Feingold Syndrome 1
Summary
Clinical characteristics.
Feingold syndrome 1 (referred to as FS1 in this GeneReview) is characterized by digital anomalies (shortening of the 2nd and 5th middle phalanx of the hand, clinodactyly of the 5th finger, syndactyly of toes 2-3 and/or 4-5, thumb hypoplasia), microcephaly, facial dysmorphism (short palpebral fissures and micrognathia), gastrointestinal atresias (primarily esophageal and/or duodenal), and mild-to-moderate learning disability.
Diagnosis/testing.
The diagnosis of FS1 is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in MYCN identified by molecular genetic testing.
Management.
Treatment of manifestations: Gastrointestinal atresia is treated surgically. Mild-to-moderate learning disabilities are treated in the usual manner.
Genetic counseling.
FS1 is inherited in an autosomal dominant manner. Approximately 60% of individuals with Feingold syndrome 1 have an affected parent; the proportion of FS1 caused by a de novo MYCN pathogenic variant is unknown. Each child of an individual with FS1 has a 50% chance of inheriting the MYCN pathogenic variant. When the MYCN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Feingold syndrome 1 (FS1) should be suspected in individuals with the following clinical findings [Marcelis et al 2008].
- Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly)
- Microcephaly (occipito-frontal circumference <10th centile)
- Short palpebral fissures
- Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI)
Establishing the Diagnosis
The diagnosis of FS1 is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in MYCN identified by molecular genetic testing (see Table 1). Note: Large contiguous-gene deletions encompassing MYCN and other genes have been reported in individuals with features of FS1 but more complex phenotypes (see Genetically Related Disorders). Of note, most individuals with these large deletions are identified by chromosomal microarray analysis (CMA) performed in the context of evaluation for multiple congenital anomalies.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic findings suggest the diagnosis of FS1, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of MYCN detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
- An intellectual disability multigene panel that includes MYCN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of FS1, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of FS1 is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Feingold Syndrome 1 (FS1)
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| MYCN | Sequence analysis 3 | 59% 4 |
| Gene-targeted deletion/duplication analysis 5 | 9% 6 | |
| Chromosomal microarray (CMA) 7 | See footnote 8. |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
van Bokhoven et al [2005], Blaumeiser et al [2008], Marcelis et al [2008], Cognet et al [2011]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by van Bokhoven et al [2005], Blaumeiser et al [2008], Marcelis et al [2008], and Cognet et al [2011]) may not be detected by these methods.
- 6.
van Bokhoven et al [2005], Marcelis et al [2008], Cognet et al [2011]
- 7.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including MYCN) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 2p24.3 region. CMA designs in current clinical use target the 2p24.3 region. Deletions reported in van Bokhoven et al [2005], Blaumeiser et al [2008], Marcelis et al [2008], and Cognet et al [2011] would be detected by CMA.
- 8.
Larger deletions of MYCN and adjacent genes detected by CMA associated with features of FS1 with additional clinical findings are not included in this table (see Genetically Related Disorders).
Clinical Characteristics
Clinical Description
Feingold syndrome 1 (FS1) as described by Feingold [1975] and Brunner & Winter [1991] is characterized by digital anomalies, microcephaly, facial dysmorphism, gastrointestinal atresias, and learning disability. To date, 69 families with 116 affected individuals having three or more of the core features of FS1 (brachymesophalangy, toe syndactyly, microcephaly, short palpebral fissures, and intestinal atresia) have been reported [Blaumeiser et al 2008, Marcelis et al 2008, Cognet et al 2011].
Features are summarized in Table 2.
Table 2.
Features in Feingold Syndrome 1 (FS1)
| Feature | % of Persons with Feature | |
|---|---|---|
| Digital anomalies | Brachymesophalangy | 100% |
| Toe syndactyly | 93% | |
| Thumb hypoplasia | 17% | |
| Microcephaly | 86% | |
| Facial dysmorphism | Short palpebral fissures | 73% |
| Micrognathia | 30% | |
| Atresia | Esophageal | 35% |
| Duodenal | 27% | |
| Jejunal | 3% | |
| Anal | 2% | |
| Multiple | 12% | |
| Mild learning deficit | 56% | |
| Stature <10th centile | 60% | |
| Other | Renal abnormalities | 19% |
| Cardiac abnormalities | 15% | |
| Hearing loss | 10% | |
Blaumeiser et al [2008], Marcelis et al [2008], Cognet et al [2011]
Digital anomalies include brachymesophalangy (shortening of the 2nd and 5th middle phalanx of the hand with clinodactyly of the 5th finger) and thumb hypoplasia (Figures 1 and 2). Toe syndactyly refers to syndactyly of toes 2-3 and/or 4-5 (Figure 3).
Figure 1.
Typical brachymesophalangy in an adult with FS1
Figure 2.
X-ray showing typical brachymesophalangy (digits 2 and 5) and thumb hypoplasia
Figure 3.
Typical syndactyly of 2nd and 3rd or 4th and 5th toe
Gastrointestinal atresia (esophageal and/or duodenal) is a cause of major medical concern in FS1 and requires immediate surgical intervention (see Management).
Mild learning deficit is frequent in FS1; most affected individuals are able to live an independent life. Clear intellectual disability is rare, but intelligence is below average when compared to the general population and healthy, unaffected family members.
Some reports show that growth is impaired in FS1 [Shaw-Smith et al 2005]. Short stature (height <3rd centile) is uncommon but average height is below that in the general population.
Associated features that occur in fewer than 50% of affected individuals include the following:
- Renal abnormalities. Horseshoe kidneys, dysplastic kidneys, hydronephrosis and pelvic dilatation, chronic nephritis, and vesicourethral reflux leading to renal dysplasia and renal failure
- Cardiac abnormalities. Patent ductus arteriosus, multiple ventricular septal defects (VSD), tricuspid valve stenosis and VSD plus tricuspid atresia, and interrupted aortic arch
- Hearing loss. Variable and can include conductive and sensorineural hearing loss; the latter is more commonly reported
Genotype-Phenotype Correlations
No significant differences are observed among individuals with deletions or missense, nonsense, or frameshift variants.
Penetrance
The penetrance for major features of FS1, especially digital abnormalities, appears to be 100% but clinical expression can vary considerably.
Nomenclature
Terms used in the past for Feingold syndrome 1:
- Microcephaly-oculo-digito-esophageal-duodenal syndrome
- Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
- Microcephaly-digital anomalies-normal intelligence syndrome
Prevalence
Prevalence is unknown; FS1 is likely rare. To date, 69 families with 116 affected individuals have been reported [Blaumeiser et al 2008, Marcelis et al 2008, Cognet et al 2011].
Differential Diagnosis
Table 3.
Other Genes of Interest in the Differential Diagnosis of Feingold Syndrome 1 (FS1)
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/FS1 | Distinguishing from FS1 | |||
| CHD7 | CHARGE syndrome | AD |
|
|
| MIR17HG 1 | Feingold syndrome 2 (OMIM 614326) | AD |
| Absence of gastrointestinal abnormalities 2 |
| 21 genes 3 | Fanconi anemia | AR AD XL |
|
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
- 1.
Feingold syndrome 2 is caused by hemizygous deletions of chromosome 13q31.3 including MIR17HG [Tassano et al 2013].
- 2.
To date, seven individuals with Feingold syndrome 2 have been described [de Pontual et al 2011, Ganjavi et al 2014, Muriello et al 2019].
- 3.
BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2
VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal and limb abnormalities) shows considerable overlap with FS1, but the two should be distinguishable by the presence of microcephaly, brachymesophalangy, and toe syndactyly in FS1. The molecular basis of VACTERL association is unknown.
See Esophageal Atresia/Tracheoesophageal Fistula Overview for a review of other genetic causes of this phenotype.
The brachymesophalangy observed in FS1 is very similar to brachydactyly type A4 (BDA4). The molecular basis of BDA4 is known. Although no pathogenic variants in MYCN have been identified in BDA4, molecular genetic testing of MYCN could be considered in families with BDA4.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Feingold syndrome 1 (FS1), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with Feingold Syndrome 1 (FS1)
| System/Concern | Evaluation | Comment |
|---|---|---|
| Hands/Feet | Assess for digital anomalies. |
|
| Gastrointestinal tract | Assess for gastrointestinal atresia (incl esophageal, duodenal, jejunal, anal). | Gastroenterologist / GI surgeon |
| Development | Developmental assessment | Incl eval of motor, speech/language, general cognitive, & vocational skills |
| Renal abnormalities | Renal ultrasound eval | Assess for renal anomalies. |
| Cardiac abnormalities | Assess for congenital heart defects. | Pediatric cardiologist |
| Hearing loss | Audiologic eval 1 | Conductive & sensorineural |
| Miscellaneous | Consultation w/clinical geneticist &/or genetic counselor |
- 1.
See Hereditary Hearing Loss and Deafness Overview for details about audiologic evaluations.
Treatment of Manifestations
Appropriate treatment includes a multidisciplinary approach to address the following possible concerns:
- Surgical treatment of gastrointestinal atresia
- Occupational therapy / surgical intervention for finger/toe anomalies
- Treatment of cardiac and/or renal anomalies as per standard practice
- Treatment for significant hearing loss (See Hereditary Hearing Loss and Deafness Overview.)
- Developmental or educational intervention for children with learning difficulties
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states and provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center-based; however, for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services are for those who require specially designed instruction / related services.
- IEP services will be reviewed annually to determine if any changes are needed.
- As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Surveillance
Table 5.
Recommended Surveillance for Individuals with Feingold Syndrome 1
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Hands/Feet | Hand function / need for occupational therapy | Per OT |
| GI tract atresia | As specified by GI consultants | Per GI consultants |
| Development/ Education | Monitor developmental progress & educational needs. | Routinely, per developmental pediatrician &/or school |
| Renal | As specified by renal consultants | Per renal consultants |
| Cardiac | As specified by cardiac consultants | Per cardiologist |
| Hearing | Audiologic reexamination to determine type & extent of hearing loss & success w/hearing habilitation | Per treating audiologist |
GI = gastrointestinal; OT = occupational therapist
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.