Ohdo Syndrome, Sbbys Variant

A number sign (#) is used with this entry because the SBBYS variant of Ohdo syndrome is caused by heterozygous mutation in the KAT6B gene (605880) on chromosome 10q22.

Description

Say-Barber-Biesecker-Young-Simpson syndrome, a variant of Ohdo syndrome (249620), is characterized by distinctive facial appearance with severe blepharophimosis, an immobile mask-like face, a bulbous nasal tip, and a small mouth with a thin upper lip. The condition presents in infancy with severe hypotonia and feeding problems. Associated skeletal problems include joint laxity, abnormally long thumbs and great toes, and dislocated or hypoplastic patellae. Structural cardiac defects are present in around 50% of cases, and dental anomalies, including small and pointed teeth, are common. Many affected individuals have abnormalities of thyroid structure or function. YSS is usually associated with severe mental retardation, delayed motor milestones, and significantly impaired speech (summary by Clayton-Smith et al., 2011).

Genitopatellar syndrome (606170) is an allelic disorder with overlapping features.

Clinical Features

Young and Simpson (1987) described a girl with congenital heart defects, hypothyroidism, mental retardation, and facial dysmorphism, including blepharophimosis. Four additional patients with similar symptoms were reported (Fryns and Moerman, 1988; Cavalcanti, 1989; Bonthron et al., 1993; Nakamura and Noma, 1997). Masuno et al. (1999) described a 5-year-old boy and a 7-year-old girl thought to have this syndrome. All 7 reported patients, including those of Masuno et al. (1999), were sporadic; however, autosomal recessive inheritance had been proposed because the parents of the patient reported by Bonthron et al. (1993) were consanguineous.

Kondoh et al. (2000) reported a 7-year-old Japanese boy thought to have YSS. Thyroid dysfunction was less severe than that in the 7 previously reported patients. Furthermore, the patient had 4 previously undescribed manifestations: bilateral macular degeneration, torticollis, talipes equinovarus, and patella dislocation.

Szakszon et al. (2011) described a female with SBBYS syndrome in whom diffusion tensor magnetic resonance imaging (MRI) and tractography of the brain showed inappropriate myelination and disturbed white matter integrity. A delayed myelination was visible in the pons, the anterior horn of the internal capsule, and the splenium of the corpus callosum. Diffusion tensor imaging revealed a circumscribed 6 to 8 mm area of decreased anisotropy in the frontal white matter adjacent to the frontal horn of the right ventricle. Fibertracking analysis identified disrupted tracts within this region particularly affecting the connections of the frontal cortex. Region of interest analysis on secondary diffusion images revealed decreased anisotropy and decreased longitudinal diffusivity in the frontal white matter of the right side compared to those of the left.

Cytogenetics

Robinson et al. (2008) described a girl with YSS who presented with the typical facial findings, global retardation, congenital hypothyroidism, and congenital dilated cardiomyopathy. This was the first case of YSS associated with dilated cardiomyopathy, which is commonly seen in patients with 1p36 monosomy (607872). CGH analysis showed a 1p36.3 deletion (encompassing approximately 5.5 Mb), a finding not previously reported in other YSS cases. Robinson et al. (2008) suggested that YSS is due to a deletion in the terminal region on the short arm of chromosome 1.

Clayton-Smith et al. (2011) described a patient (individual 17) with atypical SBBYSS syndrome who had a deletion of approximately 8.3 Mb at 1p36.21-p36.12 (chr1:13,339,380-21,692,325, NCBI36) and a duplication of approximately 1.3 Mb at 1p34 (chr1:34,572,912-35,949,096, NCBI36). This patient did not have a mutation in the KAT6B gene. Clayton-Smith et al. (2011) suggested that an atypical SBBYSS phenotype may have a separate genetic etiology.

Molecular Genetics

Clayton-Smith et al. (2011) studied a cohort of 19 patients with a presumed diagnosis of SBBYSS, in which 12 patients were considered to have typical features of the syndrome, 2 had suggestive but milder features, and 5 were classified as atypical. By whole-exome sequencing in 4 patients with typical features, Clayton-Smith et al. (2011) identified heterozygous mutations in the KAT6B gene: a nonsense mutation (E1357X; 605880.0004), a 1-bp insertion (605880.0001), and a 4-bp deletion (605880.0002). Subsequent analysis of all 19 patients with an SBBYSS or an SBBYSS-like phenotype revealed truncating mutations in exon 18 of the KAT6B gene in 12 patients, and 1 patient was found to have a heterozygous frameshift mutation in exon 15 (605880.0003) that had not been detected on whole-exome sequencing. Three of the patients with typical features had previously been reported by Clayton-Smith et al. (1994) and one by Day et al. (2008).

In 2 children with clinical features of SBBYSS, including a 4-year-old girl previously reported by Szakszon et al. (2011), Szakszon et al. (2013) identified different de novo truncating mutations in the distal region of exon 18 of the KAT6B gene (c.5064_5071, 605880.0011; c.5389C-T, 605880.0012). They stated that their findings confirm the genotype-phenotype correlation that most SBBYSS-causing mutations cluster in the distal (3-prime) region of KAT6B exon 18 (c.4069-5734), whereas GTPTS-causing mutations cluster in the proximal (5-prime) region of the same exon (c.3680-4368).