Expanding the clinical spectrum of MYCN‐related Feingold syndrome

Feingold syndrome (OMIM#164280) is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly (characteristically between second and third and fourth and fifth toes), and shortened or absent middle phalanges [Feingold et al., 1997]. Cardiac and renal malformations, vertebral anomalies, and deafness have also been described in a minority of patients [Kellermayer et al., 2005]. As a result of the versatile clinical picture, this entity has also been reported as oculo-duodeno-esophageal-digital (ODED) syndrome, microcephaly-oculo-digito-esophageal-duodenal syndrome, and microcephaly-mesobrachyphalangy-tracheoesophageal-fistula (MMT) syndrome. However, some of the variable features of Feingold syndrome are included in “microcephaly-digital abnormalities-normal intelligence” (MIM#602585), described as an independent, distinct condition [Kawame et al., 1997]. The critical region of Feingold syndrome was mapped to chromosome 2p23-p24 [Celli et al., 2003] and a recent article revealed MYCN (2p24.1), as a causative gene in this genetic entity [van Bokhoven et al., 2005]. These findings indicated that MYCN dosage is an important factor in early embryonic development and postnatal brain growth. Indeed, studies in human fetal brain and mice suggest that MYCN is involved in embryonic limb, visceral organ, and nervous system development [Hirvonen et al., 1990; Moens et al., 1992; Stanton et al., 1992]. Here, we report on a family—expressing variable features of Feingold syndrome—who carry a novel mutation of MYCN. The boy with classical features of the syndrome and his mother and maternal grandmother, only possessing the clinical phenotype of “microcephaly-digital abnormalities-normal intelligence” disorder also carry the same pathogenic mutation. The 4-year-old boy was born as a first child from non-consanguineous parents. The pregnancy was complicated by maternal nephropathy. He was delivered vaginally at 39 weeks with Apgars 4 and 8 at 1 and 5 min, birth weight 3,300 g. Esophageal atresia (Vogt III/B type) was detected shortly after birth and was repaired surgically. Cranial ultrasound showed subependymal hemorrhage. He developed seizures and has been treated with anti-epileptics since the age of 10 months. At the age of 4 he could not walk independently and his developmental quotient was 59 (Budapest-Binet). On physical examination his length was 98 cm (10–25 pc), weight 13.5 kg (5 pc), and OFC 46 cm (<−2 SD). Microcephaly and scaphocephaly, epicanthal folds, down-slanting palpebral fissures, relatively large ears, bulbous nasal tip, and dental malocclusion could be observed (Fig. 1). He also had clinodactyly of the fifth finger of the hands, small distal phalanges of the thumbs, mild brachydactyly on the feet, contractures of the wrist, elbow, ankle, and knee, and increased muscle tone. Bullet-shaped distal phalanges of the first finger, middle phalanx hypoplasia of the fifth finger, and absent middle phalanges of the fourth and fifth toes were verified by X-ray. Karyotype analysis was normal (46,XY) and the diagnosis of Feingold syndrome was entertained. Sequence analysis of the MYCN gene [van Bokhoven et al., 2005] revealed a nonsense mutation c.217G > T (p.Glu73X) in exon 2. Clinical pictures of the affected family members. A: The proband. B: The mother. C: The maternal grandmother. Note the common features of microcephaly, fifth finger clinodactyly, and mild brachy-syndactyly (most prominent in the mother) of the toes. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] The mother and the maternal grandmother of the patient were also microcephalic with OFC 49.5 cm (<−2 SD) for the mother and OFC 52 cm (<−2 SD) for the grandmother. Fifth finger clinodactyly and partial syndactyly of second to third and fourth to fifth toes could be observed on them (Fig. 1). The mother had a spontaneous abortion from an earlier relationship. She suffered from chronic nephritis syndrome, renal insufficiency, and hypertension. Her IQ was 97 according to MAWI. The grandmother's intelligence was also in normal range, and she also had a spontaneous abortion. The clinical features of the mother and grandmother correspond with “microcephaly-digital abnormalities-normal intelligence” syndrome. Both the mother and the maternal grandmother carried the truncating, Glu73X nonsense mutation in MYCN. Interestingly, a phenotypically similar family has been reported prior to the recognition of MYCN mutations in association with Feingold syndrome [Newbury-Ecob et al., 1999]. Our cases highlight the significantly variable expressivity of a MYCN mutation in Feingold syndrome and support evidence that “microcephaly-digital abnormalities-normal intelligence” syndrome represents a mild form of this genetic entity. These findings indicate that MYCN haploinsufficiency may be involved in other isolated or complex defects of visceral organs and/or brain growth. However, initial observations in patients with VATER association and non-syndromic esophageal atresia did not support this possibility, since no MYCN mutations were detected in these cases [van Bokhoven et al., 2005]. Nevertheless, further studies will be required to elucidate the pathogenic spectrum of MYCN defects.