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Feingold Syndrome 1

Synonyms: Oculodigitoesophagoduodenal Syndrome, ODED Syndrome

, PhD and , PhD.

Author Information

Initial Posting: ; Last Update: September 6, 2012.

Summary

Clinical characteristics.

Feingold syndrome 1 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.

Diagnosis is based on clinical findings. MYCN is the only gene in which mutation is known to cause Feingold syndrome 1.

Management.

Treatment of manifestations: Gastrointestinal atresia is treated surgically. Hearing loss, renal anomalies, and cardiac anomalies are treated in the usual manner.

Genetic counseling.

Feingold syndrome 1 is inherited in an autosomal dominant manner. Approximately 60% of individuals with Feingold syndrome 1 have an affected parent; the proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with Feingold syndrome 1 has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified.

Diagnosis

Clinical Diagnosis

The clinical features of Feingold syndrome 1 (FS1) have been reviewed by Marcelis et al [2008]. Major features:

  • 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).

A diagnosis of FS1 can be made when a MYCN pathogenic variant or deletion is identified. In the absence of a MYCN abnormality a clinical diagnosis of FS1 should still be considered in the presence of typical digital anomalies with microcephaly or gastrointestinal atresia or typical facial features.

Molecular Genetic Testing

Gene. MYCN is the only gene in which mutation is known to cause Feingold syndrome 1 [van Bokhoven et al 2005]

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Feingold Syndrome 1

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
MYCN 4Sequence analysis 5Sequence variants65% 6
Deletion/duplication testing 7Exon and partial-gene deletions10% 8
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Typical digital anomalies were absent in individuals with FS1 in whom no MYCN pathogenic variant was identified [Marcelis et al 2008], whereas these typical digital anomalies are present in more than 95% of individuals with FS1 who have MYCN pathogenic variants.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

6.

Sequence analysis of all three exons of MYCN detected pathogenic variants in 65% of individuals/families with a clinical suspicion of Feingold syndrome 1 [Marcelis et al 2008].

7.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8.

Deletion/duplication testing detects pathogenic variants in 10% of individuals/families with Feingold syndrome 1 [Marcelis et al 2008].

Testing Strategy

Confirming/establishing the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

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. The features are summarized in Table 2.

Table 2.

Features in Feingold Syndrome 1

Feingold Syndrome 1 Feature% of Persons with Feature
Digital anomaliesBrachymesophalangy100%
Toe syndactyly97%
Thumb hypoplasia17%
Microcephaly89%
Facial dysmorphismShort palpebral fissures73%
Micrognathia32%
AtresiaGastrointestinal55%
Esophageal32%
Duodenal31%
Jejunal3%
Anal2%
Multiple12%
Mild learning deficit51%
OtherStature <10th centile60%
Renal abnormalities18%
Cardiac abnormalities15%
PDA12%
Other10%
Hearing loss10%

The most consistent findings are digital anomalies. Brachymesophalangy (shortening of the 2nd and 5th middle phalanx of the hand with clinodactyly of the 5th finger) has been present in 100% of individuals reported to have a MYCN pathogenic variant. Toe syndactyly (2-3 and/or 4-5) has been reported in 97%. Thumb hypoplasia is also common. See Figure 1, Figure 2, and Figure 3.

Figure 1.

Figure 1.

Typical brachymesophalangy in an adult with FS1

Figure 2.

Figure 2.

X-ray showing typical brachymesophalangy (digits 2 and 5) and thumb hypoplasia

Figure 3.

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). Cardiovascular and renal malformations are seldom severe in FS1.

Mild learning deficit is frequent in FS1. 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]. Obvious short stature (height <3rd centile) is uncommon but average is decreased compared to the general population.

Associated features that occur in fewer than 50% of affected individuals include renal and cardiac abnormalities and hearing loss.

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, seems to be 100% but clinical expression can vary considerably.

Nomenclature

Terms used in the past for Feingold syndrome1:

  • 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.

Differential Diagnosis

See Feingold Syndrome: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Feingold syndrome 2 is caused by hemizygous deletions of chromosome 13q31.3 including MIR17HG [de Pontual et al 2011]. Individuals with this deletion share many features with Feingold syndrome 1 (FS1), including microcephaly, mild growth delay and the skeletal findings of Feingold syndrome, brachymesophalangy, toe syndactyly, and thumb hypoplasia. Important differences are the lack of gastrointestinal abnormalities and short palpebral fissures in Feingold syndrome 2 in the limited number of individuals described at present [de Pontual et al 2011].

See Esophageal Atresia/Tracheoesophageal Fistula Overview.

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.

Esophageal atresia, heart defects, and renal abnormalities can be seen in CHARGE syndrome.

Thumb hypoplasia and other congenital anomalies are seen in Fanconi anemia.

Brachymesophalangy in FS1 is very similar to brachydactyly type A4. Although no pathogenic variants in MYCN have been identified in brachydactyly type A4, molecular genetic testing of MYCN could be considered in families with brachydactyly type A4.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Feingold syndrome 1 (FS1), the following evaluations are recommended:

  • Cardiac investigation (echocardiogram)
  • Renal ultrasound to evaluate for structural abnormalities
  • Audiometry for the possibility of hearing loss
  • Neuropsychological evaluation if there are concerns about psychomotor development
  • Analysis of the family pedigree for other possible affected individuals
  • Clinical genetics consultation

Treatment of Manifestations

Appropriate treatment includes the following:

  • Surgical treatment of gastrointestinal atresia when present
  • Follow up and treatment of possible cardiac and renal anomalies
  • Treatment for significant hearing loss
  • Developmental or educational intervention for children with learning difficulties

Prevention of Secondary Complications

Prophylactic antibiotics may be needed when cardiac or renal anomalies are present.

Surveillance

Routine follow up for any of the above-listed medical issues by the appropriate specialist is warranted.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because of the risk for major congenital abnormalities of the gastrointestinal tract, heart, and kidney, high-resolution ultrasound investigations (including fetal echocardiogram) are advised in any pregnancy in which one of the parents is known to be affected.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Feingold syndrome 1 (FS1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals (~60%) diagnosed with FS1 have an affected parent.
  • A proband with FS1 may have the disorder as the result of a de novo pathogenic variant. De novo pathogenic variants were observed in approximately 30% of individuals with FS1 [Marcelis et al 2008; Author, personal communication].
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical examination for the presence of FS1 features (digital anomalies, microcephaly, and facial features). If a molecular diagnosis has been established in the proband, molecular testing of the parents is advised. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although many (~60%) individuals diagnosed with Feingold syndrome 1 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with FS1 has a 50% chance of inheriting the pathogenic variant.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the MYCN pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for FS1 are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • EA/TEF Child and Family Support Connection
    111 West Jackson Boulevard
    Suite 1145
    Chicago IL 60604
    Email: info@eatef.org
  • Learning Disabilities Association of America (LDA)
    4156 Library Road
    Pittsburgh PA 15234-1349
    Phone: 412-341-1515
    Fax: 412-344-0224
  • Medline Plus
  • Reach: The Association for Children with Hand or Arm Deficiency
    PO Box 54
    Helston Cornwall TR13 8WD
    United Kingdom
    Phone: +44 0845 1306 225
    Fax: +44 0845 1300 262
    Email: reach@reach.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Feingold Syndrome 1: Genes and Databases

GeneChromosome LocusProteinHGMD
MYCN2p24​.3N-myc proto-oncogene proteinMYCN

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Feingold Syndrome 1 (View All in OMIM)

164280FEINGOLD SYNDROME 1; FGLDS1
164840V-MYC AVIAN MYELOCYTOMATOSIS VIRAL-RELATED ONCOGENE, NEUROBLASTOMA-DERIVED; MYCN

Gene structure. See Table 3. Human MYCN consists of three exons. Although exon 1 does contain a potential translation start codon, initiation of MYCN protein synthesis commences at the first ATG codon in exon 2 because of an internal ribosome entry site in the 5’-untranslated region [Jopling & Willis 2001]. An alternative transcript consisting of exons 1 and 3 only has been described. This transcript encodes a truncated MYCN isoform, denoted ∆MYCN, which is initiated by using the potential start codon in exon 1 [van Bokhoven et al 2005].

Benign variants. A variant in exon 1 (p.Gln22Ter), which affects only the ∆MYCN isoform, was described in an affected individual but did not segregate with the disease in the family [Marcelis et al 2008]. Therefore, the p.Gln22Ter change of the ∆MYCN isoform is considered to be a benign variant. These data suggest that the ∆MYCN isoform contributes little or nothing to the pathogenesis of Feingold syndrome 1 (FS1). Somatic amplification of human N-Myc, now formally denoted as MYCN, is associated with poor prognosis in neuroblastoma and can be found in approximately 25% of neuroblastoma cases [Lu et al 2003].

Pathogenic variants. See Table 3. All pathogenic variants currently identified are present in either exon 2 or 3 of MYCN. No pathogenic variants in exon 1 have been described.

Table 3.

Selected MYCN Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.64C>Tp.Gln22TerNM_005378​.4
NP_005369​.2
Pathogenicc.217G>Tp.Glu73Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The Myc family of proteins is well known for its role in oncogenic processes. Members of this family include c-Myc, N-Myc and L-Myc. N-myc was identified by homology with c-Myc in amplified sequences of neuroblastomas.

The creation of knockout mice has revealed crucial roles for c-Myc and N-Myc in development as well. Mice deficient for either of these Myc genes die before embryonic day 11.5. Targeted inactivitation of murine N-myc has revealed a number of functions during development, including a role in branching morphogenesis in the lung, and roles in the development of the mesonephric tubules, the neuroepithelium, the sensory ganglia, the gut, the heart, and the limb [Charron et al 2002, Knoepfler et al 2002, Ota et al 2007]. Many of these structures are also affected in FS1. These phenotypic abnormalities are in line with the expression of the gene during development.

Abnormal gene product. The occurrence of inactivating variants of N-myc supports haploinsufficiency of N-myc proto-oncogene protein as a cause of FS1. All pathogenic variants affect the MYCN isoform of the gene.

References

Literature Cited

  • Brunner HG, Winter RM. Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia. J Med Genet. 1991;28:389–94. [PMC free article: PMC1016903] [PubMed: 1870095]
  • Charron J, Gagnon JF, Cadrin-Girard JF. Identification of N-myc regulatory regions involved in embryonic expression. Pediatr Res. 2002;51:48–56. [PubMed: 11756639]
  • de Pontual L, Yao E, Callier P, Faivre L, Drouin V, Cariou S, van Haeringen A, Genevieve D, Goldenberg A, Oufadem M, Manouvrier S, Munnich A, Vidigal JA, Vekemans M, Lyonnet S, Henrion-Caude A, Ventura A, Amiel J. Germline deletion of the miR-17-92 cluster causes growth and skeletal defects in humans. Nat Genet. 2011;43:1026–30. [PMC free article: PMC3184212] [PubMed: 21892160]
  • Feingold M. Case Report 30. Synd Ident. 1975;3:16–17.
  • Jopling CL, Willis AE. N-myc translation is initiated via an internal ribosome entry segment that displays enhanced activity in neuronal cells. Oncogene. 2001;20:2664–70. [PubMed: 11420678]
  • Knoepfler PS, Cheng PF, Eisenman RN. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 2002;16:2699–712. [PMC free article: PMC187459] [PubMed: 12381668]
  • Lu X, Pearson A, Lunec J. The MYCN oncoprotein as a drug development target. Cancer Lett. 2003;197:125–30. [PubMed: 12880971]
  • Marcelis CLM, Hol FA, Graham GE, Rieu PNMA, Kellermayer R, Meijer RPP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer APM. Genotype-Phenotype correlations in MYCN-Related Feingold syndrome. Human Mutation. 2008;29:1125–32. [PubMed: 18470948]
  • Ota S, Zhou ZQ, Keene DR, Knoepfler P, Hurlin PJ. Activities of N-Myc in the developing limb link control of skeletal size with digit separation. Development. 2007;134:1583–92. [PubMed: 17360777]
  • Shaw-Smith C, Willatt L, Thalange N. Growth deficiency in oculodigitoesophagoduodenal (Feingold) syndrome--case report and review of the literature. Clin Dysmorphol. 2005;14:155–8. [PubMed: 15930908]
  • van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B, van Beusekom E, Rieu P, Newbury-Ecob RA, Chiang C, Brunner HG. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat Genet. 2005;37:465–7. [PubMed: 15821734]

Chapter Notes

Revision History

  • 6 September 2012 (me) Comprehensive update posted live
  • 30 June 2009 (me) Review posted live
  • 23 April 2009 (cm) Original submission
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