Atypical phenotype and intrafamilial variability associated with a novel SALL1 mutation

SALL1 mutations cause Townes–Brocks syndrome (TBS), an autosomal dominant malformation syndrome [Kohlhase et al., 1998; Powell and Michaelis, 1999] known to show strong interand intrafamilial variability in expression. TBS overlaps phenotypically with other conditions such as Goldenhar syndrome, VACTERL association, or oculo-auriculo-vertrebral spectrum [Powell and Michaelis, 1999]. The phenotype associated with SALL1 mutations, especially those in the hotspot region 50 to the region encoding the first double zinc-finger domain, seemed rather specific, since most of the TBS patients in whom mutations were detected, showed at least two of three major criteria for TBS, that is, malformations of the thumbs, ears, or anus [Kohlhase et al., 1999; Marlin et al., 1999]. One family was reported previously in which the affected family members showed an atypical phenotype lacking hand and anal malformations. In this family, the three affected members (father and two daughters) showed renal disease, ear malformations, borderline intelligence (only the daughters), and hearing loss, as well as gastroesophageal reflux associated with the SALL1 c.1819delG mutation [Engels et al., 2000], positioned 30 of the mutational hotspot region and possibly, resulting in a truncated protein lacking three out of four double zinc-finger domains thought to be important for SALL1 function. Here, we report a non-consanguineous German family with three affected family members, who show some clinical signs, but not the full phenotype of TBS with intrafamilial variation. The youngest child (II.1, Fig. 1b) was referred to our department because of renal dysplasia and ear anomalies (Fig. 1a). The boy was born after an uneventful pregnancy. Birth measurements were normal (weight 3,560 g, 50th centile; length 53 cm, 50th centile; OFC 35 cm, 25th centile). Features noted at birth were: preauricular tags on both sides, overfolded helices, renal hypoand dysplasia, vesicoureteral reflux, hypospadias, underriding 3rd toes. At the age of 6 months, the boy showed normal body measurements (length 65 cm, 50th centile; weight 6.5 kg, 50th centile; OFC 42 cm, 25th centile), normal psychomotor development, normal thumbs and hands, no anorectal anomaly, and moderately impaired renal function. There was no indication of hearing loss. His elder brother (II.2, Fig. 1b) had hypospadias and underriding 3rd toes. Otherwise, he had normal psychomotor development, normal body measurements at the age of 21⁄2 years (height 94 cm, 75th centile; weight 14 kg, 25th centile; OFC 50.5 cm, 50th centile), no craniofacial dysmorphism, normal ear shape with a slightly protruding left ear, no preauricular tags, no renal or anorectal anomalies, and normal hands. Hearing loss was not reported. The mother of the two boys was unaffected. The father (I.2, Fig. 1b) had preauricular tags and overfolded helices (surgically corrected), hearing impairment, impaired renal function with tubular dysfunction, hypospadias, and thin 3rd toes. The paternal grandparents were not reported to be affected, but a formal clinical evaluation was denied. Although none of the affected family members had TBS as defined by presence of anal, hand, and ear malformations (Table I), all features observed in the affected family members may be seen in TBS. Therefore, mutation analysis in the SALL1 gene was performed and revealed a heterozygous mutation c.967 C>T (Fig. 1b,c) leading to a stop codon (Q323X) in all three patients. Like in patients with typical TBS the stop codon lies 50 to the region encoding the first double zinc-finger domain, causing a prematurely terminated SALL1 protein lacking all double zinc-finger domains or resulting in no protein at all [Kohlhase, 2000]. The family presented here shows a phenotype lacking most of the typical malformations of TBS which is similar to the atypical, branchio-oto-renal syndromelike phenotype seen in a family with the SALL1 mutation c.1819delG [Engels et al., 2000]. In this family, the affected members likewise had no anal or thumb malformation, but typically malformed ears. As in two of the three patients reported here, they also had renal dysplasia and impaired renal function. However, the phenotype was different from the family reported here Grant sponsor: Wilhelm-Sander-Stiftung (to J.K.); Grant number: 98.075. 2.