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.

Suggestive Findings

Feingold syndrome 1 (FS1) should be suspected in probands 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 (or likely pathogenic) variant in MYCN identified by molecular genetic testing (see Table 1). Note: (1) 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. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of a heterozygous MYCN variant of uncertain significance does not establish or rule out the diagnosis.

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).

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.

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].

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.

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

Surveillance

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.

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 MYCN pathogenic variant. De novo pathogenic variants were observed in approximately 40% of individuals with FS1 [Marcelis et al 2008; Author, personal communication].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with FS1 may appear to be negative because of failure to recognize the disorder in a family member with a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and/or molecular genetic testing have been performed.
• Note: If the parent is the family member in whom the pathogenic variant first occurred, the parent 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 clinical/genetic status of the proband's parents.

• If a parent of the proband is affected and/or known to have the MYCN pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the MYCN pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for FS1 because of the theoretic possibility of parental germline mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MYCN pathogenic variant, the parent's 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 identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the MYCN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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 the fetus is known to have an MYCN pathogenic variant or in which the genetic status of a fetus at 50% risk is unknown.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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. The gene N-myc was identified by homology with c-Myc in amplified sequences of neuroblastomas.

c-Myc and N-Myc also play a crucial role in development. Mice deficient for either of these Myc genes die before embryonic day 11.5. Inactivation of murine N-myc demonstrates its developmental importance [Charron et al 2002, Knoepfler et al 2002, Ota et al 2007]. N-myc plays a role in branching morphogenesis in the lung and development of the mesonephric tubules, neuroepithelium, sensory ganglia, gut, heart, and limb, many of which are also affected in FS1.

Mechanism of disease causation. Feingold syndrome 1 is caused by a loss-of-function variant resulting in haploinsufficiency of MYCN.

MYCN-specific laboratory considerations. MYCN encodes three exons. Although exon 1 contains 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]. A missense nucleotide change in exon 1, which introduced a termination codon, was determined to be benign [Marcelis et al 2008]. The effect of this variant on alternative transcripts and their role in pathogenesis of FS1 is unknown.

Cancer and Benign Tumors

Somatic amplification of MYCN is found in up to 25% of a diverse range of cancers, such as neuroblastoma and skin, lung, and prostate cancer. This invariably leads to overexpression of MYCN resulting in a poor prognosis [Ruiz-Pérez et al 2017]. This is in sharp contrast to the variants causing FS1, which are germline variants that without exception result in a loss of function.

Revision History

• 4 April 2019 (bp) Comprehensive update posted live
• 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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