Stromme Syndrome

Mendelian MONDO:0009477 Pathograph 32 Show in embeddings browser multiple congenital anomalies/dysmorphic syndrome-intellectual disability primary ciliary dyskinesia hereditary lethal multiple congenital anomalies/dysmorphic syndrome

Stromme syndrome is an ultra-rare autosomal recessive congenital malformation syndrome caused by biallelic pathogenic variants in CENPF. The classic phenotype combines microcephaly, ocular anomalies such as microphthalmia or anterior chamber abnormalities, and apple-peel intestinal or jejunal atresia. CENPF encodes a centromere and centriolar protein with roles in cilium assembly, intraflagellar transport protein targeting, mitotic spindle organization, and cortical neurogenesis; severe loss-of-function alleles can cause a lethal fetal ciliopathy spectrum with brain, craniofacial, gastrointestinal, renal, and cardiac malformations.

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2
Definitions
1
Inheritance
3
Pathophys.
1
Histopath.
27
Phenotypes
32
Pathograph
1
Genes
2
Medical Actions
2
Subtypes
6
References
1
Deep Research
📘

Definitions

2
Orphanet Stromme syndrome definition
Orphanet defines Stromme syndrome as a rare multiple congenital anomalies syndrome centered on microcephaly, ocular anomalies, and apple-peel intestinal atresia, with variable craniofacial, renal, cardiac, neurologic, and hematologic findings.
OTHER
Show evidence (2 references)
ORPHA:506307 SUPPORT Other
"A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
Orphanet provides the structured clinical definition for Stromme syndrome.
PMID:26820108 SUPPORT Human Clinical
"Strømme syndrome was first described by Strømme et al. (1993) in siblings presenting with "apple peel" type intestinal atresia, ocular anomalies and microcephaly."
The CENPF discovery paper anchors the classic triad in affected siblings.
CENPF ciliopathy definition
CENPF-related Stromme syndrome is modeled as a ciliopathy because patient, fetal tissue, cell, and zebrafish data link CENPF dysfunction to basal-body localization, IFT88 ciliary targeting, short or abnormal cilia, and ciliopathy phenotypes.
OTHER
Show evidence (1 reference)
PMID:25564561 SUPPORT Human Clinical
"CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes."
This directly supports defining CENPF disease as a centriolar/ciliopathy disorder.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Stromme syndrome is caused by biallelic CENPF variants, including compound heterozygous and homozygous truncating alleles reported in affected sibling pairs and families.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:506307 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
PMID:26820108 SUPPORT Human Clinical
"We show for the first time that Strømme syndrome is an autosomal-recessive disease caused by mutations in CENPF that can result in a wide phenotypic spectrum."
The discovery report directly states autosomal recessive CENPF disease.
◆

Subtypes

2
Classic Stromme syndrome
The classic presentation combines microcephaly, ocular anomalies, and apple-peel intestinal or jejunal atresia, with variable developmental, craniofacial, renal, cardiac, and hematologic involvement.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
Orphanet supports the classic phenotype definition.
Lethal fetal CENPF ciliopathy spectrum
The severe fetal phenotype includes mid-gestation lethality with hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis, duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia, and dysmorphic craniofacial features.
Show evidence (1 reference)
ORPHA:444069 SUPPORT Other
"Clinical manifestations include hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis, duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia, and dysmorphic craniofacial features"
Orphanet supports the severe fetal CENPF-associated subtype description.
⚙

Pathophysiology

3
Biallelic CENPF dysfunction
Biallelic truncating, splice-site, or frameshift CENPF variants reduce CENP-F function at the kinetochore, centrosome, and ciliary basal body, initiating Stromme syndrome and the severe fetal CENPF ciliopathy spectrum.
CENPF hgnc:1857 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CENPF (hgnc:1857). hgnc:1857 is a gene from the HUGO Gene Nomenclature Committee.
cilium assembly GO:0060271 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. mitotic spindle organization GO:0007052 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitotic spindle organization (GO:0007052). GO:0007052 is a biological process from the Gene Ontology.
ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology.
Downstream
Defective CENPF-dependent IFT88 ciliary targeting Loss of CENP-F function impairs localization of IFT88 and related ciliary transport components to ciliary axonemes.
Cortical neurogenesis impairment CENP-F interacts with spindle-orientation and cortical polarity machinery, providing a mechanism for microcephaly.
Show evidence (2 references)
PMID:26820108 SUPPORT Human Clinical
"Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
Human sequencing evidence places biallelic truncating CENPF variants at the start of the disease mechanism.
PMID:25564561 SUPPORT Human Clinical
"CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis."
The mechanistic study links CENPF function to the key cellular processes modeled downstream.
Defective CENPF-dependent IFT88 ciliary targeting
CENP-F localizes to the ciliary basal body and interacts with IFT88/KIF3B; mutant CENPF kidneys show short abnormal renal epithelial cilia and loss of IFT88 localization to ciliary axonemes and centrioles. Zebrafish cenpf knockdown produces ciliary-function phenotypes including abnormal heart looping, hydrocephalus, and pronephric cysts.
kidney epithelial cell CL:0002518 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney epithelial cell (CL:0002518). CL:0002518 is a cell type from the Cell Ontology.
CENPF hgnc:1857 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CENPF (hgnc:1857). hgnc:1857 is a gene from the HUGO Gene Nomenclature Committee.
intraciliary transport GO:0042073 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intraciliary transport (GO:0042073). GO:0042073 is a biological process from the Gene Ontology. protein localization to cilium GO:0061512 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to cilium (GO:0061512). GO:0061512 is a biological process from the Gene Ontology.
cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology. ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology.
Downstream
Jejunal atresia The ciliary developmental defect is consistent with the core congenital apple-peel jejunal atresia phenotype.
Microphthalmia Ciliary developmental disruption contributes to ocular malformation.
Abnormal anterior chamber morphology Ciliary developmental disruption contributes to anterior segment anomalies.
Renal hypoplasia Fetal CENPF ciliopathy includes renal developmental hypoplasia.
Hydrocephalus CENPF ciliary dysfunction causes hydrocephalus in the severe developmental spectrum.
Abnormal heart morphology Zebrafish cenpf knockdown supports heart-looping and laterality effects relevant to variable cardiac anomalies.
Corneal opacity
Visual impairment
Duodenal atresia
Intestinal malrotation
Hypertelorism
Low-set ears
Wide nasal bridge
Anteverted nares
Long philtrum
Micrognathia
Wide mouth
Cleft palate
Prominent nose
Macrotia
Lower limb edema
Thrombocytopenia
Show evidence (2 references)
PMID:25564561 SUPPORT Human Clinical
"IFT88 did not localise to ciliary axonemes and centrioles in mutant CENPF kidneys"
Mutant human fetal kidney tissue directly supports defective IFT88 ciliary localization.
PMID:25564561 SUPPORT Model Organism
"The occurrence of these morphological findings support a role for CENP-F in zebrafish ciliary function."
Zebrafish knockdown phenotypes support CENP-F function in ciliary biology.
Cortical neurogenesis impairment
CENP-F has a putative role in cortical neurogenesis and asymmetric division through interactions with spindle-orientation and cortical polarity proteins; impaired function provides a mechanistic basis for microcephaly and neurodevelopmental findings.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
CENPF hgnc:1857 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CENPF (hgnc:1857). hgnc:1857 is a gene from the HUGO Gene Nomenclature Committee.
asymmetric cell division GO:0008356 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal asymmetric cell division (GO:0008356). GO:0008356 is a biological process from the Gene Ontology. cell division GO:0051301 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell division (GO:0051301). GO:0051301 is a biological process from the Gene Ontology.
Downstream
Microcephaly Impaired cortical neurogenesis manifests as congenital microcephaly.
Motor delay Neurodevelopmental disruption contributes to delayed motor milestones.
Intellectual disability Neurodevelopmental disruption contributes to cognitive impairment.
Agenesis of corpus callosum Severe fetal CENPF ciliopathy can include major brain malformations.
Cerebellar vermis hypoplasia Severe fetal CENPF ciliopathy can include posterior fossa malformations.
Show evidence (2 references)
PMID:25564561 SUPPORT Human Clinical
"Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes."
Human genetic and fetal data support CENPF as a microcephaly-related disease gene.
PMID:25564561 SUPPORT Human Clinical
"MCPH phenotypes have been ascribed to defective asymmetric divisions of neuronal progenitors and failure of correct neural cell fate specification."
The mechanistic discussion links microcephaly to neuronal progenitor asymmetric division and cell fate specification.
✶

Histopathology

1
Short renal epithelial cilia with IFT88 mislocalization
Mutant CENPF fetal kidneys show short abnormal cilia on renal epithelial cells and loss of IFT88 localization to ciliary axonemes and centrioles, supporting a tissue-level ciliopathy mechanism.
Show evidence (2 references)
PMID:25564561 SUPPORT Human Clinical
"GT335-positive cilia are shorter than cilia in control kidneys."
Human fetal kidney immunofluorescence supports short renal epithelial cilia.
PMID:25564561 SUPPORT Human Clinical
"IFT88 did not localise to ciliary axonemes and centrioles in mutant CENPF kidneys"
Human fetal kidney immunofluorescence supports IFT88 mislocalization.
⬡

Pathograph

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

27
Blood 1
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"thrombocytopenia"
Orphanet records thrombocytopenia among variable anomalies.
Cardiovascular 1
Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac abnormality, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present."
Orphanet records variable heart abnormalities.
Digestive 3
Jejunal atresia HP:0005235 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jejunal atresia (HP:0005235). HP:0005235 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28407396 SUPPORT Human Clinical
"Stromme syndrome is a rare genetic disorder characterized by microcephaly, anterior ocular chamber anomalies, and "apple peel" type jejunal atresia."
A CENPF family report directly supports apple-peel type jejunal atresia.
PMID:26820108 SUPPORT Human Clinical
"presenting with "apple peel" type intestinal atresia, ocular anomalies and microcephaly."
The discovery cohort supports apple-peel intestinal atresia as part of the core triad.
Duodenal atresia HP:0002247 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Duodenal atresia (HP:0002247). HP:0002247 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"duodenal atresia"
Orphanet records duodenal atresia in the lethal fetal phenotype.
PMID:25564561 SUPPORT Human Clinical
"Examination of a dissected gastrointestinal tract from the same affected fetus revealed complete duodenal atresia."
Human fetal autopsy directly supports complete duodenal atresia.
Intestinal malrotation HP:0002566 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal malrotation (HP:0002566). HP:0002566 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:444069 SUPPORT Other
"gastrointestinal malrotation"
Orphanet records gastrointestinal malrotation in the lethal fetal phenotype.
Ear 2
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"low-set ears"
Orphanet records low-set ears in the severe fetal phenotype.
PMID:25564561 SUPPORT Human Clinical
"dysmorphic craniofacial features such as a high nasal bridge, short columella, micrognathia, wide mouth and low-set ears."
Human fetal morphology directly supports low-set ears.
Macrotia HP:0000400 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large ears, annotated with Macrotia (HP:0000400). HP:0000400 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"large or low set ears"
Orphanet records large or low-set ears among reported facial features.
Eye 5
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:506307 SUPPORT Other
"ocular anomalies such as microphthalmia"
Orphanet identifies microphthalmia among ocular anomalies.
PMID:18203155 SUPPORT Human Clinical
"We describe another patient with the combination of apple peel intestinal atresia, microcephaly, microphthalmia, and anterior eye chamber anomalies."
This case report directly supports microphthalmia in the clinical syndrome.
Abnormal anterior chamber morphology HP:0000593 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anterior chamber anomalies, annotated with Abnormal anterior chamber morphology (HP:0000593). HP:0000593 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28407396 SUPPORT Human Clinical
"Stromme syndrome is a rare genetic disorder characterized by microcephaly, anterior ocular chamber anomalies, and "apple peel" type jejunal atresia."
The case report directly identifies anterior ocular chamber anomalies.
PMID:18203155 SUPPORT Human Clinical
"microcephaly, microphthalmia, and anterior eye chamber anomalies."
The case report supports anterior chamber anomalies in the classic syndrome.
Corneal opacity HP:0007957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal opacity (HP:0007957). HP:0007957 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18203155 SUPPORT Human Clinical
"there is major visual impairment due to the corneal clouding."
This directly supports corneal clouding as the cause of visual impairment.
Visual impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18203155 SUPPORT Human Clinical
"Development so far seems to be normal, although there is major visual impairment due to the corneal clouding."
This case report directly supports major visual impairment.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"Facial dysmorphism is reported in some cases and may include narrow or sloped forehead, hypertelorism, microphthalmia"
Orphanet records hypertelorism among reported facial features.
Genitourinary 1
Renal hypoplasia HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089). HP:0000089 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"bilateral renal hypoplasia"
Orphanet records bilateral renal hypoplasia in the lethal fetal phenotype.
PMID:25564561 SUPPORT Human Clinical
"Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
Human fetal autopsy findings directly support bilateral renal hypoplasia.
Head and Neck 8
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:506307 SUPPORT Other
"A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
Orphanet identifies microcephaly as part of the usual syndrome characterization.
PMID:28407396 SUPPORT Human Clinical
"A 3-month-old girl was hospitalized due to prenatally diagnosed microcephaly, microphthalmia, and dysmorphological features."
A CENPF-confirmed family report supports prenatal microcephaly.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal root, annotated with Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"broad nasal root"
Orphanet records broad nasal root among reported facial features.
Anteverted nares HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"anteverted or broad nasal tip"
Orphanet records anteverted or broad nasal tip.
Long philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"long philtrum"
Orphanet records long philtrum among reported facial features.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:506307 SUPPORT Other
"micrognathia"
Orphanet records micrognathia among reported facial features.
PMID:25564561 SUPPORT Human Clinical
"dysmorphic craniofacial features such as a high nasal bridge, short columella, micrognathia, wide mouth and low-set ears."
Human fetal morphology directly supports micrognathia.
Wide mouth HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:506307 SUPPORT Other
"large mouth"
Orphanet records large mouth among reported facial features.
PMID:25564561 SUPPORT Human Clinical
"dysmorphic craniofacial features such as a high nasal bridge, short columella, micrognathia, wide mouth and low-set ears."
Human fetal morphology directly supports wide mouth.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"cleft palate"
Orphanet records cleft palate in the severe fetal phenotype.
PMID:25564561 SUPPORT Human Clinical
"Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
Human fetal autopsy directly supports cleft palate.
Prominent nose HP:0000448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent nose (HP:0000448). HP:0000448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:444069 SUPPORT Other
"prominent nose"
Orphanet records prominent nose in the severe fetal phenotype.
Metabolism 1
Lower limb edema HP:0000969 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb edema, annotated with Edema (HP:0000969). HP:0000969 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"lower limb edema"
Orphanet records lower limb edema among variable anomalies.
Nervous System 5
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"Motor delay and intellectual disability have been reported."
Orphanet reports motor delay in Stromme syndrome.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"Motor delay and intellectual disability have been reported."
Orphanet reports intellectual disability in Stromme syndrome.
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"Clinical manifestations include hydrocephalus"
Orphanet records hydrocephalus in the lethal fetal phenotype.
PMID:25564561 SUPPORT Model Organism
"At 72 hpf, hydrocephalus was observed in cenpf morphants"
Zebrafish cenpf knockdown supports hydrocephalus as a ciliary-function phenotype.
Cerebellar vermis hypoplasia HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"cerebellar vermis hypoplasia"
Orphanet records cerebellar vermis hypoplasia in the lethal fetal phenotype.
PMID:25564561 SUPPORT Human Clinical
"Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
Human fetal autopsy directly supports cerebellar vermis hypoplasia.
Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"corpus callosum agenesis"
Orphanet records corpus callosum agenesis in the lethal fetal phenotype.
PMID:25564561 SUPPORT Human Clinical
"Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
Human fetal autopsy directly supports corpus callosum agenesis.
🧬

Genetic Associations

1
Biallelic CENPF pathogenic variants (Biallelic pathogenic variants causing autosomal recessive Stromme syndrome)
Gene: CENPF hgnc:1857 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CENPF (hgnc:1857). hgnc:1857 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
ORPHA:506307 SUPPORT Other
"CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) in"
Orphanet identifies CENPF as the disease-causing germline gene.
PMID:26820108 SUPPORT Human Clinical
"Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
This directly supports truncating CENPF variants in affected sibling pairs.
PMID:28407396 SUPPORT Human Clinical
"we report a Stromme syndrome family with two affected siblings with a homozygous truncating frameshift mutation in CENPF."
This independently supports homozygous truncating CENPF variation in Stromme syndrome.
+ 1 more reference
🗃️

External Assertions

2
Orphanet Stromme syndrome structured disease record
Orphanet structured disease record ORPHA:506307
ORPHA:506307 supplies the Stromme syndrome definition, synonyms, inheritance, antenatal onset, prevalence, CENPF gene association, and MONDO/OMIM cross-references used in this entry.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) in"
Orphanet identifies CENPF as the disease-causing germline gene for Stromme syndrome.
Orphanet lethal fetal CENPF ciliopathy record
Orphanet structured disease record ORPHA:444069
ORPHA:444069 records the severe lethal fetal CENPF-associated ciliopathy spectrum with duodenal atresia, renal hypoplasia, brain malformations, and dysmorphic craniofacial findings.
Show evidence (1 reference)
ORPHA:444069 SUPPORT Other
"CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet records CENPF loss-of-function germline mutations for the lethal fetal phenotype.
💊

Medical Actions

2
Symptom-directed supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is supportive and multidisciplinary, directed at the congenital gastrointestinal, ocular, neurologic, renal, cardiac, and craniofacial manifestations present in an individual child.
Target Phenotypes: Jejunal atresia HP:0005235 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Jejunal atresia (HP:0005235). HP:0005235 is a phenotype from the Human Phenotype Ontology. Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology. Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present."
The multisystem variable phenotype supports symptom-directed multidisciplinary care.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling addresses autosomal recessive inheritance, carrier testing for parents and relatives, recurrence risk, prenatal diagnostic options, and genotype-informed counseling for the severe fetal spectrum.
Show evidence (2 references)
PMID:26820108 SUPPORT Human Clinical
"Compound heterozygous inheritance was confirmed in both families."
Confirmed familial biallelic inheritance supports recurrence-risk counseling.
ORPHA:506307 SUPPORT Other
"Autosomal recessive"
Orphanet inheritance supports genetic counseling for affected families.
🔬

Diagnosis

2
Clinical whole-exome sequencing
Exome sequencing or equivalent molecular genetic testing can identify biallelic pathogenic CENPF variants in patients or fetuses with the Stromme syndrome phenotype.
clinical whole-exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26820108 SUPPORT Human Clinical
"Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
This directly supports exome sequencing as a molecular diagnostic approach.
PMID:28407396 SUPPORT Human Clinical
"Exome-sequencing of these two cases showed the homozygous mutation (c.5912_5913insA)/(p.T1974Nfs*9) in CENPF."
Independent cases support exome sequencing for CENPF variant detection.
Clinical assessment of the congenital triad
Clinical and prenatal assessment should consider the combination of microcephaly, ocular anomalies, and apple-peel intestinal or jejunal atresia, with evaluation for renal, cardiac, neurologic, and craniofacial involvement.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:28407396 SUPPORT Human Clinical
"Regarding the clinical features of both affected siblings, a diagnosis of Stromme syndrome was established."
The report supports clinical diagnosis based on the recurrent feature pattern.
ORPHA:506307 SUPPORT Other
"A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
Orphanet provides the key clinical pattern for assessment.
📈

Progression

2
Onset
Age: Antenatal
Core structural malformations are congenital and Orphanet records antenatal onset.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"Age of onset: Antenatal"
Orphanet records antenatal onset for Stromme syndrome.
Severe fetal spectrum
Age: Mid-gestation
Severe CENPF loss-of-function presentations can be lethal in utero, with brain, renal, gastrointestinal, and craniofacial malformations recognized at fetal autopsy.
Show evidence (2 references)
ORPHA:444069 SUPPORT Other
"A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by mid-gestation lethality and features of a ciliopathy."
Orphanet records the lethal fetal CENPF-associated ciliopathy phenotype.
PMID:25564561 SUPPORT Human Clinical
"Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene."
Human fetal data support the severe antenatal/lethal end of the CENPF spectrum.
📊

Prevalence

1
Worldwide
Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000
Orphanet classifies Stromme syndrome as ultra-rare worldwide.
Show evidence (1 reference)
ORPHA:506307 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:28407396"
Orphanet records worldwide point prevalence below one per million.
{ }

Source YAML

click to show 
name: Stromme Syndrome
creation_date: "2026-05-08T05:44:00Z"
category: Mendelian
synonyms:
- Apple-peel intestinal atresia-ocular anomalies-microcephaly syndrome
- Jejunal atresia-microcephaly-ocular anomalies syndrome
- Apple peel syndrome with microcephaly and ocular anomalies
- Jejunal atresia with microcephaly and ocular anomalies
- Ciliary dyskinesia, primary, type 31
- Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
description: >-
  Stromme syndrome is an ultra-rare autosomal recessive congenital malformation
  syndrome caused by biallelic pathogenic variants in CENPF. The classic
  phenotype combines microcephaly, ocular anomalies such as microphthalmia or
  anterior chamber abnormalities, and apple-peel intestinal or jejunal atresia.
  CENPF encodes a centromere and centriolar protein with roles in cilium
  assembly, intraflagellar transport protein targeting, mitotic spindle
  organization, and cortical neurogenesis; severe loss-of-function alleles can
  cause a lethal fetal ciliopathy spectrum with brain, craniofacial,
  gastrointestinal, renal, and cardiac malformations.
disease_term:
  preferred_term: Stromme syndrome
  term:
    id: MONDO:0009477
    label: Stromme syndrome
parents:
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability
- primary ciliary dyskinesia
- hereditary lethal multiple congenital anomalies/dysmorphic syndrome
external_assertions:
- name: Orphanet Stromme syndrome structured disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:506307
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=506307
  description: >-
    ORPHA:506307 supplies the Stromme syndrome definition, synonyms,
    inheritance, antenatal onset, prevalence, CENPF gene association, and
    MONDO/OMIM cross-references used in this entry.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies CENPF as the disease-causing germline gene for Stromme syndrome.
- name: Orphanet lethal fetal CENPF ciliopathy record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:444069
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=444069
  description: >-
    ORPHA:444069 records the severe lethal fetal CENPF-associated ciliopathy
    spectrum with duodenal atresia, renal hypoplasia, brain malformations, and
    dysmorphic craniofacial findings.
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet records CENPF loss-of-function germline mutations for the lethal fetal phenotype.
definitions:
- name: Orphanet Stromme syndrome definition
  definition_type: OTHER
  description: >-
    Orphanet defines Stromme syndrome as a rare multiple congenital anomalies
    syndrome centered on microcephaly, ocular anomalies, and apple-peel
    intestinal atresia, with variable craniofacial, renal, cardiac,
    neurologic, and hematologic findings.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
    explanation: Orphanet provides the structured clinical definition for Stromme syndrome.
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strømme syndrome was first described by Strømme et al. (1993) in siblings presenting with \"apple peel\" type intestinal atresia, ocular anomalies and microcephaly."
    explanation: The CENPF discovery paper anchors the classic triad in affected siblings.
- name: CENPF ciliopathy definition
  definition_type: OTHER
  description: >-
    CENPF-related Stromme syndrome is modeled as a ciliopathy because patient,
    fetal tissue, cell, and zebrafish data link CENPF dysfunction to basal-body
    localization, IFT88 ciliary targeting, short or abnormal cilia, and
    ciliopathy phenotypes.
  evidence:
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes."
    explanation: This directly supports defining CENPF disease as a centriolar/ciliopathy disorder.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Stromme syndrome is caused by biallelic CENPF variants, including compound
    heterozygous and homozygous truncating alleles reported in affected sibling
    pairs and families.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show for the first time that Strømme syndrome is an autosomal-recessive disease caused by mutations in CENPF that can result in a wide phenotypic spectrum."
    explanation: The discovery report directly states autosomal recessive CENPF disease.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  percentage: <1 per 1,000,000
  notes: Orphanet classifies Stromme syndrome as ultra-rare worldwide.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:28407396"
    explanation: Orphanet records worldwide point prevalence below one per million.
progression:
- phase: Onset
  age_range: Antenatal
  notes: >-
    Core structural malformations are congenital and Orphanet records
    antenatal onset.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Antenatal"
    explanation: Orphanet records antenatal onset for Stromme syndrome.
- phase: Severe fetal spectrum
  age_range: Mid-gestation
  notes: >-
    Severe CENPF loss-of-function presentations can be lethal in utero, with
    brain, renal, gastrointestinal, and craniofacial malformations recognized
    at fetal autopsy.
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by mid-gestation lethality and features of a ciliopathy."
    explanation: Orphanet records the lethal fetal CENPF-associated ciliopathy phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene."
    explanation: Human fetal data support the severe antenatal/lethal end of the CENPF spectrum.
has_subtypes:
- name: Classic
  display_name: Classic Stromme syndrome
  description: >-
    The classic presentation combines microcephaly, ocular anomalies, and
    apple-peel intestinal or jejunal atresia, with variable developmental,
    craniofacial, renal, cardiac, and hematologic involvement.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
    explanation: Orphanet supports the classic phenotype definition.
- name: Lethal fetal
  display_name: Lethal fetal CENPF ciliopathy spectrum
  description: >-
    The severe fetal phenotype includes mid-gestation lethality with
    hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis,
    duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia,
    and dysmorphic craniofacial features.
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical manifestations include hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis, duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia, and dysmorphic craniofacial features"
    explanation: Orphanet supports the severe fetal CENPF-associated subtype description.
genetic:
- name: Biallelic CENPF pathogenic variants
  gene_term:
    preferred_term: CENPF
    term:
      id: hgnc:1857
      label: CENPF
  association: Biallelic pathogenic variants causing autosomal recessive Stromme syndrome
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported alleles include compound heterozygous truncating or splice-site
    variants and homozygous frameshift variants. More severe fetal cases have
    loss-of-function alleles with absent or severely reduced CENP-F activity,
    while residual CENP-F activity may contribute to milder microcephaly-dominant
    phenotypes.
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies CENPF as the disease-causing germline gene.
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
    explanation: This directly supports truncating CENPF variants in affected sibling pairs.
  - reference: PMID:28407396
    reference_title: "A further family of Stromme syndrome carrying CENPF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a Stromme syndrome family with two affected siblings with a homozygous truncating frameshift mutation in CENPF."
    explanation: This independently supports homozygous truncating CENPF variation in Stromme syndrome.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]."
    explanation: The fetal ciliopathy study supports biallelic CENPF variants segregating with disease.
pathophysiology:
- name: Biallelic CENPF dysfunction
  description: >-
    Biallelic truncating, splice-site, or frameshift CENPF variants reduce
    CENP-F function at the kinetochore, centrosome, and ciliary basal body,
    initiating Stromme syndrome and the severe fetal CENPF ciliopathy spectrum.
  genes:
  - preferred_term: CENPF
    term:
      id: hgnc:1857
      label: CENPF
  biological_processes:
  - preferred_term: cilium assembly
    modifier: ABNORMAL
    term:
      id: GO:0060271
      label: cilium assembly
  - preferred_term: mitotic spindle organization
    modifier: ABNORMAL
    term:
      id: GO:0007052
      label: mitotic spindle organization
  cellular_components:
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  evidence:
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
    explanation: Human sequencing evidence places biallelic truncating CENPF variants at the start of the disease mechanism.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis."
    explanation: The mechanistic study links CENPF function to the key cellular processes modeled downstream.
  downstream:
  - target: Defective CENPF-dependent IFT88 ciliary targeting
    causal_link_type: DIRECT
    description: >-
      Loss of CENP-F function impairs localization of IFT88 and related ciliary
      transport components to ciliary axonemes.
    evidence:
    - reference: PMID:25564561
      reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys."
      explanation: Human fetal kidney evidence supports CENP-F-dependent IFT88 ciliary targeting.
  - target: Cortical neurogenesis impairment
    causal_link_type: DIRECT
    description: >-
      CENP-F interacts with spindle-orientation and cortical polarity machinery,
      providing a mechanism for microcephaly.
    evidence:
    - reference: PMID:25564561
      reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our data supports a role for CENP-F in asymmetric cell divisions through its putative interactions with p150-dynactin, NuMA and Par3, proteins which have been implicated in this pathway."
      explanation: Cell-based interaction data support a CENPF role in asymmetric division relevant to cortical neurogenesis.
- name: Defective CENPF-dependent IFT88 ciliary targeting
  description: >-
    CENP-F localizes to the ciliary basal body and interacts with IFT88/KIF3B;
    mutant CENPF kidneys show short abnormal renal epithelial cilia and loss of
    IFT88 localization to ciliary axonemes and centrioles. Zebrafish cenpf
    knockdown produces ciliary-function phenotypes including abnormal heart
    looping, hydrocephalus, and pronephric cysts.
  genes:
  - preferred_term: CENPF
    term:
      id: hgnc:1857
      label: CENPF
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: intraciliary transport
    modifier: ABNORMAL
    term:
      id: GO:0042073
      label: intraciliary transport
  - preferred_term: protein localization to cilium
    modifier: DECREASED
    term:
      id: GO:0061512
      label: protein localization to cilium
  cellular_components:
  - preferred_term: cilium
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  evidence:
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IFT88 did not localise to ciliary axonemes and centrioles in mutant CENPF kidneys"
    explanation: Mutant human fetal kidney tissue directly supports defective IFT88 ciliary localization.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The occurrence of these morphological findings support a role for CENP-F in zebrafish ciliary function."
    explanation: Zebrafish knockdown phenotypes support CENP-F function in ciliary biology.
  downstream:
  - target: Jejunal atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The ciliary developmental defect is consistent with the core congenital
      apple-peel jejunal atresia phenotype.
  - target: Microphthalmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ciliary developmental disruption contributes to ocular malformation.
  - target: Abnormal anterior chamber morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ciliary developmental disruption contributes to anterior segment anomalies.
  - target: Renal hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Fetal CENPF ciliopathy includes renal developmental hypoplasia.
  - target: Hydrocephalus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: CENPF ciliary dysfunction causes hydrocephalus in the severe developmental spectrum.
  - target: Abnormal heart morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Zebrafish cenpf knockdown supports heart-looping and laterality effects relevant to variable cardiac anomalies.
  - target: Corneal opacity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Duodenal atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intestinal malrotation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Wide nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anteverted nares
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Long philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Wide mouth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Prominent nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Macrotia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lower limb edema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cortical neurogenesis impairment
  description: >-
    CENP-F has a putative role in cortical neurogenesis and asymmetric
    division through interactions with spindle-orientation and cortical
    polarity proteins; impaired function provides a mechanistic basis for
    microcephaly and neurodevelopmental findings.
  genes:
  - preferred_term: CENPF
    term:
      id: hgnc:1857
      label: CENPF
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: asymmetric cell division
    modifier: ABNORMAL
    term:
      id: GO:0008356
      label: asymmetric cell division
  - preferred_term: cell division
    modifier: ABNORMAL
    term:
      id: GO:0051301
      label: cell division
  evidence:
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes."
    explanation: Human genetic and fetal data support CENPF as a microcephaly-related disease gene.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCPH phenotypes have been ascribed to defective asymmetric divisions of neuronal progenitors and failure of correct neural cell fate specification."
    explanation: The mechanistic discussion links microcephaly to neuronal progenitor asymmetric division and cell fate specification.
  downstream:
  - target: Microcephaly
    causal_link_type: DIRECT
    description: Impaired cortical neurogenesis manifests as congenital microcephaly.
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neurodevelopmental disruption contributes to delayed motor milestones.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neurodevelopmental disruption contributes to cognitive impairment.
  - target: Agenesis of corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe fetal CENPF ciliopathy can include major brain malformations.
  - target: Cerebellar vermis hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe fetal CENPF ciliopathy can include posterior fossa malformations.
phenotypes:
- name: Microcephaly
  description: >-
    Microcephaly is a core congenital feature in classic Stromme syndrome and
    also appears in the severe fetal CENPF spectrum.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
    explanation: Orphanet identifies microcephaly as part of the usual syndrome characterization.
  - reference: PMID:28407396
    reference_title: "A further family of Stromme syndrome carrying CENPF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 3-month-old girl was hospitalized due to prenatally diagnosed microcephaly, microphthalmia, and dysmorphological features."
    explanation: A CENPF-confirmed family report supports prenatal microcephaly.
- name: Jejunal atresia
  description: >-
    The classic intestinal manifestation is apple-peel type jejunal or
    intestinal atresia.
  phenotype_term:
    preferred_term: Jejunal atresia
    term:
      id: HP:0005235
      label: Jejunal atresia
  evidence:
  - reference: PMID:28407396
    reference_title: "A further family of Stromme syndrome carrying CENPF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stromme syndrome is a rare genetic disorder characterized by microcephaly, anterior ocular chamber anomalies, and \"apple peel\" type jejunal atresia."
    explanation: A CENPF family report directly supports apple-peel type jejunal atresia.
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with \"apple peel\" type intestinal atresia, ocular anomalies and microcephaly."
    explanation: The discovery cohort supports apple-peel intestinal atresia as part of the core triad.
- name: Microphthalmia
  description: Microphthalmia is a recurrent ocular malformation in Stromme syndrome.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ocular anomalies such as microphthalmia"
    explanation: Orphanet identifies microphthalmia among ocular anomalies.
  - reference: PMID:18203155
    reference_title: "Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe another patient with the combination of apple peel intestinal atresia, microcephaly, microphthalmia, and anterior eye chamber anomalies."
    explanation: This case report directly supports microphthalmia in the clinical syndrome.
- name: Abnormal anterior chamber morphology
  description: Anterior chamber anomalies are part of the ocular phenotype.
  phenotype_term:
    preferred_term: Anterior chamber anomalies
    term:
      id: HP:0000593
      label: Abnormal anterior chamber morphology
  evidence:
  - reference: PMID:28407396
    reference_title: "A further family of Stromme syndrome carrying CENPF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stromme syndrome is a rare genetic disorder characterized by microcephaly, anterior ocular chamber anomalies, and \"apple peel\" type jejunal atresia."
    explanation: The case report directly identifies anterior ocular chamber anomalies.
  - reference: PMID:18203155
    reference_title: "Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, microphthalmia, and anterior eye chamber anomalies."
    explanation: The case report supports anterior chamber anomalies in the classic syndrome.
- name: Corneal opacity
  description: Corneal clouding can cause major visual impairment.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:18203155
    reference_title: "Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is major visual impairment due to the corneal clouding."
    explanation: This directly supports corneal clouding as the cause of visual impairment.
- name: Visual impairment
  description: Visual impairment may be severe when ocular anomalies include corneal clouding.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:18203155
    reference_title: "Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Development so far seems to be normal, although there is major visual impairment due to the corneal clouding."
    explanation: This case report directly supports major visual impairment.
- name: Motor delay
  description: Motor delay has been reported in affected individuals.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Motor delay and intellectual disability have been reported."
    explanation: Orphanet reports motor delay in Stromme syndrome.
- name: Intellectual disability
  description: Intellectual disability is variably reported in survivors.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Motor delay and intellectual disability have been reported."
    explanation: Orphanet reports intellectual disability in Stromme syndrome.
- name: Abnormal heart morphology
  description: Cardiac malformations are variably present.
  phenotype_term:
    preferred_term: Cardiac abnormality
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present."
    explanation: Orphanet records variable heart abnormalities.
- name: Renal hypoplasia
  subtype: Lethal fetal
  description: Bilateral renal hypoplasia is part of the severe fetal CENPF ciliopathy spectrum.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "bilateral renal hypoplasia"
    explanation: Orphanet records bilateral renal hypoplasia in the lethal fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
    explanation: Human fetal autopsy findings directly support bilateral renal hypoplasia.
- name: Hydrocephalus
  subtype: Lethal fetal
  description: Hydrocephalus occurs in the severe fetal phenotype.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical manifestations include hydrocephalus"
    explanation: Orphanet records hydrocephalus in the lethal fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At 72 hpf, hydrocephalus was observed in cenpf morphants"
    explanation: Zebrafish cenpf knockdown supports hydrocephalus as a ciliary-function phenotype.
- name: Cerebellar vermis hypoplasia
  subtype: Lethal fetal
  description: Cerebellar vermis hypoplasia is reported in the severe fetal phenotype.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cerebellar vermis hypoplasia"
    explanation: Orphanet records cerebellar vermis hypoplasia in the lethal fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
    explanation: Human fetal autopsy directly supports cerebellar vermis hypoplasia.
- name: Agenesis of corpus callosum
  subtype: Lethal fetal
  description: Corpus callosum agenesis is part of the severe fetal brain malformation spectrum.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "corpus callosum agenesis"
    explanation: Orphanet records corpus callosum agenesis in the lethal fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
    explanation: Human fetal autopsy directly supports corpus callosum agenesis.
- name: Duodenal atresia
  subtype: Lethal fetal
  description: Complete duodenal atresia is reported in the severe fetal phenotype.
  phenotype_term:
    preferred_term: Duodenal atresia
    term:
      id: HP:0002247
      label: Duodenal atresia
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "duodenal atresia"
    explanation: Orphanet records duodenal atresia in the lethal fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of a dissected gastrointestinal tract from the same affected fetus revealed complete duodenal atresia."
    explanation: Human fetal autopsy directly supports complete duodenal atresia.
- name: Intestinal malrotation
  subtype: Lethal fetal
  description: Gastrointestinal malrotation is reported in the severe fetal phenotype.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "gastrointestinal malrotation"
    explanation: Orphanet records gastrointestinal malrotation in the lethal fetal phenotype.
- name: Hypertelorism
  description: Hypertelorism is among reported dysmorphic craniofacial features.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Facial dysmorphism is reported in some cases and may include narrow or sloped forehead, hypertelorism, microphthalmia"
    explanation: Orphanet records hypertelorism among reported facial features.
- name: Low-set ears
  description: Low-set ears are reported in the severe fetal and classic dysmorphic spectra.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "low-set ears"
    explanation: Orphanet records low-set ears in the severe fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic craniofacial features such as a high nasal bridge, short columella, micrognathia, wide mouth and low-set ears."
    explanation: Human fetal morphology directly supports low-set ears.
- name: Wide nasal bridge
  description: A broad nasal root or high/wide nasal bridge is part of the craniofacial phenotype.
  phenotype_term:
    preferred_term: Broad nasal root
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "broad nasal root"
    explanation: Orphanet records broad nasal root among reported facial features.
- name: Anteverted nares
  description: Anteverted or broad nasal tip is reported in the craniofacial spectrum.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "anteverted or broad nasal tip"
    explanation: Orphanet records anteverted or broad nasal tip.
- name: Long philtrum
  description: Long philtrum is among reported facial dysmorphic features.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "long philtrum"
    explanation: Orphanet records long philtrum among reported facial features.
- name: Micrognathia
  description: Micrognathia is reported in both classic and severe fetal records.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "micrognathia"
    explanation: Orphanet records micrognathia among reported facial features.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic craniofacial features such as a high nasal bridge, short columella, micrognathia, wide mouth and low-set ears."
    explanation: Human fetal morphology directly supports micrognathia.
- name: Wide mouth
  description: Large or wide mouth is reported in the craniofacial phenotype.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "large mouth"
    explanation: Orphanet records large mouth among reported facial features.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic craniofacial features such as a high nasal bridge, short columella, micrognathia, wide mouth and low-set ears."
    explanation: Human fetal morphology directly supports wide mouth.
- name: Cleft palate
  subtype: Lethal fetal
  description: Cleft palate is part of the severe fetal craniofacial phenotype.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cleft palate"
    explanation: Orphanet records cleft palate in the severe fetal phenotype.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autopsy findings revealed ciliopathy features, such as cerebellar vermis hypoplasia, corpus callosum agenesis, cleft palate, duodenal atresia and bilateral renal hypoplasia."
    explanation: Human fetal autopsy directly supports cleft palate.
- name: Prominent nose
  subtype: Lethal fetal
  description: Prominent nose is reported in the severe fetal craniofacial phenotype.
  phenotype_term:
    preferred_term: Prominent nose
    term:
      id: HP:0000448
      label: Prominent nose
  evidence:
  - reference: ORPHA:444069
    reference_title: "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "prominent nose"
    explanation: Orphanet records prominent nose in the severe fetal phenotype.
- name: Macrotia
  description: Large ears are among reported facial features.
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "large or low set ears"
    explanation: Orphanet records large or low-set ears among reported facial features.
- name: Lower limb edema
  description: Lower limb edema is variably reported.
  phenotype_term:
    preferred_term: Lower limb edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "lower limb edema"
    explanation: Orphanet records lower limb edema among variable anomalies.
- name: Thrombocytopenia
  description: Thrombocytopenia is among variable reported anomalies.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "thrombocytopenia"
    explanation: Orphanet records thrombocytopenia among variable anomalies.
histopathology:
- name: Short renal epithelial cilia with IFT88 mislocalization
  description: >-
    Mutant CENPF fetal kidneys show short abnormal cilia on renal epithelial
    cells and loss of IFT88 localization to ciliary axonemes and centrioles,
    supporting a tissue-level ciliopathy mechanism.
  evidence:
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GT335-positive cilia are shorter than cilia in control kidneys."
    explanation: Human fetal kidney immunofluorescence supports short renal epithelial cilia.
  - reference: PMID:25564561
    reference_title: "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IFT88 did not localise to ciliary axonemes and centrioles in mutant CENPF kidneys"
    explanation: Human fetal kidney immunofluorescence supports IFT88 mislocalization.
biochemical: []
environmental: []
treatments:
- name: Symptom-directed supportive care
  description: >-
    Management is supportive and multidisciplinary, directed at the congenital
    gastrointestinal, ocular, neurologic, renal, cardiac, and craniofacial
    manifestations present in an individual child.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Jejunal atresia
    term:
      id: HP:0005235
      label: Jejunal atresia
  - preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  - preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present."
    explanation: The multisystem variable phenotype supports symptom-directed multidisciplinary care.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses autosomal recessive inheritance, carrier
    testing for parents and relatives, recurrence risk, prenatal diagnostic
    options, and genotype-informed counseling for the severe fetal spectrum.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous inheritance was confirmed in both families."
    explanation: Confirmed familial biallelic inheritance supports recurrence-risk counseling.
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet inheritance supports genetic counseling for affected families.
diagnosis:
- name: Clinical whole-exome sequencing
  description: >-
    Exome sequencing or equivalent molecular genetic testing can identify
    biallelic pathogenic CENPF variants in patients or fetuses with the
    Stromme syndrome phenotype.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:26820108
    reference_title: "Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
    explanation: This directly supports exome sequencing as a molecular diagnostic approach.
  - reference: PMID:28407396
    reference_title: "A further family of Stromme syndrome carrying CENPF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome-sequencing of these two cases showed the homozygous mutation (c.5912_5913insA)/(p.T1974Nfs*9) in CENPF."
    explanation: Independent cases support exome sequencing for CENPF variant detection.
- name: Clinical assessment of the congenital triad
  description: >-
    Clinical and prenatal assessment should consider the combination of
    microcephaly, ocular anomalies, and apple-peel intestinal or jejunal
    atresia, with evaluation for renal, cardiac, neurologic, and craniofacial
    involvement.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:28407396
    reference_title: "A further family of Stromme syndrome carrying CENPF mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regarding the clinical features of both affected siblings, a diagnosis of Stromme syndrome was established."
    explanation: The report supports clinical diagnosis based on the recurrent feature pattern.
  - reference: ORPHA:506307
    reference_title: "Stromme syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia."
    explanation: Orphanet provides the key clinical pattern for assessment.
clinical_trials: []
references:
- reference: ORPHA:506307
  title: Stromme syndrome
  findings:
  - statement: >-
      Orphanet provides the structured Stromme syndrome definition,
      inheritance, antenatal onset, prevalence, CENPF gene association, and
      cross-references.
    supporting_text: "CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) in"
- reference: ORPHA:444069
  title: Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
  findings:
  - statement: >-
      Orphanet provides the severe fetal CENPF-associated ciliopathy spectrum.
    supporting_text: "A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by mid-gestation lethality and features of a ciliopathy."
- reference: PMID:26820108
  title: Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF.
  findings:
  - statement: >-
      Family-based exome sequencing identified truncating CENPF variants in
      Stromme syndrome sibling pairs and established autosomal recessive CENPF
      disease.
    supporting_text: "Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
- reference: PMID:28407396
  title: A further family of Stromme syndrome carrying CENPF mutation.
  findings:
  - statement: >-
      An independent affected sibling family carried a homozygous truncating
      frameshift CENPF mutation and showed the classic Stromme syndrome triad.
    supporting_text: "we report a Stromme syndrome family with two affected siblings with a homozygous truncating frameshift mutation in CENPF."
- reference: PMID:18203155
  title: Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature.
  findings:
  - statement: >-
      A pre-CENPF case report supports the classic apple-peel intestinal
      atresia, microcephaly, microphthalmia, anterior chamber anomaly, and
      corneal clouding phenotype.
    supporting_text: "We describe another patient with the combination of apple peel intestinal atresia, microcephaly, microphthalmia, and anterior eye chamber anomalies."
- reference: PMID:25564561
  title: The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.
  findings:
  - statement: >-
      CENPF variants segregated with severe fetal ciliopathy and microcephaly,
      and mechanistic data support CENP-F roles in IFT88 ciliary targeting,
      ciliary function, and cortical neurogenesis.
    supporting_text: "CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes."
notes: >-
  ORPHA:506307 is the primary structured Stromme syndrome record. ORPHA:444069
  is modeled here as a severe fetal CENPF ciliopathy spectrum rather than as a
  separate disorder entry because MONDO:0009477 aggregates both Orphanet
  cross-references under Stromme syndrome.
📚

References & Deep Research

References

6
ORPHA:506307
Stromme syndrome
1 finding
Orphanet provides the structured Stromme syndrome definition, inheritance, antenatal onset, prevalence, CENPF gene association, and cross-references.
"CENPF | centromere protein F | hgnc:1857 | Disease-causing germline mutation(s) in"
ORPHA:444069
Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
1 finding
Orphanet provides the severe fetal CENPF-associated ciliopathy spectrum.
"A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by mid-gestation lethality and features of a ciliopathy."
PMID:26820108
Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF.
1 finding
Family-based exome sequencing identified truncating CENPF variants in Stromme syndrome sibling pairs and established autosomal recessive CENPF disease.
"Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs."
PMID:28407396
A further family of Stromme syndrome carrying CENPF mutation.
1 finding
An independent affected sibling family carried a homozygous truncating frameshift CENPF mutation and showed the classic Stromme syndrome triad.
"we report a Stromme syndrome family with two affected siblings with a homozygous truncating frameshift mutation in CENPF."
PMID:18203155
Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature.
1 finding
A pre-CENPF case report supports the classic apple-peel intestinal atresia, microcephaly, microphthalmia, anterior chamber anomaly, and corneal clouding phenotype.
"We describe another patient with the combination of apple peel intestinal atresia, microcephaly, microphthalmia, and anterior eye chamber anomalies."
PMID:25564561
The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.
1 finding
CENPF variants segregated with severe fetal ciliopathy and microcephaly, and mechanistic data support CENP-F roles in IFT88 ciliary targeting, ciliary function, and cortical neurogenesis.
"CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes."

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Stromme Syndrome Deep Research Fallback ▸

Stromme Syndrome Deep Research Fallback

Scope

This fallback artifact supports curation of Stromme syndrome, represented by MONDO:0009477 and structured Orphanet records ORPHA:506307 and ORPHA:444069.

Structured Sources

  • ORPHA:506307 provides the primary Stromme syndrome definition, synonyms, autosomal recessive inheritance, antenatal onset, ultra-rare worldwide prevalence, CENPF gene association, and MONDO/OMIM cross-references.
  • ORPHA:444069 provides the severe fetal CENPF-associated ciliopathy spectrum with mid-gestation lethality, hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis, duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia, and craniofacial features.

PubMed Sources Used

  • PMID:26820108: CENPF discovery report for classic Stromme syndrome sibling pairs, including autosomal recessive inheritance, whole-exome sequencing, truncating CENPF mutations, and the classic apple-peel intestinal atresia, ocular anomaly, and microcephaly triad.
  • PMID:28407396: independent affected sibling family with homozygous truncating frameshift CENPF mutation and classic clinical features.
  • PMID:18203155: pre-CENPF clinical report supporting the classic phenotype, including apple-peel intestinal atresia, microcephaly, microphthalmia, anterior chamber anomalies, corneal clouding, and visual impairment.
  • PMID:25564561: human fetal, cell, and zebrafish evidence linking CENPF to a severe fetal ciliopathy, IFT88 ciliary targeting, short renal epithelial cilia, ciliary function, and cortical neurogenesis.

Curation Boundaries

  • ORPHA:506307 has no HPO phenotype table in the local structured cache, so phenotype frequencies are intentionally omitted unless supported by an exact quantitative source.
  • ORPHA:444069 is modeled as a severe fetal CENPF-associated subtype/spectrum within MONDO:0009477 rather than as a separate disorder entry.
  • Treatment curation is limited to symptom-directed supportive care and genetic counseling because the cached Stromme-specific sources do not provide direct drug or disease-modifying therapy evidence.

Provider Attempts

  • just research-disorder openai Stromme_Syndrome was started and remained silent after the startup line for about 60 seconds. The process was terminated with signal 15 before producing an OpenAI provider artifact.
  • timeout 60s just research-disorder falcon Stromme_Syndrome was terminated by the timeout (signal 15 / exit 124) before producing a Falcon provider artifact.

The curation was completed from structured Orphanet rows and cached PubMed evidence to avoid blocking on provider availability.