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Frias syndrome

1. Disease Information

2026-05-10
Falcon MONDO:0012324 Model: Edison Scientific Literature 27 citations

1. Disease Information

1.1 Concise overview (current understanding)

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)

1.2 Key identifiers

  • OMIM: Frías syndrome reported as OMIM: 609640 in the BMP4-haploinsufficiency-focused AJMG paper. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2)
  • MONDO ID: Not identified in the retrieved evidence; requires confirmation from MONDO/OMIM cross-references outside the current retrieved set. (kera2021anophthalmiaglobaldevelopmental pages 1-2)
  • MeSH / ICD-10 / ICD-11 / Orphanet: Not available in the retrieved full text evidence set; should be looked up in OMIM/Orphanet/ICD browsers during knowledge-base ingestion. (kera2021anophthalmiaglobaldevelopmental pages 1-2)

1.3 Synonyms / alternative names

1.4 Evidence source type

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)

2. Etiology

2.1 Disease causal factors

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)

2.2 Risk factors

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.

3. Phenotypes

A structured phenotype-to-HPO mapping derived from retrieved clinical reports is provided in the artifact below.

Table (click to expand)
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.

3.1 Core phenotype domains and clinical spectrum

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)

3.2 Age of onset, severity, progression

4. Genetic / Molecular Information

4.1 Causal genes / genomic lesion

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)

4.2 Pathogenic variant class

  • Copy-number variant (CNV): heterozygous interstitial deletions (Mb-scale) detected by array-CGH/CMA. (apamgarduno2019therelevanceof pages 1-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)

4.3 Functional consequence

4.4 Inheritance pattern

A structured summary is provided below.

Table (click to expand)
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.

5. Environmental Information

No Frias-syndrome-specific environmental contributors, protective factors, or infectious triggers were identified in the retrieved sources.

6. Mechanism / Pathophysiology

6.1 Mechanistic causal chain (current model)

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)

6.2 Relevant pathway context and model-organism evidence (recent)

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)

6.3 Ontology suggestions

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

7. Anatomical Structures Affected

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)

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology

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)

9.2 Inheritance

  • Familial inheritance documented for a specific deletion (mother and two daughters), consistent with autosomal dominant transmission of the deletion in that pedigree. (martinez‐fernandez2014haploinsufficiencyofbmp4 pages 1-2)
  • De novo documented in at least one OTX2-region deletion case (normal parental karyotypes). (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)

10. Diagnostics

10.1 Genetic testing (current practice)

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)

10.2 Clinical tests and evaluations (phenotype-driven)

A structured summary of real-world diagnostic and management actions is provided below.

Table (click to expand)
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.

10.3 Differential diagnosis

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)

11. Outcome / Prognosis

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.

12. Treatment

12.1 Current applications / real-world implementations

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)

12.2 Growth hormone therapy

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)

12.3 MAXO (Medical Action Ontology) suggestions (examples)

  • Chromosomal microarray analysis (genetic diagnostic test)
  • Ophthalmologic evaluation
  • Endocrine evaluation / growth hormone replacement therapy (case-dependent)
  • Gastrostomy tube placement
  • Tracheostomy
  • Surgical repair of congenital diaphragmatic hernia
  • Ventriculoperitoneal shunt placement

12.4 Clinical trials

No disease-specific clinical trials for Frias syndrome/14q22q23 microdeletion were identified in the retrieved ClinicalTrials.gov search results. (apamgarduno2019therelevanceof pages 1-4)

13. Prevention

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.

14. Other Species / Natural Disease

No naturally occurring veterinary analog or OMIA entry was identified in the retrieved evidence.

15. Model Organisms

15.1 Available model evidence (gene/pathway level)

15.2 Limitations (syndrome-level)

No model organism replicating the combined haploinsufficiency of BMP4 + OTX2 ± SIX1/SIX6 (i.e., the contiguous deletion syndrome) was found in the retrieved corpus.

Recent developments and latest research (prioritizing 2023–2024)

  • Pathway-level advances (2024): A 2024 Frontiers review emphasizes that TGF-β/BMP signaling is critical across stages of craniofacial development and highlights zebrafish as an experimentally tractable system for dissecting mechanisms and potentially gene–environment interactions affecting craniofacial phenotypes relevant to BMP pathway perturbations. (Published 2024-02-07; https://doi.org/10.3389/fcell.2024.1338070) (fox2024transforminggrowthfactor pages 1-2)
  • Genetic diagnostics (2024 broader field): A 2024 Genes review (not specific to Frias syndrome) reinforces the role of cytogenomic microarray in evaluating unexplained congenital and syndromic findings, supporting current diagnostic practice for contiguous-gene deletion syndromes. (Published 2024-05-23; https://doi.org/10.3390/genes15060677) (bonati2024contiguousgenesyndromes pages 1-2)

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)

Expert opinion / analysis (evidence-grounded)

  1. Frias syndrome is best treated as a CNV-defined developmental disorder where phenotype severity and organ involvement are largely driven by gene content and breakpoint variation; hence, high-resolution CNV testing (CMA/aCGH) is central to diagnosis and counseling. (apamgarduno2019therelevanceof pages 1-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)
  2. Variable expressivity and reduced penetrance are important counseling concepts, especially where BMP4 is involved, as BMP4-related disorders can lack classic “hallmark” findings in some carriers. (blackburn2019variableexpressivityof pages 1-2)
  3. Clinical management is inherently multidisciplinary and supportive, because patients can present with severe ocular impairment plus endocrine, neurologic, feeding/airway, and cardiac issues in different combinations. (kera2021anophthalmiaglobaldevelopmental pages 2-4, martinez‐frias2014interstitialdeletion14q22.3‐q23.2 pages 1-2)

Key statistics and data (from recent/authoritative sources)

Evidence gaps (for knowledge-base completion)

  • Formal MONDO/Orphanet/ICD/MeSH identifiers were not retrievable from the current paper set.
  • Frias-syndrome-specific prevalence/incidence and standardized clinical diagnostic criteria remain sparse.
  • Detailed endocrine treatment outcome data (e.g., GH therapy dosing/response) requires retrieval of the primary 2014 Molecular Cytogenetics series referenced secondarily. (apamgarduno2019therelevanceof pages 5-5)

References

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