Acrocallosal Syndrome

Mendelian MONDO:0008708 Pathograph 16 Show in embeddings browser Ciliopathies

Acrocallosal syndrome (ACLS) is a rare autosomal recessive multiple congenital anomaly disorder caused by biallelic mutations in KIF7, 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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1
Inheritance
3
Pathophys.
12
Phenotypes
16
Pathograph
1
Genes
3
Medical Actions
2
Differentials
5
References
👪

Inheritance

1
Autosomal Recessive
Acrocallosal syndrome is inherited in an autosomal recessive manner, caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in KIF7.
Show evidence (2 references)
PMID:26648833 SUPPORT Human Clinical
"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"
Establishes the autosomal recessive inheritance and the cardinal malformation tetrad of ACLS.
PMID:23125460 SUPPORT Human Clinical
"We describe the first four compound heterozygous cases"
Documents compound heterozygous KIF7 genotypes, consistent with recessive inheritance.
⚙

Pathophysiology

3
KIF7 Cilium-Tip Dysfunction and Impaired Hedgehog Signal Transduction
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. Biallelic loss-of-function KIF7 mutations deregulate most GLI target genes and impair GLI3 processing, disrupting the tightly dosed Hedgehog output required for midline brain, limb, and craniofacial patterning.
Neuron CL:0000540
KIF7 hgnc:30497
Smoothened (Hedgehog) Signaling GO:0007224 ⚠ ABNORMAL Regulation of Hedgehog Signaling GO:0008589 ↓ DECREASED
Ciliary Tip GO:0097542 Primary Cilium GO:0005929
Downstream
Cerebellar and CNS Malformation Deregulated cilium-dependent Hedgehog/GLI signaling disrupts dorsoventral patterning and midline development of the brain, producing corpus callosum agenesis and cerebellar vermis hypoplasia.
Limb and Craniofacial Patterning Defect Deregulated Hedgehog/GLI3 output also disrupts anterior-posterior limb patterning and midline craniofacial development.
Show evidence (5 references)
PMID:21552264 SUPPORT Human Clinical
"KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway"
Identifies KIF7 as a core Hedgehog pathway component (Costal2 ortholog), establishing the molecular basis of the ACLS mechanism.
PMID:21552264 SUPPORT Human Clinical
"we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations"
Demonstrates the downstream molecular consequence of KIF7 loss in patient tissues: deregulated GLI targets and impaired GLI3 processing.
PMID:21552264 SUPPORT Human Clinical
"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"
Places ACLS within the primary-cilium Hedgehog-signaling ciliopathy spectrum, supporting conformance to the ciliopathy module Hedgehog node.
+ 2 more references
Cerebellar and CNS Malformation
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.
Neuron CL:0000540
Corpus Callosum Development GO:0022038 ⚠ ABNORMAL Cerebellum Development GO:0021549 ⚠ ABNORMAL
Downstream
Agenesis of Corpus Callosum Abnormal callosal development produces the eponymous corpus callosum agenesis phenotype.
Cerebellar Vermis Hypoplasia Abnormal cerebellar development produces vermis hypoplasia or dysgenesis.
Molar Tooth Sign Severe cerebellar and brainstem malformation can produce the molar tooth sign.
Intellectual Disability The CNS malformation burden contributes to neurodevelopmental impairment and intellectual disability.
Show evidence (2 references)
PMID:23125460 SUPPORT Human Clinical
"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"
Establishes corpus callosum agenesis/hypoplasia as a defining CNS feature of ACLS.
PMID:23125460 SUPPORT Human Clinical
"vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis"
Documents cerebellar vermis dysgenesis and the molar tooth sign as diagnostically informative CNS malformations in ACLS.
Limb and Craniofacial Patterning Defect
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.
limb morphogenesis GO:0035108 ⚠ ABNORMAL palate development GO:0060021 ⚠ ABNORMAL
Downstream
Postaxial Polydactyly Abnormal limb patterning produces postaxial polydactyly.
Preaxial Polydactyly Abnormal limb patterning produces preaxial polydactyly.
Duplication of the Hallux Preaxial foot patterning disruption produces hallux duplication.
Cutaneous Syndactyly Digital patterning disruption produces soft-tissue syndactyly.
Cleft Palate Midline craniofacial patterning disruption produces cleft palate.
Macrocephaly ACLS craniofacial patterning disruption contributes to macrocephaly.
Hypertelorism Craniofacial patterning disruption produces hypertelorism.
Prominent Forehead Craniofacial patterning disruption produces a prominent forehead.
Show evidence (2 references)
PMID:21552264 SUPPORT Human Clinical
"overlapping features that include polydactyly, brain abnormalities and cleft palate"
Original KIF7 report supports limb and craniofacial malformations as part of the KIF7 ciliopathy spectrum.
PMID:26349186 SUPPORT Human Clinical
"characterized by postaxial and/or preaxial polydactyly, cutaneous syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the corpus callosum, and intellectual disability"
Review evidence connects KIF7-associated ACLS to polydactyly, syndactyly, macrocephaly, and hypertelorism.
⬡

Pathograph

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

Phenotypes

12
Eye 1
Hypertelorism VERY_FREQUENT Hypertelorism HP:0000316
Show evidence (1 reference)
PMID:23125460 SUPPORT Human Clinical
"Facial dysmorphism with hypertelorism and prominent forehead in all the cases"
Hypertelorism was present in all cases of this ACLS series, supporting VERY_FREQUENT classification.
Head and Neck 3
Macrocephaly Macrocephaly HP:0000256
Show evidence (1 reference)
PMID:26349186 SUPPORT Human Clinical
"characterized by postaxial and/or preaxial polydactyly, cutaneous syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the corpus callosum, and intellectual disability"
Macrocephaly is enumerated among the characteristic features of ACLS.
Prominent Forehead VERY_FREQUENT Prominent forehead HP:0011220
Show evidence (1 reference)
PMID:23125460 SUPPORT Human Clinical
"Facial dysmorphism with hypertelorism and prominent forehead in all the cases"
Prominent forehead was present in all cases of this ACLS series, supporting VERY_FREQUENT classification.
Cleft Palate Cleft palate HP:0000175
Show evidence (1 reference)
PMID:21552264 SUPPORT Human Clinical
"polydactyly, brain abnormalities and cleft palate"
Cleft palate is listed among the overlapping malformation features of hydrolethalus and acrocallosal syndromes in the original KIF7 discovery paper.
Limbs 3
Postaxial Polydactyly Postaxial polydactyly HP:0100259
Show evidence (1 reference)
PMID:26349186 SUPPORT Human Clinical
"Acrocallosal syndrome is a multiple congenital anomaly disorder characterized by postaxial and/or preaxial polydactyly"
Postaxial polydactyly is a cardinal limb malformation of ACLS.
Preaxial Polydactyly Preaxial polydactyly HP:0100258
Show evidence (1 reference)
PMID:26648833 SUPPORT Human Clinical
"postaxial polydactyly of the hands as well as preaxial polydactyly of the feet"
Preaxial polydactyly of the feet is a recognized cardinal limb feature of ACLS.
Cutaneous Syndactyly Cutaneous syndactyly HP:0012725
Show evidence (1 reference)
PMID:26349186 SUPPORT Human Clinical
"characterized by postaxial and/or preaxial polydactyly, cutaneous syndactyly, macrocephaly, widely spaced eyes, absence or hypoplasia of the corpus callosum, and intellectual disability"
Cutaneous syndactyly is enumerated among the characteristic limb features of ACLS in this KIF7 syndromology review.
Nervous System 4
Agenesis of Corpus Callosum Agenesis of corpus callosum HP:0001274
Show evidence (1 reference)
PMID:26648833 SUPPORT Human Clinical
"Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum"
Corpus callosum agenesis is the eponymous, defining CNS malformation of ACLS.
Intellectual Disability Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:26349186 SUPPORT Human Clinical
"absence or hypoplasia of the corpus callosum, and intellectual disability"
Intellectual disability is a defining neurodevelopmental feature of ACLS.
Cerebellar Vermis Hypoplasia Cerebellar vermis hypoplasia HP:0001320
Show evidence (1 reference)
PMID:23125460 SUPPORT Human Clinical
"vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis"
Cerebellar vermis dysgenesis is a CNS malformation supporting the diagnosis of ACLS.
Molar Tooth Sign OCCASIONAL Molar tooth sign on MRI HP:0002419
Show evidence (1 reference)
PMID:26349186 SUPPORT Human Clinical
"They present with features like molar tooth sign and hyperventilation that are not very typical in ACLS, but do occur in other ciliopathies"
The molar tooth sign is described as "not very typical" in ACLS, supporting OCCASIONAL frequency classification.
Other 1
Duplication of the Hallux Duplication of phalanx of hallux HP:0010066
Show evidence (1 reference)
PMID:23125460 SUPPORT Human Clinical
"corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly"
Hallux duplication is listed among the defining clinical features of ACLS.
🧬

Genetic Associations

1
KIF7 Mutations (Causative)
Gene: KIF7 hgnc:30497
Show evidence (3 references)
PMID:21552264 SUPPORT Human Clinical
"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"
Original report identifying KIF7 as the causative gene for both ACLS and the allelic hydrolethalus syndrome.
PMID:23125460 SUPPORT Human Clinical
"Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel"
Mutation series confirming KIF7 as the recurrent disease locus and expanding the allelic spectrum of ACLS.
PMID:26648833 SUPPORT Human Clinical
"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"
Confirms KIF7 causation of ACLS and the allelic relationship with hydrolethalus and Joubert syndromes.
💊

Medical Actions

3
Supportive and Multidisciplinary Care
Action: supportive care MAXO:0000950
There is no disease-modifying therapy for ACLS. Management is supportive and multidisciplinary, addressing the neurodevelopmental, neurological, and structural manifestations through early intervention, developmental support, and management of seizures and feeding/respiratory issues as needed.
Surgical Correction of Polydactyly and Malformations
Action: surgical procedure MAXO:0000004
Surgical correction of polydactyly and other structural malformations (e.g., cleft palate) is performed as clinically indicated.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Autosomal recessive inheritance entails a 25% recurrence risk for siblings. Once the biallelic KIF7 variants are identified, carrier testing, prenatal testing, and preimplantation genetic testing become available to families.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Acrocallosal Syndrome:

Hydrolethalus Syndrome
Overlapping Features Hydrolethalus syndrome is an allelic KIF7-related disorder at the severe, frequently lethal end of the spectrum, sharing polydactyly, brain abnormalities, and cleft palate with ACLS.
Show evidence (1 reference)
PMID:21552264 SUPPORT Human Clinical
"hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate"
Establishes hydrolethalus syndrome as the allelic, phenotypically overlapping disorder distinguishing the severe end of the KIF7 spectrum.
Joubert Syndrome
Overlapping Features 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.
Show evidence (1 reference)
PMID:26648833 SUPPORT Human Clinical
"have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome"
Documents the KIF7 allelic overlap between ACLS and Joubert syndrome, relevant to differential diagnosis.
{ }

Source YAML

click to show 
name: Acrocallosal Syndrome
creation_date: "2026-06-13T20:27:42Z"
category: Mendelian
description: >-
  Acrocallosal syndrome (ACLS) is a rare autosomal recessive multiple
  congenital anomaly disorder caused by biallelic mutations in KIF7, 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
  description: >-
    Acrocallosal syndrome is inherited in an autosomal recessive manner, caused
    by biallelic (homozygous or compound heterozygous) loss-of-function
    mutations in KIF7.
  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.
prevalence:
- population: Published clinical estimates
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  percentage: Fewer than 50 reported cases
  notes: >-
    Acrocallosal syndrome is a very rare disorder; fewer than 50 cases have been
    reported in the literature since its first description by Schinzel in 1979,
    and the diagnosis remains challenging because of variable expressivity.
  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: >-
      It was first described by Albert Schinzel as early as in 1979, but the
      diagnosis of this syndrome still remains challenging
    explanation: >-
      Confirms the syndrome's rarity, historical first description (1979), and
      ongoing diagnostic difficulty.
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. Biallelic
    loss-of-function KIF7 mutations deregulate most GLI target genes and impair
    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: ABNORMAL
  - preferred_term: Regulation of Hedgehog Signaling
    term:
      id: GO:0008589
      label: regulation of smoothened signaling pathway
    modifier: DECREASED
  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: Neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Cerebellar and CNS Malformation
    description: >-
      Deregulated cilium-dependent Hedgehog/GLI signaling disrupts dorsoventral
      patterning and midline development of the brain, producing corpus callosum
      agenesis and cerebellar vermis hypoplasia.
  - target: Limb and Craniofacial Patterning Defect
    description: >-
      Deregulated Hedgehog/GLI3 output also disrupts anterior-posterior limb
      patterning and midline craniofacial development.
  evidence:
  - reference: PMID:21552264
    reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: 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
  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: Agenesis of Corpus Callosum
    causal_link_type: DIRECT
    description: Abnormal callosal development produces the eponymous corpus callosum agenesis phenotype.
  - target: Cerebellar Vermis Hypoplasia
    causal_link_type: DIRECT
    description: Abnormal cerebellar development produces vermis hypoplasia or dysgenesis.
  - target: Molar Tooth Sign
    causal_link_type: DIRECT
    description: Severe cerebellar and brainstem malformation can produce the molar tooth sign.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - corpus callosum agenesis
    - cerebellar and brain malformation
    description: The CNS malformation burden contributes to neurodevelopmental impairment and intellectual disability.
- 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.
  - target: Preaxial Polydactyly
    causal_link_type: DIRECT
    description: Abnormal limb patterning produces preaxial polydactyly.
  - target: Duplication of the Hallux
    causal_link_type: DIRECT
    description: Preaxial foot patterning disruption produces hallux duplication.
  - target: Cutaneous Syndactyly
    causal_link_type: DIRECT
    description: Digital patterning disruption produces soft-tissue syndactyly.
  - target: Cleft Palate
    causal_link_type: DIRECT
    description: Midline craniofacial patterning disruption produces cleft palate.
  - target: Macrocephaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - craniofacial dysmorphism
    - altered head growth
    description: ACLS craniofacial patterning disruption contributes to macrocephaly.
  - target: Hypertelorism
    causal_link_type: DIRECT
    description: Craniofacial patterning disruption produces hypertelorism.
  - target: Prominent Forehead
    causal_link_type: DIRECT
    description: Craniofacial patterning disruption produces a prominent forehead.
phenotypes:
- name: Agenesis of Corpus Callosum
  category: Neurologic
  description: >-
    Agenesis or hypoplasia of the corpus callosum is one of the two cardinal
    features of ACLS and gives the syndrome its name.
  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: 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 polydactyly
    term:
      id: HP:0100259
      label: 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: >-
      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 polydactyly
    term:
      id: HP:0100258
      label: 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: >-
      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: 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
  frequency: OCCASIONAL
  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
      OCCASIONAL frequency classification.
- 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.
genetic:
- name: KIF7 Mutations
  association: Causative
  gene_term:
    preferred_term: KIF7
    term:
      id: hgnc:30497
      label: KIF7
  notes: >-
    Biallelic (homozygous or compound heterozygous) loss-of-function mutations
    in KIF7 (15q26.1) cause acrocallosal syndrome. KIF7 encodes the human
    ortholog of Drosophila Costal2, a cilium-tip kinesin-4 regulator of the
    Sonic hedgehog pathway. Allelic KIF7 mutations also cause the more severe,
    frequently lethal hydrolethalus syndrome and a subset of Joubert syndrome.
  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.
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.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  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.
differential_diagnoses:
- name: Hydrolethalus Syndrome
  description: >-
    Hydrolethalus syndrome is an allelic KIF7-related disorder at the severe,
    frequently lethal end of the spectrum, sharing polydactyly, brain
    abnormalities, and cleft palate with 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
  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.
  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.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    There is no disease-modifying therapy for ACLS. Management is supportive and
    multidisciplinary, addressing the neurodevelopmental, neurological, and
    structural manifestations through early intervention, developmental support,
    and management of seizures and feeding/respiratory issues as needed.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Surgical Correction of Polydactyly and Malformations
  description: >-
    Surgical correction of polydactyly and other structural malformations (e.g.,
    cleft palate) is performed as clinically indicated.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance entails a 25% recurrence risk for siblings.
    Once the biallelic KIF7 variants are identified, carrier testing, prenatal
    testing, and preimplantation genetic testing become available to families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
references:
- reference: PMID:21552264
  title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
- reference: PMID:23125460
  title: "Novel KIF7 mutations extend the phenotypic spectrum 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:34705483
  title: "Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7's microtubule binding."
📚

References & Deep Research

References

5
PMID:21552264
KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.
No top-level findings curated for this source.
PMID:23125460
Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome.
No top-level findings curated for this source.
PMID:26349186
Molar tooth sign and acrocallosal syndrome--a report on a Polish family and review of KIF7 syndromology.
No top-level findings curated for this source.
PMID:26648833
Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature.
No top-level findings curated for this source.
PMID:34705483
Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7's microtubule binding.
No top-level findings curated for this source.