Frias syndrome is a rare 14q22-q23 contiguous-gene deletion syndrome. The core presentation centers on congenital eye, pituitary, and hand/foot anomalies, with variable facial, neurodevelopmental, cranial, and digestive involvement. Current evidence supports dosage loss of developmental regulators in the interval, especially BMP4, OTX2, and neighboring SIX-family genes, rather than a single uniform sequence-variant mechanism.
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name: Frias syndrome
creation_date: "2026-05-10T16:46:45Z"
updated_date: "2026-05-10T17:51:39Z"
category: Mendelian
synonyms:
- 14q22-q23 microdeletion syndrome
- 14q22q23 microdeletion syndrome
- 14q22-q23 contiguous gene deletion syndrome
- Del(14)(q22q23)
- monosomy 14q22-q23
description: >-
Frias syndrome is a rare 14q22-q23 contiguous-gene deletion syndrome. The
core presentation centers on congenital eye, pituitary, and hand/foot
anomalies, with variable facial, neurodevelopmental, cranial, and digestive
involvement. Current evidence supports dosage loss of developmental
regulators in the interval, especially BMP4, OTX2, and neighboring SIX-family
genes, rather than a single uniform sequence-variant mechanism.
disease_term:
preferred_term: Frias syndrome
term:
id: MONDO:0012324
label: Frias syndrome
parents:
- hereditary disease
- chromosomal disorder
inheritance:
- name: Familial autosomal dominant transmission
description: >-
Familial transmission has been reported for a 14q22.1-q22.3 deletion shared
by an affected mother and two daughters, consistent with autosomal dominant
transmission of the deletion in that pedigree.
inheritance_term:
preferred_term: autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:24311462
reference_title: Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We performed array-CGH, which identified an identical interstitial deletion
of chromosome 14q22.1-q22.3 in the mother and two daughters.
explanation: >-
This directly supports familial transmission of the same 14q22 deletion
across an affected mother and daughters.
- name: De novo occurrence
description: >-
De novo 14q22q23 microdeletions also occur, so recurrence counseling depends
on parental testing and family history.
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To the best of our knowledge, this is the earliest detection of this
microdeletion (occurred de novo), the first case detected by MLPA and
confirmed by microarray.
explanation: >-
This prenatal case report explicitly documents a de novo 14q22q23
microdeletion confirmed by molecular testing.
pathophysiology:
- name: 14q22-q23 contiguous gene deletion
description: >-
The initiating lesion is a heterozygous interstitial deletion of the
14q22-q23 region. Variable deletion breakpoints alter gene content, which
explains why ocular, endocrine, craniofacial, limb, and neurodevelopmental
manifestations vary across individuals.
genes:
- preferred_term: BMP4
modifier: DECREASED
term:
id: hgnc:1071
label: BMP4
- preferred_term: OTX2
modifier: DECREASED
term:
id: hgnc:8522
label: OTX2
- preferred_term: SIX1
modifier: DECREASED
term:
id: hgnc:10887
label: SIX1
- preferred_term: SIX4
modifier: DECREASED
term:
id: hgnc:10890
label: SIX4
- preferred_term: SIX6
modifier: DECREASED
term:
id: hgnc:10892
label: SIX6
downstream:
- target: BMP4 haploinsufficiency and BMP developmental signaling disruption
causal_link_type: DIRECT
- target: OTX2 and SIX-region ocular-pituitary developmental disruption
causal_link_type: DIRECT
evidence:
- reference: PMID:34408948
reference_title: Anophthalmia, Global Developmental Delay, and Severe Dysphagia in a Young Girl With 14q22q23 Microdeletion Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
14q22q23 microdeletion syndrome, also called Frias syndrome, is an
extremely rare partial deletion of the long arm of chromosome 14
characterized by the anomalies of the pituitary gland, eyes, and
hand/foot.
explanation: >-
This defines Frias syndrome as a partial 14q deletion with the core organ
systems represented in this pathophysiology graph.
- reference: PMID:34408948
reference_title: Anophthalmia, Global Developmental Delay, and Severe Dysphagia in a Young Girl With 14q22q23 Microdeletion Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This case report presents the case of a young child with a deletion in
14q22.2q23.1 region containing both BMP4 and OTX2 genes as well as
sineoculis homeobox homolog 1 (SIX1) and sineoculis homeobox homolog 6
(SIX6) genes.
explanation: >-
This directly supports inclusion of BMP4, OTX2, SIX1, and SIX6 as
recurrent genes within the deleted interval.
- name: BMP4 haploinsufficiency and BMP developmental signaling disruption
description: >-
BMP4 dosage loss disrupts BMP/TGF-beta developmental signaling. This
affects embryonic morphogenesis, eye development, skeletal development, and
limb/digit patterning, contributing to ocular, craniofacial, and hand/foot
findings.
genes:
- preferred_term: BMP4
modifier: DECREASED
term:
id: hgnc:1071
label: BMP4
biological_processes:
- preferred_term: embryonic morphogenesis
modifier: ABNORMAL
term:
id: GO:0048598
label: embryonic morphogenesis
- preferred_term: eye development
modifier: ABNORMAL
term:
id: GO:0001654
label: eye development
- preferred_term: embryonic limb morphogenesis
modifier: ABNORMAL
term:
id: GO:0030326
label: embryonic limb morphogenesis
downstream:
- target: Microphthalmia
- target: Anophthalmia
- target: Polydactyly
- target: Syndactyly
- target: Micrognathia
evidence:
- reference: PMID:24311462
reference_title: Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This gene family plays an important role during early embryogenesis, and
the complex synergistic functions and redundancies of the BMPs led us to
conclude that haploinsufficiency of BMP4 is likely to be responsible for
the clinical expression of Frías syndrome.
explanation: >-
This directly supports BMP4 haploinsufficiency as a causal mechanism for
the syndrome.
- reference: PMID:31053785
reference_title: "Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: A review of the literature and description of three new cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BMP4 has a number of roles in embryonic development including
neurogenesis, lens induction, development of cartilage and bone,
urogenital development, limb and digit patterning, hair follicle
regeneration, as well as tooth formation.
explanation: >-
This supports the developmental-process annotations and links BMP4 dosage
loss to eye, limb, skeletal, and other congenital findings.
- name: OTX2 and SIX-region ocular-pituitary developmental disruption
description: >-
Dosage loss of OTX2 and neighboring SIX-family genes disrupts ocular,
pituitary, hypothalamic, facial-bone, and brain developmental programs.
genes:
- preferred_term: OTX2
modifier: DECREASED
term:
id: hgnc:8522
label: OTX2
- preferred_term: SIX1
modifier: DECREASED
term:
id: hgnc:10887
label: SIX1
- preferred_term: SIX4
modifier: DECREASED
term:
id: hgnc:10890
label: SIX4
- preferred_term: SIX6
modifier: DECREASED
term:
id: hgnc:10892
label: SIX6
biological_processes:
- preferred_term: eye development
modifier: ABNORMAL
term:
id: GO:0001654
label: eye development
- preferred_term: pituitary gland development
modifier: ABNORMAL
term:
id: GO:0021983
label: pituitary gland development
- preferred_term: regulation of transcription by RNA polymerase II
modifier: DECREASED
term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
downstream:
- target: Pituitary gland hypoplasia
- target: Corpus callosum hypoplasia
- target: Cerebellar vermis hypoplasia
- target: Abnormal cerebral white matter morphology
- target: Short stature
- target: Intellectual disability
evidence:
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The 6.5 Mb deletion contains 27 genes, including three genes of the SIX
family: SIX1, SIX4, and SIX6.
explanation: >-
This supports loss of SIX-family genes in a 14q22.3-q23.2 deletion case.
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In mammals, Six1 has been shown to be involved in ocular differentiation,
whereas Six4 and Six6 are primarily expressed in the hypothalamus,
pituitary gland, and facial bones.
explanation: >-
This mouse-expression and comparative-development evidence supports the
ocular, pituitary, hypothalamic, and craniofacial mechanism assigned to
SIX-region dosage loss.
- reference: PMID:30268123
reference_title: "New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this report, we describe a case of large microdeletion encompassing
OTX2 but not BMP4 presenting with a syndromic anophthalmia with corpus
callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia.
explanation: >-
This supports OTX2-region deletion as sufficient for major ocular,
pituitary, corpus-callosum, and cerebellar-vermis phenotypes.
phenotypes:
- name: Microphthalmia
category: Ophthalmologic
diagnostic: true
description: >-
Microphthalmia is a defining congenital ocular manifestation in the
14q22q23 deletion spectrum.
phenotype_term:
preferred_term: Microphthalmia
term:
id: HP:0000568
label: Microphthalmia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interstitial microdeletion 14q22q23 is a rare chromosomal syndrome
associated with variable defects: microphthalmia/anophthalmia, pituitary
anomalies, polydactyly/syndactyly of hands and feet,
micrognathia/retrognathia.
explanation: >-
This directly lists microphthalmia/anophthalmia among the variable defects
of 14q22q23 microdeletion syndrome.
- name: Anophthalmia
category: Ophthalmologic
diagnostic: true
description: >-
Anophthalmia represents the severe end of the congenital ocular
malformation spectrum in Frias syndrome.
phenotype_term:
preferred_term: Anophthalmia
term:
id: HP:0000528
label: Anophthalmia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:23103883
reference_title: "Concurrent deletion of BMP4 and OTX2 genes, two master genes in ophthalmogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations of BMP4 and OTX2 often lead to eye defects, including
anophthalmia-microphthalmia.
explanation: >-
This supports severe ocular malformations when BMP4 and OTX2 are deleted
or mutated.
- name: Proptosis
category: Ophthalmologic
description: >-
Mild exophthalmia or prominent eyes can occur in familial BMP4-region
deletion cases.
phenotype_term:
preferred_term: Proptosis
term:
id: HP:0000520
label: Proptosis
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:24311462
reference_title: Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral
fissures, and hypertelorism.
explanation: >-
Exophthalmia is a synonym of proptosis and is reported in affected family
members with a 14q22.1-q22.3 deletion.
- name: Ptosis
category: Ophthalmologic
description: >-
Bilateral palpebral ptosis is part of the ocular/facial presentation.
phenotype_term:
preferred_term: Ptosis
term:
id: HP:0000508
label: Ptosis
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:24311462
reference_title: Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral
fissures, and hypertelorism.
explanation: This directly supports palpebral ptosis in the familial deletion phenotype.
- name: Downslanted palpebral fissures
category: Ophthalmologic
description: >-
Downslanting palpebral fissures are reported with the ocular and
craniofacial features in familial 14q22.1-q22.3 deletion cases.
phenotype_term:
preferred_term: Downslanted palpebral fissures
term:
id: HP:0000494
label: Downslanted palpebral fissures
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:24311462
reference_title: Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral
fissures, and hypertelorism.
explanation: >-
This directly supports downslanting palpebral fissures in affected family
members with a 14q22.1-q22.3 deletion.
- name: Hypertelorism
category: Craniofacial
description: >-
Hypertelorism is a recurring craniofacial feature in familial Frías
syndrome.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:24311462
reference_title: Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral
fissures, and hypertelorism.
explanation: This directly supports hypertelorism in affected family members.
- name: Abnormal facial shape
category: Craniofacial
description: >-
Facial dysmorphism is a common manifestation of the syndrome and can include
an abnormal facial profile.
phenotype_term:
preferred_term: facial dysmorphism
term:
id: HP:0001999
label: Abnormal facial shape
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:34408948
reference_title: Anophthalmia, Global Developmental Delay, and Severe Dysphagia in a Young Girl With 14q22q23 Microdeletion Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Intellectual disability and facial dysmorphism are other common
manifestations.
explanation: This directly supports facial dysmorphism as a common feature.
- name: Micrognathia
category: Craniofacial
description: >-
Micrognathia or retrognathia can be detected prenatally and is part of the
orofacial phenotype.
phenotype_term:
preferred_term: Micrognathia
term:
id: HP:0000347
label: Micrognathia
onset:
onset_category: ANTENATAL
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interstitial microdeletion 14q22q23 is a rare chromosomal syndrome
associated with variable defects: microphthalmia/anophthalmia, pituitary
anomalies, polydactyly/syndactyly of hands and feet,
micrognathia/retrognathia.
explanation: This directly supports micrognathia/retrognathia in the phenotype spectrum.
- name: Pituitary gland hypoplasia
category: Endocrine
diagnostic: true
description: >-
Pituitary hypoplasia is a core endocrine manifestation of the deletion
syndrome. The local HPO cache does not expose a separate general
"pituitary gland hypoplasia" term, so this entry uses anterior pituitary
hypoplasia as the closest phenotype-level HPO mapping.
phenotype_term:
preferred_term: Anterior pituitary hypoplasia
term:
id: HP:0010627
label: Anterior pituitary hypoplasia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:30268123
reference_title: "New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this report, we describe a case of large microdeletion encompassing
OTX2 but not BMP4 presenting with a syndromic anophthalmia with corpus
callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia.
explanation: >-
This directly supports pituitary gland hypoplasia in an OTX2-region
deletion; HP:0010627 is used as the closest available HPO term after a
targeted OAK lookup did not identify a general pituitary-gland
hypoplasia class.
- name: Short stature
category: Growth
description: >-
Short stature is part of the extra-ocular phenotype associated with OTX2
disruption.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:30268123
reference_title: "New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations occurring in the orthodenticle homeobox 2 gene (OTX2) are
responsible for a rare genetic syndrome, characterized mainly by
microphthalmia/anophthalmia associated with extra-ocular defects such as
brain malformations, pituitary abnormalities, short stature and
intellectual disability.
explanation: This directly supports short stature among OTX2-region deletion features.
- name: Polydactyly
category: Skeletal
description: >-
Supernumerary digits may occur as part of the hand/foot anomaly spectrum.
phenotype_term:
preferred_term: Polydactyly
term:
id: HP:0010442
label: Polydactyly
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interstitial microdeletion 14q22q23 is a rare chromosomal syndrome
associated with variable defects: microphthalmia/anophthalmia, pituitary
anomalies, polydactyly/syndactyly of hands and feet,
micrognathia/retrognathia.
explanation: This directly supports polydactyly in the hand/foot phenotype.
- name: Syndactyly
category: Skeletal
description: >-
Webbing or fusion of digits can accompany polydactyly in the hand/foot
anomaly spectrum.
phenotype_term:
preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interstitial microdeletion 14q22q23 is a rare chromosomal syndrome
associated with variable defects: microphthalmia/anophthalmia, pituitary
anomalies, polydactyly/syndactyly of hands and feet,
micrognathia/retrognathia.
explanation: This directly supports syndactyly in the hand/foot phenotype.
- name: Global developmental delay
category: Neurodevelopmental
description: >-
Developmental delay is variable and can be moderate to severe depending on
deletion content and multisystem involvement.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we present a 12-year-old girl with dysmorphic face, choanal atresia,
gastroesophageal reflux, and moderate developmental delay, in whom an
interstitial deletion 14q22.3-q23.2 was detected using a 180k array
comparative genome hybridization.
explanation: This directly supports developmental delay in a 14q22.3-q23.2 deletion case.
- name: Intellectual disability
category: Neurodevelopmental
description: >-
Intellectual disability is a common neurodevelopmental manifestation.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:34408948
reference_title: Anophthalmia, Global Developmental Delay, and Severe Dysphagia in a Young Girl With 14q22q23 Microdeletion Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Intellectual disability and facial dysmorphism are other common
manifestations.
explanation: This directly supports intellectual disability as a common feature.
- name: Corpus callosum hypoplasia
category: Neurologic
description: >-
Corpus callosum hypoplasia can occur in OTX2-region 14q22q23 deletions.
phenotype_term:
preferred_term: Corpus callosum hypoplasia
term:
id: HP:0002079
label: Hypoplasia of the corpus callosum
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:30268123
reference_title: "New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this report, we describe a case of large microdeletion encompassing
OTX2 but not BMP4 presenting with a syndromic anophthalmia with corpus
callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia.
explanation: This directly supports corpus callosum hypoplasia.
- name: Cerebellar vermis hypoplasia
category: Neurologic
description: >-
Vermian hypoplasia broadens the brain-malformation spectrum of OTX2-region
deletions.
phenotype_term:
preferred_term: Cerebellar vermis hypoplasia
term:
id: HP:0001320
label: Cerebellar vermis hypoplasia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:30268123
reference_title: "New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this report, we describe a case of large microdeletion encompassing
OTX2 but not BMP4 presenting with a syndromic anophthalmia with corpus
callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia.
explanation: This directly supports cerebellar vermis hypoplasia.
- name: Abnormal cerebral white matter morphology
category: Neurologic
description: >-
Decreased cerebral white matter volume has been reported in a substantial
fraction of reviewed 14q22 microdeletion cases.
phenotype_term:
preferred_term: Abnormal cerebral white matter morphology
term:
id: HP:0002500
label: Abnormal cerebral white matter morphology
evidence:
- reference: PMID:23103883
reference_title: "Concurrent deletion of BMP4 and OTX2 genes, two master genes in ophthalmogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A review of twelve previously reported patients with 14q22 microdeletion
revealed decreased white matter volume in half of the patients.
explanation: >-
This supports cerebral white matter morphology abnormality in the 14q22
microdeletion spectrum.
- name: Choanal atresia
category: Craniofacial
description: >-
Choanal atresia is a reported craniofacial/airway malformation in a
14q22.3-q23.2 deletion case.
phenotype_term:
preferred_term: Choanal atresia
term:
id: HP:0000453
label: Choanal atresia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we present a 12-year-old girl with dysmorphic face, choanal atresia,
gastroesophageal reflux, and moderate developmental delay, in whom an
interstitial deletion 14q22.3-q23.2 was detected using a 180k array
comparative genome hybridization.
explanation: This directly supports choanal atresia in a molecularly defined case.
- name: Gastroesophageal reflux
category: Gastrointestinal
description: >-
Gastroesophageal reflux has been reported in a child with a 14q22.3-q23.2
deletion.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we present a 12-year-old girl with dysmorphic face, choanal atresia,
gastroesophageal reflux, and moderate developmental delay, in whom an
interstitial deletion 14q22.3-q23.2 was detected using a 180k array
comparative genome hybridization.
explanation: This directly supports gastroesophageal reflux in a molecularly defined case.
genetic:
- name: Chromosome 14q22-q23 microdeletion
association: Causal chromosomal deletion
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report a detection of the microdeletion 14q22.1q23.1 spanning 7,7 Mb
and involving the genes BMP4 and OTX2 in the foetus by multiplex
ligation-dependent probe amplification (MLPA) and verified by microarray
subsequently.
explanation: >-
This supports a causal 14q22q23 copy-number deletion involving BMP4 and
OTX2 and detected by CNV methods.
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The 6.5 Mb deletion contains 27 genes, including three genes of the SIX
family: SIX1, SIX4, and SIX6.
explanation: This supports SIX1/SIX4/SIX6 inclusion in some pathogenic 14q22-q23 deletions.
diagnosis:
- name: Chromosomal microarray or array-CGH
description: >-
Chromosomal microarray, array-CGH, or related CNV testing is used to detect
the 14q22-q23 deletion and define the deleted gene content.
diagnosis_term:
preferred_term: chromosomal microarray testing
term:
id: MAXO:0001612
label: chromosomal microarray testing
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Usage of quick and sensitive methods (MLPA, microarray) is preferable for
discovering a causal aberration because some of the CNVs cannot be
detected with conventional karyotyping in these cases.
explanation: >-
This directly supports molecular CNV testing over conventional karyotype
for detecting causal 14q22q23 microdeletions.
treatments:
- name: Genetic counseling
description: >-
Genetic counseling is important because both de novo and familial deletions
have been reported, and prenatal detection is possible when fetal anomalies
raise suspicion.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:29299063
reference_title: Haploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patients should be provided with genetic counselling.
explanation: >-
This directly supports genetic counseling in the context of suspected or
confirmed prenatal 14q22q23 microdeletion.
- name: Multidisciplinary supportive care
description: >-
Supportive care is phenotype-directed across the multisystem presentation,
including ophthalmologic, endocrine, neurodevelopmental, craniofacial,
hand/foot, gastrointestinal, and airway manifestations when present.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
target_phenotypes:
- preferred_term: Anophthalmia
term:
id: HP:0000528
label: Anophthalmia
- preferred_term: Anterior pituitary hypoplasia
term:
id: HP:0010627
label: Anterior pituitary hypoplasia
- preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
- preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
- preferred_term: Choanal atresia
term:
id: HP:0000453
label: Choanal atresia
evidence:
- reference: PMID:34408948
reference_title: Anophthalmia, Global Developmental Delay, and Severe Dysphagia in a Young Girl With 14q22q23 Microdeletion Syndrome.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
14q22q23 microdeletion syndrome, also called Frias syndrome, is an
extremely rare partial deletion of the long arm of chromosome 14
characterized by the anomalies of the pituitary gland, eyes, and
hand/foot.
explanation: >-
This supports the multisystem congenital presentation that requires
phenotype-directed supportive care; the abstract does not describe a
syndrome-specific curative treatment.
- reference: PMID:24357464
reference_title: "Interstitial deletion 14q22.3-q23.2: genotype-phenotype correlation."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we present a 12-year-old girl with dysmorphic face, choanal atresia,
gastroesophageal reflux, and moderate developmental delay, in whom an
interstitial deletion 14q22.3-q23.2 was detected using a 180k array
comparative genome hybridization.
explanation: >-
This case report documents craniofacial, airway, gastrointestinal, and
neurodevelopmental manifestations that support symptom-directed
supportive care.
datasets:
Frias syndrome (14q22q23 microdeletion syndrome) is an extremely rare contiguous deletion of chromosome 14q characterized by a core triad of pituitary, eye, and hand/foot anomalies, frequently accompanied by intellectual disability and facial dysmorphism. (kera2021anophthalmiaglobaldevelopmental pages 1-2)
Direct abstract quote (definition): “14q22q23 microdeletion syndrome, also called Frias syndrome, is an extremely rare partial deletion of the long arm of chromosome 14 characterized by the anomalies of the pituitary gland, eyes, and hand/foot. Intellectual disability and facial dysmorphism are other common manifestations.” (Kera et al., Cureus, published 2021-07-14; https://doi.org/10.7759/cureus.16395) (kera2021anophthalmiaglobaldevelopmental pages 1-2)
Knowledge is derived primarily from: - Human case reports and small case series with chromosomal microarray-defined deletions (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 1-2) - Letters/reviews summarizing compiled cases of syndromic microphthalmia/anophthalmia due to OTX2-region deletions (apamgarduno2019therelevanceof pages 1-4)
Primary cause: Heterozygous interstitial microdeletions in chromosome 14q22–q23 that remove one copy (haploinsufficiency) of developmental regulators. (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
Key genes implicated (recurrently deleted): - BMP4 and OTX2 are repeatedly highlighted as major drivers of the phenotype in 14q22q23 deletions. (kera2021anophthalmiaglobaldevelopmental pages 1-2) - SIX1 and SIX6 may be included depending on breakpoints and are discussed as contributors to pituitary/optic nerve/craniofacial phenotypes. (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
Direct abstract quote (genetic interpretation): “Haploinsufficiency of the genes bone morphogenetic protein 4 (BMP4) and orthodenticle homeobox 2 (OTX2) accounts for most of the phenotypic abnormalities seen in these patients.” (Kera et al., Cureus, 2021-07-14; https://doi.org/10.7759/cureus.16395) (kera2021anophthalmiaglobaldevelopmental pages 1-2)
For a contiguous-gene microdeletion syndrome, “risk factors” are primarily genetic: - De novo CNVs: documented in at least one reported case where “both parents had normal karyotypes,” consistent with a de novo event. (apamgarduno2019therelevanceof pages 1-4) - Familial transmission: also documented—one report described a mother and two affected daughters sharing the same 14q22.1–q22.3 deletion. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2)
Environmental risk factors, protective factors, and gene–environment interactions specific to Frias syndrome were not identified in the retrieved evidence.
A structured phenotype-to-HPO mapping derived from retrieved clinical reports is provided in the artifact below.
| Phenotype domain | Core phenotype(s) reported in Frias syndrome / 14q22q23 microdeletion | Suggested HPO term(s) | Onset / severity / variability notes | Key supporting evidence |
|---|---|---|---|---|
| Ocular | Anophthalmia, microphthalmia, mild exophthalmia, ptosis, hypertelorism, absent/rudimentary optic nerves, optic chiasm abnormalities, corneal opacity, need for glasses in some cases | HP:0000528 Anophthalmia; HP:0000568 Microphthalmia; HP:0000613 Photophobia not supported; HP:0000532 Abnormality of eye morphology; HP:0000653 Optic nerve hypoplasia; HP:0000508 Ptosis; HP:0000316 Hypertelorism; HP:0000603 Corneal opacity; HP:0000622 Exophthalmos | Typically congenital/neonatal; often severe and among the most recognizable features, but variable expressivity is substantial, including milder ocular findings in some familial BMP4 deletions (kera2021anophthalmiaglobaldevelopmental pages 1-2, apamgarduno2019therelevanceof pages 1-4, kera2021anophthalmiaglobaldevelopmental pages 4-7, blackburn2019variableexpressivityof pages 2-3, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2) | Kera 2021; Apam-Garduño 2019; Blackburn 2019; Martínez-Fernández 2014 (kera2021anophthalmiaglobaldevelopmental pages 1-2, apamgarduno2019therelevanceof pages 1-4, blackburn2019variableexpressivityof pages 2-3, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2) |
| Pituitary / endocrine | Pituitary hypoplasia/aplasia, high-riding posterior pituitary, possible hypopituitarism and growth hormone deficiency, growth retardation/short stature | HP:0000822 Pituitary hypoplasia; HP:0003070 Growth hormone deficiency; HP:0001508 Failure to thrive; HP:0004322 Short stature; HP:0001510 Growth delay | Congenital structural abnormality with variable endocrine expression; some patients have GH deficiency/growth retardation, while others have normal hormone studies and no pituitary dysfunction despite similar regional deletions (kera2021anophthalmiaglobaldevelopmental pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 2-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7) | Kera 2021; Martínez-Frías 2014; Apam-Garduño 2019 (kera2021anophthalmiaglobaldevelopmental pages 2-4, kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| Limb / digits | Short square hands, short digits, broad halluces, proximal syndactyly, postaxial or preaxial polydactyly, pes cavus, progressive distal phalangeal hypoplasia | HP:0009381 Short hand; HP:0001169 Syndactyly; HP:0010442 Postaxial polydactyly; HP:0100259 Preaxial polydactyly; HP:0001761 Pes cavus; HP:0009882 Short distal phalanx | Usually congenital; severity ranges from subtle hand/foot changes to frank poly/syndactyly; hallmark in many reports but absent in at least one recent case, showing reduced penetrance/variable expressivity (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, apamgarduno2019therelevanceof pages 4-5, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7) | Martínez-Fernández 2014; Kera 2021; Apam-Garduño 2019; Martínez-Frías 2014 (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, apamgarduno2019therelevanceof pages 4-5, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7) |
| Neurodevelopment / CNS | Global developmental delay, psychomotor delay, moderate intellectual disability, speech delay/dysarthria/logoclonia, seizures, corpus callosum hypoplasia, ventriculomegaly, polymicrogyria, deep gray matter and white matter abnormalities | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0001270 Motor delay; HP:0001250 Seizure; HP:0002079 Corpus callosum abnormality; HP:0002119 Ventriculomegaly; HP:0012650 Polymicrogyria; HP:0002500 Abnormal cerebral white matter morphology | Congenital structural CNS findings may become clearer over infancy/childhood; neurodevelopmental impairment is common but severity varies from mild psychomotor delay to severe global delay with seizures (martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, apamgarduno2019therelevanceof pages 1-4, kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7) | Kera 2021; Apam-Garduño 2019; Martínez-Fernández 2014; Martínez-Frías 2014 (apamgarduno2019therelevanceof pages 1-4, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7) |
| Hearing | Mild right hearing loss, bilateral sensorineural hearing loss reported in OTX2-region deletions; hearing may also be normal in some patients | HP:0000365 Hearing impairment; HP:0000407 Sensorineural hearing impairment | Variable; not universal. Reported in some familial/de novo cases and literature summaries, but normal hearing documented in at least one patient with 14q22.3-q23.2 deletion (kera2021anophthalmiaglobaldevelopmental pages 1-2, apamgarduno2019therelevanceof pages 1-4, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) | Apam-Garduño 2019; Kera 2021; Martínez-Fernández 2014; Martínez-Frías 2014 (apamgarduno2019therelevanceof pages 1-4, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| Feeding / airway | Oropharyngeal dysphagia, aspiration, severe protein-calorie malnutrition, increased secretions, tracheomalacia, tracheostomy requirement, gastroesophageal reflux, bilateral choanal atresia | HP:0002015 Dysphagia; HP:0002093 Respiratory insufficiency not directly established; HP:0002020 Gastroesophageal reflux; HP:0000453 Choanal atresia; HP:0002205 Tracheomalacia; HP:0004395 Malnutrition | Can present neonatally or in early childhood; severity may be high in complex cases, requiring feeding tubes and airway support. Reflux/aspiration and choanal atresia broaden the respiratory/feeding phenotype beyond classic ocular-limb findings (kera2021anophthalmiaglobaldevelopmental pages 4-7, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) | Kera 2021; Martínez-Frías 2014 (kera2021anophthalmiaglobaldevelopmental pages 4-7, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| Cardiac | Atrial septal defect, ventricular septal defect; cardiac malformations noted in literature summaries of OTX2-region deletions | HP:0001631 Atrial septal defect; HP:0001629 Ventricular septal defect; HP:0001627 Abnormal heart morphology | Reported as variable/less frequent than ocular-pituitary findings; present in some cases and reviews but not clearly universal across the syndrome (apamgarduno2019therelevanceof pages 1-4, kera2021anophthalmiaglobaldevelopmental pages 4-7) | Apam-Garduño 2019; Kera 2021 (apamgarduno2019therelevanceof pages 1-4, kera2021anophthalmiaglobaldevelopmental pages 4-7) |
| Renal / genitourinary | Congenital genitourinary malformations; renal anomalies noted in some 14q21-q23 deletion reports | HP:0000078 Abnormality of the genitourinary system; HP:0000119 Abnormal renal morphology | Reported variably in literature summaries; current retrieved evidence does not define a single dominant renal phenotype or frequency (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, apamgarduno2019therelevanceof pages 1-4) | Kera 2021; Martínez-Frías 2014; Apam-Garduño 2019 (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, apamgarduno2019therelevanceof pages 1-4) |
| Craniofacial | Facial dysmorphism, depressed nasal bridge, small nostrils, abnormal auricles/ear anomalies, downslanting palpebral fissures, bilateral ptosis, hypertelorism, choanal atresia | HP:0001999 Facial dysmorphism; HP:0000431 Broad nasal bridge / HP:0005280 Depressed nasal bridge; HP:0000582 Downslanted palpebral fissures; HP:0000508 Ptosis; HP:0000316 Hypertelorism; HP:0000377 Abnormal pinna morphology; HP:0000453 Choanal atresia | Congenital and common; often recognizable at birth. Facial phenotype ranges from relatively mild familial presentations to complex dysmorphism with airway involvement (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2) | Martínez-Fernández 2014; Martínez-Frías 2014; Kera 2021 (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
Table: This table summarizes core clinical features reported for Frias syndrome (14q22q23 microdeletion syndrome), with suggested HPO terms and brief notes on onset, variability, and supporting evidence. It is useful for structured phenotype curation in a disease knowledge base.
Pituitary/endocrine: pituitary hypoplasia/aplasia and endocrine dysfunction (often GH axis) are a commonly described part of the syndrome spectrum, but may be absent in some patients even with overlapping deletions. (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
Ocular/visual pathway: anophthalmia/microphthalmia and optic nerve/chiasm abnormalities are prominent and typically congenital. (kera2021anophthalmiaglobaldevelopmental pages 1-2, apamgarduno2019therelevanceof pages 1-4)
Limb/digits: syndactyly/polydactyly/short digits are common in many cases, but can be absent (illustrating variable expressivity). (kera2021anophthalmiaglobaldevelopmental pages 4-7)
Neurodevelopment: global developmental delay and intellectual disability are frequently reported; seizures and brain malformations can occur. (martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, apamgarduno2019therelevanceof pages 1-4)
Feeding/airway (expanded phenotype): severe dysphagia, tracheomalacia, feeding-tube dependence, and tracheostomy were reported in a child with 14q22q23 deletion, highlighting that morbidity can be multisystem and substantial in individual cases. (kera2021anophthalmiaglobaldevelopmental pages 2-4, kera2021anophthalmiaglobaldevelopmental pages 4-7)
Frias syndrome is best conceptualized as a contiguous-gene deletion syndrome, where the causal unit is the 14q22q23 deletion rather than a single-gene variant, although haploinsufficiency of BMP4 has been proposed as a major driver of the classic “Frías syndrome” phenotype in some families. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2)
Evidence of implicated genes: - Case with 14q22.2q23.1 deletion containing BMP4, OTX2, SIX1, SIX6. (kera2021anophthalmiaglobaldevelopmental pages 1-2) - 6.5 Mb 14q22.3-q23.2 deletion including SIX1, SIX4, SIX6. (martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) - Familial 4.06 Mb 14q22.1–q22.3 deletion including BMP4. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2)
A structured summary is provided below.
| Entity | Also called | Genetic lesion type | Key genes commonly deleted | Key papers (year, journal) | Notes on inheritance (de novo vs familial) with evidence IDs |
|---|---|---|---|---|---|
| Frias syndrome | 14q22q23 microdeletion syndrome; 14q22–q23 contiguous gene deletion syndrome | Interstitial heterozygous microdeletion of chromosome 14q22.1–q23.2/14q22.2–q23.1; contiguous-gene deletion syndrome | BMP4, OTX2, SIX1, SIX6; some reports also include SIX4 and additional neighboring genes depending on breakpoint | Martínez-Fernández et al. 2014, Am J Med Genet A; Martínez-Frías et al. 2014, Am J Med Genet A; Kera et al. 2021, Cureus; Apam-Garduño et al. 2019, Ophthalmic Genetics (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 1-2, apamgarduno2019therelevanceof pages 1-4) | Evidence supports both familial and de novo occurrence. Familial transmission: a mother and two affected daughters with a 4.06 Mb 14q22.1–q22.3 deletion including BMP4 were reported, supporting inherited autosomal dominant transmission of the deletion in that pedigree (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2). De novo occurrence: a 7.16 Mb 14q22.2–q23.2 deletion including OTX2 and SIX6 was reported with normal parental karyotypes, supporting a de novo event (apamgarduno2019therelevanceof pages 1-4). Some additional case reports lack explicit parental testing or inheritance data (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| 14q22q23 microdeletion involving OTX2/BMP4 region | Frias syndrome spectrum; OTX2/BMP4-region deletion syndrome | Variable-size 14q22.2–q23.2 microdeletions, often 1.28–9.66 Mb in compiled cases | OTX2 and BMP4 are recurrently implicated; SIX6 frequently co-deleted in ocular/pituitary phenotypes; SIX1/SIX4 may also be included in larger deletions | Blackburn et al. 2019, Eur J Hum Genet; Apam-Garduño et al. 2019, Ophthalmic Genetics; Kera et al. 2021, Cureus (blackburn2019variableexpressivityof pages 2-3, apamgarduno2019therelevanceof pages 4-5, kera2021anophthalmiaglobaldevelopmental pages 1-2) | Review-level evidence indicates marked phenotypic variability due to breakpoint/gene-content differences. Inheritance is mixed across the literature: inherited multigenerational 14q22 deletion families exist, but de novo deletions are also documented; no aggregate de novo/familial frequency was available in the retrieved evidence (blackburn2019variableexpressivityof pages 2-3, apamgarduno2019therelevanceof pages 1-4, apamgarduno2019therelevanceof pages 4-5) |
Table: This table summarizes the disease entity commonly called Frias syndrome/14q22q23 microdeletion syndrome, its lesion type, recurrent genes, core papers, and the available evidence on familial versus de novo inheritance.
No Frias-syndrome-specific environmental contributors, protective factors, or infectious triggers were identified in the retrieved sources.
Upstream trigger: heterozygous deletion of 14q22q23 developmental regulators (CNV). (kera2021anophthalmiaglobaldevelopmental pages 1-2)
Molecular mechanisms (gene/pathway level): - BMP4 is a TGF-β superfamily ligand with broad roles in embryogenesis. (blackburn2019variableexpressivityof pages 1-2) - Direct abstract quote (BMP4 mechanism and functions): “Microphthalmia with brain and digital anomalies (MCOPS6… ) is an autosomal dominant disorder caused by loss-of-function variants or large deletions involving BMP4… a member of the TGF-β protein superfamily. BMP4 has a number of roles in embryonic development including neurogenesis, lens induction… limb and digit patterning… as well as tooth formation.” (Blackburn et al., Eur J Hum Genet, published online 2019-05-03; https://doi.org/10.1038/s41431-019-0423-4) (blackburn2019variableexpressivityof pages 1-2) - BMP4 signaling proceeds via type I/II serine/threonine kinase receptors with SMAD-dependent and SMAD-independent downstream signaling. (blackburn2019variableexpressivityof pages 2-3) - OTX2 functions as a transcription factor critical for pituitary/brain/sensory development; in microdeletion contexts it is associated with ocular defects and pituitary malformations. (apamgarduno2019therelevanceof pages 1-4) - SIX genes (SIX1/SIX6) are discussed as contributors to craniofacial/pituitary/optic nerve phenotypes, consistent with the syndrome’s triad. (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
Tissue/cellular consequences (developmental biology): impaired patterning and morphogenesis of (i) eye/optic nerve/visual pathways, (ii) pituitary/hypothalamic region, (iii) limb/digit patterning, with variable additional effects on craniofacial structures, CNS development, and other organs depending on breakpoint. (kera2021anophthalmiaglobaldevelopmental pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
Downstream clinical manifestations: congenital anophthalmia/microphthalmia, pituitary anomalies ± GH deficiency/growth delay, limb anomalies, neurodevelopmental delay, and variable multisystem disease (e.g., feeding/airway, cardiac). (kera2021anophthalmiaglobaldevelopmental pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 2-4)
A 2024 zebrafish-focused review underscores that TGF-β and BMP pathways are essential for craniofacial development and that zebrafish enable mechanistic dissection of developmental signaling and gene–environment modifiers; it also notes that human disease and malformations can arise from pathway perturbations. (Fox & Waskiewicz, Frontiers in Cell and Developmental Biology, 2024-02-07; https://doi.org/10.3389/fcell.2024.1338070) (fox2024transforminggrowthfactor pages 1-2)
GO Biological Process (examples, to be curated to match exact gene annotations): - GO:0001501 skeletal system development - GO:0030326 embryonic limb morphogenesis - GO:0001654 eye development - GO:0001947 heart morphogenesis (for cases with CHD) - GO:0021517 ventral midbrain development / broader neurodevelopment terms (case dependent)
Cell Ontology (CL) candidates (high-level, developmentally relevant): - CL:0000135 neural crest cell (craniofacial patterning context; supported by BMP/TGF-β craniofacial review) (fox2024transforminggrowthfactor pages 1-2)
UBERON (anatomy) candidates: - UBERON:0000970 eye - UBERON:0000007 pituitary gland - UBERON:0002101 limb
Based on reported phenotypes: - Eye and visual pathway (optic nerve/chiasm). (apamgarduno2019therelevanceof pages 1-4) - Pituitary/hypothalamic region (structural pituitary anomalies and endocrine effects). (kera2021anophthalmiaglobaldevelopmental pages 2-4) - Limbs/digits. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2) - Brain (corpus callosum, cortical malformations, hydrocephalus in some individuals). (apamgarduno2019therelevanceof pages 1-4, kera2021anophthalmiaglobaldevelopmental pages 2-4) - Airway/GI feeding structures in some severe cases (dysphagia, tracheomalacia). (kera2021anophthalmiaglobaldevelopmental pages 2-4) - Heart (ASD/VSD in at least one case). (kera2021anophthalmiaglobaldevelopmental pages 1-2)
Disease-specific prevalence/incidence for Frias syndrome was not available in the retrieved sources, consistent with its description as “extremely rare” and “only a few cases reported.” (kera2021anophthalmiaglobaldevelopmental pages 1-2)
However, relevant statistics from the associated microphthalmia/anophthalmia (M/A) literature provide context: - Chromosomal rearrangements in M/A: “In 10%–15% of patients, the cause of M/A is secondary to chromosomal rearrangements.” (Apam-Garduño et al., published online 2019-12-06; https://doi.org/10.1080/13816810.2019.1698618) (apamgarduno2019therelevanceof pages 1-4) - OTX2 contribution to M/A: “Heterozygous mutations… (OTX2)… account for 0.7%–10% of patients with M/A.” (apamgarduno2019therelevanceof pages 1-4) - Case-count signal: “since 1991, 17 patients have been diagnosed with syndromic M/A associated with a chromosomal deletion involving the OTX2 gene.” (apamgarduno2019therelevanceof pages 1-4)
Penetrance/expressivity are variable; reduced penetrance is explicitly emphasized for BMP4-related MAC-spectrum disorders, supporting variable expressivity as a key counseling point for deletions involving BMP4. (blackburn2019variableexpressivityof pages 1-2)
Chromosomal microarray (CMA/aCGH) is the principal diagnostic modality in the retrieved cases, enabling precise breakpoint and gene-content determination. (apamgarduno2019therelevanceof pages 1-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
Karyotype vs microarray (quantitative diagnostic yield context): - “Standard karyotype… rate of detection is 7%–15%” (in syndromic M/A), while “Analysis with aCGH allows the identification of cryptic chromosomal abnormalities in 10%–15%” of those with syndromic M/A and normal karyotype. (apamgarduno2019therelevanceof pages 1-4)
A structured summary of real-world diagnostic and management actions is provided below.
| Domain | Specific tests/interventions | Real-world notes | Evidence type (case report/review) | Key citations with year+URL | Evidence IDs |
|---|---|---|---|---|---|
| Genetic test | Chromosomal microarray / array-CGH (aCGH/CMA) | Highest-yield test in retrieved literature for defining 14q22q23 deletions and breakpoints; identified 4.06 Mb familial deletion including BMP4, 6.5 Mb deletion including SIX1/SIX4/SIX6, and 7.16 Mb OTX2-region deletion; useful when routine karyotype is normal and for genotype-phenotype correlation | Case report/series; diagnostic review | Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618; Martínez-Fernández et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36224; Martínez-Frías et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36330 | (apamgarduno2019therelevanceof pages 1-4, martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| Genetic test | Standard karyotype | Can confirm an interstitial deletion once suspected, but may miss submicroscopic lesions; one report states detection rate for chromosomal anomalies in syndromic microphthalmia/anophthalmia is ~7%–15%; parental karyotypes may help establish de novo status | Case report; review/letter | Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618 | (apamgarduno2019therelevanceof pages 1-4) |
| Genetic test | FISH / targeted molecular cytogenetics | Mentioned as adjunctive testing in a familial Frías syndrome study when high-resolution G-banded karyotype was apparently normal; useful if a specific 14q22 deletion is suspected | Thesis/report-derived evidence | Martínez-Fernández, 2016, Estudio clínico epidemiológico... (no stable journal URL available in retrieved evidence) | (fernandez2016estudioclínicoepidemiológico pages 62-63) |
| Imaging / endocrine eval | Brain MRI; pituitary-focused neuroimaging; hormone testing including GH-axis assessment | MRI can identify absent/hypoplastic optic tracts/chiasm, corpus callosum abnormalities, hydrocephalus, high-riding posterior pituitary, and other CNS anomalies; pituitary structure/function is variable, so endocrine evaluation is warranted even if imaging appears normal | Case report; review | Kera et al., 2021, Cureus, https://doi.org/10.7759/cureus.16395; Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618; Martínez-Frías et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36330 | (kera2021anophthalmiaglobaldevelopmental pages 2-4, kera2021anophthalmiaglobaldevelopmental pages 4-7, apamgarduno2019therelevanceof pages 1-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| Ophthalmology | Comprehensive ophthalmologic exam; visual pathway evaluation; orbital/brain imaging; ptosis repair when indicated | Ocular disease is often congenital and severe (anophthalmia/microphthalmia, optic nerve/chiasm anomalies), but some familial BMP4 deletions show milder findings such as exophthalmia/ptosis; surgical ptosis correction was reported in one child | Case report/series | Kera et al., 2021, Cureus, https://doi.org/10.7759/cureus.16395; Martínez-Fernández et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36224 | (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7) |
| Hearing | Audiology / hearing assessment | Hearing loss is variable rather than universal; mild unilateral hearing loss reported in one familial case, while another 14q22.3-q23.2 deletion case had normal hearing; because contiguous deletions involving OTX2/SIX6 can include deafness, audiologic surveillance is reasonable | Case report; review/letter | Martínez-Fernández et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36224; Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618; Martínez-Frías et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36330 | (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, apamgarduno2019therelevanceof pages 1-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2) |
| Feeding / airway | Feeding-tube support; gastrostomy; airway evaluation for tracheomalacia; tracheostomy when necessary | Severe dysphagia/airway disease can dominate management in complex cases; one child required gastrostomy, then developed respiratory compromise from tracheomalacia necessitating tracheostomy, later complicated by MRSA tracheitis and fatal sepsis | Case report | Kera et al., 2021, Cureus, https://doi.org/10.7759/cureus.16395 | (kera2021anophthalmiaglobaldevelopmental pages 2-4, kera2021anophthalmiaglobaldevelopmental pages 4-7) |
| Cardiac | Echocardiography / cardiology assessment and follow-up | Cardiac defects are not universal but have been documented, including secundum ASD and restrictive VSD; one patient was followed in pediatric cardiology | Case report; review | Kera et al., 2021, Cureus, https://doi.org/10.7759/cureus.16395; Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618 | (kera2021anophthalmiaglobaldevelopmental pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 4-7, apamgarduno2019therelevanceof pages 1-4) |
| Surgery | Diaphragmatic hernia repair; ptosis correction; neurosurgical shunt procedures | Management is phenotype-driven rather than syndrome-specific; reported surgeries include neonatal diaphragmatic hernia repair, bilateral ptosis correction, and ventriculoperitoneal shunt placement for hydrocephalus | Case report/series | Martínez-Fernández et al., 2014, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.36224; Kera et al., 2021, Cureus, https://doi.org/10.7759/cureus.16395 | (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 2-4) |
| Multidisciplinary management | Coordinated care across genetics, ophthalmology, endocrinology, neurology, ENT/audiology, nutrition/feeding, pulmonology/airway, cardiology, rehabilitation | No formal disease-specific guideline was retrieved, but the multisystem phenotype and real-world cases support multidisciplinary follow-up and individualized supportive care | Inference grounded in case reports/review | Kera et al., 2021, Cureus, https://doi.org/10.7759/cureus.16395; Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618 | (kera2021anophthalmiaglobaldevelopmental pages 2-4, kera2021anophthalmiaglobaldevelopmental pages 4-7, apamgarduno2019therelevanceof pages 1-4) |
| Growth hormone / endocrine treatment | Consider endocrine referral and GH-axis evaluation; GH therapy reported in related 14q22q23 microdeletion literature | Retrieved evidence did not include the full primary report, but a literature summary cited “three children with microdeletions of 14q22q23” who had abnormal pituitary development and response to growth hormone therapy; direct treatment-effect details were not available in current context | Review/letter summarizing prior case series | Apam-Garduño et al., 2019, Ophthalmic Genetics, https://doi.org/10.1080/13816810.2019.1698618 | (apamgarduno2019therelevanceof pages 5-5) |
Table: This table summarizes the main diagnostic approaches and phenotype-directed management reported for Frias syndrome / 14q22q23 microdeletion syndrome. It highlights the central role of chromosomal microarray, the variability of multisystem involvement, and the supportive, multidisciplinary nature of current care.
Within the retrieved corpus, Frias syndrome overlaps with: - Other causes of syndromic M/A (SOX2-related, single-gene BMP4 loss-of-function, OTX2 sequence variants). (blackburn2019variableexpressivityof pages 1-2, apamgarduno2019therelevanceof pages 1-4)
Prognosis is case-dependent and driven by the degree of multisystem involvement: - One familial case report noted neonatal death after diaphragmatic hernia repair in an affected newborn. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2) - Another detailed case described severe airway/infectious complications culminating in death from sepsis at age seven (MRSA tracheitis context). (kera2021anophthalmiaglobaldevelopmental pages 2-4)
No cohort-level survival statistics were retrieved.
There is no syndrome-specific curative therapy in the retrieved evidence; treatment is supportive and multidisciplinary, directed at organ-specific manifestations: - Surgical interventions: diaphragmatic hernia repair, ptosis correction, ventriculoperitoneal shunt for hydrocephalus. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2, kera2021anophthalmiaglobaldevelopmental pages 2-4) - Feeding/airway support: gastrostomy/feeding tubes, tracheostomy where needed. (kera2021anophthalmiaglobaldevelopmental pages 2-4) - Cardiology follow-up for congenital heart defects (ASD/VSD). (kera2021anophthalmiaglobaldevelopmental pages 1-2)
A literature summary cited “three children with microdeletions of 14q22q23” with abnormal pituitary development and “response to growth hormone therapy,” but the underlying primary report was not retrievable in the present context, so effect sizes/dosing/outcomes cannot be extracted here. (apamgarduno2019therelevanceof pages 5-5)
No disease-specific clinical trials for Frias syndrome/14q22q23 microdeletion were identified in the retrieved ClinicalTrials.gov search results. (apamgarduno2019therelevanceof pages 1-4)
No primary prevention is available for de novo CNVs. Practical prevention is mainly reproductive/genetic counseling: - For de novo deletions: recurrence risk is generally low but not zero (not quantified in retrieved sources). - For familial deletions: recurrence risk can be substantial; family testing and counseling are relevant. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2)
Prenatal testing is plausible via CNV detection (CMA), but no prenatal case was retrieved in this evidence set.
No naturally occurring veterinary analog or OMIA entry was identified in the retrieved evidence.
No model organism replicating the combined haploinsufficiency of BMP4 + OTX2 ± SIX1/SIX6 (i.e., the contiguous deletion syndrome) was found in the retrieved corpus.
Direct 2023–2024 Frias-syndrome-specific primary case reports were not retrieved beyond the above pathway/diagnostic context; the most directly informative Frias syndrome case report in the retrieved set remains 2021 (Cureus). (kera2021anophthalmiaglobaldevelopmental pages 1-2)
References
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