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trigonocephaly 2 - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

trigonocephaly 2

MONDO:0013774

Also known as:FREM1 isolated trigonocephalyisolated trigonocephaly caused by mutation in FREM1trigonocephaly type 2

Overview

Any isolated trigonocephaly in which the cause of the disease is a mutation in the FREM1 gene.

GeneticsAutosomal dominant · FREM1 (chr 9)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Trigonocephaly; and common findings: Microcephaly, Downslanted palpebral fissures, Wide nasal bridge, and Global developmental delay and others. 8 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	2	Global developmental delay, Depressed nasal bridge

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

FREM1 encodes FRAS1 related extracellular matrix 1 (2,179 aa). Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development Highest expression in Uterus (12.8 TPM) and Brain Cerebellar Hemisphere (11.8 TPM).

Trigonocephaly 2 is associated with mutations in the FREM1 gene on chromosome 9.

FREM1 is classified as a druggable target (Druggable Genome category) with score 0.0.

GeneReviews

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

No consensus clinical diagnostic criteria for FREM1 autosomal recessive disorders have been published.

Suggestive Findings

A FREM1 autosomal recessive disorder should be suspected in an individual with clinical findings and/or family history of Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR) syndrome, or congenital anomalies of kidney and urinary tract (CAKUT).

MOTA syndrome

Source: GeneReviews — "FREM1 Autosomal Recessive Disorders"

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for trigonocephaly 2. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for FREM1 autosomal recessive disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a FREM1 autosomal recessive disorder, the evaluations summarized in , , or (depending on the phenotype), if not performed as part of the evaluation that led to the diagnosis, are recommended.

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 7.

FREM1 Autosomal Recessive Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Kidney malformations

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for trigonocephaly 2.

243 publications have been identified in PubMed for trigonocephaly 2. Research spans Clinical Trial Publication (28%), Epidemiology / Natural History (21%), and Review / Meta-Analysis (18%).

Research Type	Count	% of Total
Clinical study results	68	28%

Data assembled from 6 of 12 sources · Last updated Sep 18, 2026, 7:12 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:614485

GARD

Genetic and Rare Diseases Info Center

GARD:18559

Questions for Your Care Team

→Should I pursue genetic testing for FREM1, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

Differential Diagnosis

Disorders of known genetic cause in the differential diagnosis of Manitoba oculotrichoanal (MOTA) syndrome and bifid nose with or without anorectal and renal anomalies (BNAR) syndrome are listed in . Table 2. Genes of Interest in the Differential Diagnosis of MOTA Syndrome and BNAR Syndrome

Gene(s)	Disorder	MOI	Features of Disorder
ALX4	Frontonasal dysplasia (OMIM PS136760)	AR	Widely spaced eyes; Broad forehead; Widow's peak; Broad nasal root; absence of nasal tip formation; unilateral/bilateral cleft ala nasi1
EFNB1	Craniofrontonasal dysplasia (OMIM 304110)	XL	In females:3; Widely spaced eyes; Broad nasal bridge, bifid nasal tip
GRIP1	Fraser syndrome (OMIM PS219000)	AR	Anophthalmia/microphthalmia, cryptophthalmos, eyelid colobomas, widely spaced eyes; Wedge-shaped lateral anterior hairline; Bifid nasal tip/ notched ala nasi; Anal stenosis or imperforate anus4
Donnai-Barrow syndrome	AR	Widely spaced eyes; Omphalocele	Agenesis of corpus callosum; Sensorineural hearing loss; Diaphragmatic hernia
MED12	FG syndrome type 1 (See MED12-Related Disorders.)	XL	In male infants:; Widely spaced eyes; Anteriorly placed anus, anal stenosis
SALL1-related Townes-Brocks syndrome	AD	Anteriorly placed anus, imperforate anus, anal stenosis AD = autosomal dominant; AR = autosomal recessive; BNAR = bifid nose with or without anorectal and renal anomalies; MOI = mode of inheritance; MOTA = Manitoba oculotrichoanal; XL = X-linked 1. 2.	—

Source: GeneReviews — "FREM1 Autosomal Recessive Disorders"

Kisho

trigonocephaly 2

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Kidney malformations

Research Landscape

Medical References

External Resources

OMIM

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Manitoba Oculotrichoanal (MOTA) Syndrome

Explore clinical features

Clinical Guidance

Differential Diagnosis

Ocular

Gastrointestinal

Kidneys

Genetic counseling

Therapies Under Investigation

Clinical Trials

Family/Community

Recent Publications

trigonocephaly 2

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Kidney malformations

Research Landscape

Medical References

External Resources

OMIM

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Manitoba Oculotrichoanal (MOTA) Syndrome

Explore clinical features

Clinical Guidance

Differential Diagnosis

Ocular

Gastrointestinal

Kidneys

Genetic counseling

Therapies Under Investigation

Clinical Trials

Family/Community

Recent Publications