >-
Olfactory-bulb and olfactory-tract abnormalities were reported on
neuroimaging in one child with a KIF7-confirmed acrocallosal phenotype. The
available abstract does not isolate the modality for this finding, so none
is asserted here. This is an emerging single-case extension, not a defining
or frequency-estimated imaging feature.
diagnostic: false
context: Single KIF7-confirmed case report
evidence:
- reference: PMID:31399769
reference_title: "Olfactory bulb and olfactory tract abnormalities in acrocallosal syndrome and Greig cephalopolysyndactyly syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe association of olfactory bulb and olfactory tract
abnormalities in a child with acrocallosal syndrome caused by kinesin
family membrane 7 (KIF7) mutation in sonic hedgehog pathway.
explanation: >-
Molecularly confirmed single-case evidence supports this explicitly
qualified imaging extension.
genetic:
- name: Biallelic KIF7 Variants
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: KIF7
term:
id: hgnc:30497
label: KIF7
notes: >-
Biallelic pathogenic variants in KIF7 (15q26.1) cause the autosomal
recessive form modeled here. Truncating and splice-disrupting alleles are
well established; biallelic missense substitutions have also been reported,
but individual missense findings require variant-level interpretation.
Allelic KIF7 disease spans the more severe hydrolethalus syndrome 2 and
Joubert-spectrum presentations. Rare de novo GLI3-related acrocallosal
phenocopies are handled as a differential, not as a second causal gene in
this KIF7-scoped entry.
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we report mutations in KIF7 in individuals with hydrolethalus and
acrocallosal syndromes, two multiple malformation disorders with
overlapping features that include polydactyly, brain abnormalities and
cleft palate
explanation: >-
Original report identifying KIF7 as the causative gene for both ACLS and
the allelic hydrolethalus syndrome.
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Seven mutations were identified at the KIF7 locus in these five cases, six
of which are novel
explanation: >-
Mutation series confirming KIF7 as the recurrent disease locus and
expanding the allelic spectrum of ACLS.
- reference: PMID:26648833
reference_title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog
(SHH) pathway, have been identified as causative for ACLS but also for the
fatal hydrolethalus syndrome and some cases of Joubert syndrome
explanation: >-
Confirms KIF7 causation of ACLS and the allelic relationship with
hydrolethalus and Joubert syndromes.
- reference: PMID:26174511
reference_title: "Novel KIF7 missense substitutions in two patients presenting with multiple malformations and features of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We present two children who both had two missense mutations in the Kinesin
Family Member 7 (KIF7) gene.
explanation: >-
Supports only that biallelic missense substitutions have been reported;
the paper itself was tentative and does not establish every reported
missense allele as pathogenic.
diagnosis:
- name: Clinical and Molecular Diagnosis
description: >-
Acrocallosal syndrome is suspected from the combination of corpus callosum
agenesis/hypoplasia, craniofacial dysmorphism (macrocephaly, prominent
forehead, hypertelorism), and polydactyly, and is confirmed by
identification of biallelic KIF7 pathogenic variants. Because expressivity
is variable, KIF7 testing is warranted in patients with suggestive
craniofacial features even when polydactyly or callosal anomalies are
absent. If targeted KIF7 testing is negative, a broader ciliopathy/
polydactyly panel or exome analysis can evaluate phenocopies involving
CPLANE1/C5orf42, GLI3, SHH, and other developmental-pathway genes.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:23125460
reference_title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
KIF7 should be tested in less typical patients in whom craniofacial
features are suggestive of ACLS
explanation: >-
Defines the molecular diagnostic recommendation for ACLS, including in
atypical presentations.
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis in our cohort of patients with craniofacial appearance
fitting into the ACLS clinical spectrum and variable additional
ciliopathy features revealed (likely) pathogenic variants not only in
KIF7, but also secondly in C5orf42
explanation: >-
Demonstrates locus heterogeneity in ACLS-like presentations and supports
broader sequencing when KIF7 testing is unrevealing.
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, in one patient we found a heterozygous de novo frameshift
variant in SHH, the most common cause of non-chromosomal holoprosencephaly
(HPE)
explanation: >-
Supports inclusion of SHH-related phenocopies in a broader negative-KIF7
diagnostic workup.
- name: Prenatal Ultrasound Assessment
description: >-
In an at-risk pregnancy, second-trimester ultrasound can identify
polydactyly and major central-nervous-system malformations, but variable
expressivity means a normal scan does not exclude KIF7-related disease.
diagnosis_term:
preferred_term: clinical imaging procedure
term:
id: NCIT:C17369
label: Imaging Procedure
evidence:
- reference: PMID:24949054
reference_title: "The acrocallosal syndrome in a neonate with further widening of phenotypic expression."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Polydactyly, and central nervous system malformations can be detected by
ultrasonography in the second trimester, but due to variability of
presentation, prenatal diagnosis may not always be possible.
explanation: >-
Supports both the detectable prenatal features and the limitation of
ultrasound caused by variable presentation.
differential_diagnoses:
- name: KIF7-Related Hydrolethalus Syndrome 2
disease_term:
preferred_term: hydrolethalus syndrome 2
term:
id: MONDO:0013585
label: hydrolethalus syndrome 2
description: >-
Hydrolethalus syndrome 2 is the KIF7-related, severe fetal/lethal end of the
allelic spectrum and shares polydactyly, brain abnormalities, and cleft
palate with ACLS. Hydrolethalus syndrome is genetically heterogeneous, so
this statement does not assign every hydrolethalus presentation to KIF7.
distinguishing_features:
- Fetal or perinatal lethality and more severe multisystem malformations favor hydrolethalus syndrome 2 over ACLS.
evidence:
- reference: PMID:21552264
reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hydrolethalus and acrocallosal syndromes, two multiple malformation
disorders with overlapping features that include polydactyly, brain
abnormalities and cleft palate
explanation: >-
Establishes hydrolethalus syndrome as the allelic, phenotypically
overlapping disorder distinguishing the severe end of the KIF7 spectrum.
- name: Joubert Syndrome
disease_term:
preferred_term: Joubert syndrome
term:
id: MONDO:0018772
label: Joubert syndrome
description: >-
Joubert syndrome shares the molar tooth sign and is caused in a subset of
cases by KIF7 mutations; distinguished by the predominance of the
cerebellar/brainstem malformation and characteristic abnormal eye movements
and breathing dysregulation.
distinguishing_features:
- A predominant molar-tooth imaging phenotype with oculomotor apraxia or breathing dysregulation favors a Joubert-spectrum diagnosis over classic ACLS.
evidence:
- reference: PMID:26648833
reference_title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
have been identified as causative for ACLS but also for the fatal
hydrolethalus syndrome and some cases of Joubert syndrome
explanation: >-
Documents the KIF7 allelic overlap between ACLS and Joubert syndrome,
relevant to differential diagnosis.
- reference: PMID:26349186
reference_title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They present with features like molar tooth sign and hyperventilation
that are not very typical in ACLS, but do occur in other ciliopathies
explanation: >-
Supports the molar-tooth and breathing-regulation distinction from
classic ACLS.
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
none of the KIF7 patients but all the C5orf42 patients in our cohort
presented with ocular motor apraxia, which is commonly associated with
the MTS in JBTS patients
explanation: >-
Supports oculomotor apraxia as a discriminator in ACLS-like versus
Joubert-spectrum presentations while preserving gene-specific context.
- name: CPLANE1-Related Joubert Syndrome 17
disease_term:
preferred_term: Joubert syndrome 17
term:
id: MONDO:0013824
label: Joubert syndrome 17
description: >-
Biallelic CPLANE1/C5orf42-related Joubert syndrome 17 can closely resemble
ACLS through macrocephaly, hypertelorism, polydactyly, developmental
impairment, and a molar tooth/vermis phenotype.
distinguishing_features:
- Near-constant molar tooth sign or vermis hypoplasia and ocular motor apraxia favor CPLANE1-related Joubert syndrome 17.
- Corpus-callosum abnormality is more prominent across the KIF7-positive spectrum.
evidence:
- reference: PMID:29321670
reference_title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
C5orf42 (likely) pathogenic variants are nearly invariably associated to
the MTS/vermis hypoplasia and less often to corpus callosum abnormalities,
while it is the opposite for KIF7.
explanation: >-
Establishes the overlapping phenotype and the clinical discriminators of
CPLANE1/C5orf42-related disease.
- name: GLI3-Related Greig-Acrocallosal Spectrum
disease_term:
preferred_term: Greig cephalopolysyndactyly syndrome
term:
id: MONDO:0008287
label: Greig cephalopolysyndactyly syndrome
description: >-
Rare de novo GLI3 variants have produced an acrocallosal phenotype, and
GLI3 disorders such as Greig cephalopolysyndactyly overlap through
macrocephaly, hypertelorism, and polysyndactyly. This is modeled as a
dominant phenocopy rather than broadening the focal KIF7 entry.
distinguishing_features:
- A heterozygous or de novo GLI3 variant supports a dominant GLI3-spectrum diagnosis rather than autosomal recessive KIF7-related ACLS.
evidence:
- reference: PMID:23633388
reference_title: "A de novo GLI3 mutation in a patient with acrocallosal syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data confirm that mutations in GLI3 are a cause of the acrocallosal
phenotype.
explanation: >-
Supports the explicit GLI3 phenocopy boundary and its placement in the
differential rather than the focal KIF7 genetic model.
treatments:
- name: Supportive and Multidisciplinary Care
description: >-
Management is symptom-directed and multidisciplinary. Early physical,
occupational, developmental, and communication support addresses hypotonia
and developmental disability; seizures are treated with standard
antiseizure therapy when present. Available evidence is case-report and
clinical-review level rather than ACLS-specific comparative trials.
action_category: THERAPEUTIC
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
- preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
- preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:22696705
reference_title: "Acrocallosal syndrome in a young hypertensive male."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment includes physical therapy in infancy which may assist in the
development of motor skills and muscle tone.
explanation: Supports early physical therapy for hypotonia and motor delay.
- reference: PMID:22696705
reference_title: "Acrocallosal syndrome in a young hypertensive male."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Antiepileptic therapy for seizure disorder and antihypertensives for
renoparenchymal hypertension are to be given.
explanation: Supports symptom-directed antiseizure treatment when seizures occur.
- reference: PMID:29910499
reference_title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At present, the child is referred to a neurodevelopment specialist, for
neurodevelopment assessment and occupational therapist for infant
stimulation program.
explanation: >-
A genetically confirmed case documents specialist developmental follow-up
and occupational-therapy referral.
- name: Surgical Correction of Polydactyly and Malformations
description: >-
Individually indicated surgery may remove functionally limiting extra
digits, release syndactyly, or repair orofacial and other structural
malformations. These procedures treat local manifestations rather than the
underlying ciliary signaling defect.
action_category: THERAPEUTIC
therapeutic_modality: SURGERY
treatment_term:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
target_phenotypes:
- preferred_term: Postaxial hand polydactyly
term:
id: HP:0001162
label: Postaxial hand polydactyly
- preferred_term: Preaxial foot polydactyly
term:
id: HP:0001841
label: Preaxial foot polydactyly
- preferred_term: Cutaneous syndactyly
term:
id: HP:0012725
label: Cutaneous syndactyly
- preferred_term: Cleft palate
term:
id: HP:0000175
label: Cleft palate
evidence:
- reference: PMID:22696705
reference_title: "Acrocallosal syndrome in a young hypertensive male."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surgery to remove extra fingers and toes and release fused fingers may
improve movement and grasp, may assist in walking and the comfort of
footwear.
explanation: >-
Supports symptom-directed surgery for polydactyly and syndactyly while
making no disease-modifying claim.
- reference: PMID:29910499
reference_title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She underwent Nissen fundoplication at 4 months of age, cleft lip repair
at 6 months age and cleft palate repair at 18 months of age using the same
technique.
explanation: >-
A KIF7-confirmed case documents actual surgical repair of associated
structural manifestations, including cleft palate.
- name: Genetic Counseling
description: >-
When biallelic KIF7 disease is confirmed, parents should be counseled about
autosomal recessive inheritance and a 25% recurrence risk in each pregnancy.
Prenatal ultrasound can detect polydactyly and major CNS malformations but
cannot exclude disease because presentation is variable. This recurrence
statement does not apply to a rare de novo GLI3 phenocopy.
action_category: COUNSELING_INFORMATIONAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:24949054
reference_title: "The acrocallosal syndrome in a neonate with further widening of phenotypic expression."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As the mode of inheritance of ACLS is autosomal recessive, the risk of
recurrence is 25%. Genetic counselling is of prime importance
explanation: >-
Directly supports recurrence-risk counseling for the autosomal recessive
KIF7 form.
- reference: PMID:24949054
reference_title: "The acrocallosal syndrome in a neonate with further widening of phenotypic expression."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Polydactyly, and central nervous system malformations can be detected by
ultrasonography in the second trimester, but due to variability of
presentation, prenatal diagnosis may not always be possible.
explanation: Supports balanced counseling about prenatal ultrasound capabilities and limits.
references:
- reference: PMID:21552264
title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
- reference: PMID:22696705
title: "Acrocallosal syndrome in a young hypertensive male."
- reference: PMID:23125460
title: "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome."
- reference: PMID:23633388
title: "A de novo GLI3 mutation in a patient with acrocallosal syndrome."
- reference: PMID:24949054
title: "The acrocallosal syndrome in a neonate with further widening of phenotypic expression."
- reference: PMID:26174511
title: "Novel KIF7 missense substitutions in two patients presenting with multiple malformations and features of acrocallosal syndrome."
- reference: PMID:26349186
title: "Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology."
- reference: PMID:26648833
title: "Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature."
- reference: PMID:29321670
title: "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling."
- reference: PMID:29910499
title: "Anaesthetising an infant with acrocallosal syndrome: An unusual case."
- reference: PMID:30445565
title: "Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice."
- reference: PMID:31399769
title: "Olfactory bulb and olfactory tract abnormalities in acrocallosal syndrome and Greig cephalopolysyndactyly syndrome."
- reference: PMID:34705483
title: "Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7's microtubule binding."