Verheij Syndrome

A number sign (#) is used with this entry because Verheij syndrome (VRJS) can be caused by heterozygous mutation in the PUF60 gene (604819) on chromosome 8q24.3. The same VRJS phenotype results from a contiguous gene deletion involving the PUF60 and SCRIB (607733) genes on 8q24.3.

Description

Verheij syndrome is characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal, mainly vertebral, abnormalities. Additional variable features may include coloboma, renal defects, and cardiac defects (summary by Verheij et al., 2009 and Dauber et al., 2013).

Clinical Features

Chromosome 8q24.3 Deletion Syndrome

Verheij et al. (2009) reported 2 unrelated Dutch children born with multiple and somewhat overlapping congenital anomalies associated with large heterozygous de novo deletions of chromosome 8q24. A 20-month-old boy had delayed psychomotor development, poor growth, seizures, ventricular septal defect, postaxial polydactyly, and hip dislocation. Dysmorphic features included plagiocephaly, anteverted nares, short columella, high palate, micrognathia, low-set and posteriorly rotated ears, short neck, and coloboma. He also had laryngotracheomalacia. Brain MRI showed hypoplastic corpus callosum, delayed myelination, and cerebral atrophy. The second child was a girl with poor growth, unilateral coloboma, atrial septal defects, clenched thumbs, syndactyly of the hands and feet, metatarsal fusion, unilateral hip luxation, severe failure to thrive, and seizures. Dysmorphic features included triangular ears with flattened helices, prominent nasal tip, and hypoplastic nasal alae. Some features were reminiscent of Langer-Giedion syndrome (150230), but she died at age 11 months from a subdural hematoma before classic features of that syndrome could develop.

Dauber et al. (2013) reported 5 unrelated children with 5 different heterozygous de novo interstitial deletions of chromosome 8q24.3; the children were identified from a cohort of patients who underwent array comparative genomic hybridization (aCGH). The 5 children ranged in age from 3 to 17 years, and all had facial dysmorphism and global growth retardation, including 3 with microcephaly; all but 1 had developmental delay. Common dysmorphic facial features included long philtrum, anteverted nares, short nose, thin upper lip, and broad nasal root. More variable features included microretrognathia, coloboma, short neck, preauricular pits, and bitemporal narrowing. All but 1 patient had renal abnormalities, including unilateral renal agenesis, renal hypoplasia, polycystic kidneys, and ectopic renal fusion. Three patients had vertebral abnormalities, such as sacral dysplasia, coccyx agenesis, vertebral fusion, or hemivertebrae, and 4 had joint laxity or hip dislocation. Two patients had cardiac ventricular defects.

Verheij Syndrome with PUF60 Mutations

Dauber et al. (2013) reported a patient with features similar to those reported by Verheij et al. (2009), including severe growth retardation, delayed psychomotor development, microcephaly (-4.1 SD), dysmorphic facial features, seizures, ventricular septal defect, hip dislocation, hemivertebrae, and scoliosis. Coloboma and renal abnormalities were not present. Exome sequencing of this patient identified a heterozygous de novo missense mutation in the PUF60 gene (see MOLECULAR GENETICS).

El Chehadeh et al. (2017) reported 5 patients with features of Verheij syndrome who had de novo heterozygous mutations in the PUF60 gene. All of the patients had facial features similar to those seen in patients with 8q24.3 microdeletions and developmental delay. Other findings included feeding difficulties (3/5), cardiac defects (4/5), short stature (4/5), joint laxity and/or dislocation (4/5), vertebral anomalies (2/5), bilateral microphthalmia and iridoretinal coloboma (1/5), bilateral optic nerve hypoplasia (2/5), renal anomalies (2/5), and branchial arch defects (2/5).

Low et al. (2017) reported 12 patients with features of Verheij syndrome and de novo heterozygous mutations in PUF60. Based on the phenotype in their patients and those previously reported, Low et al. (2017) suggested that short stature, relative microcephaly, and developmental delay are consistent findings, although one of their patients had macrocephaly, hydrocephalus, and normal stature. Similar findings with the reported cases included abnormal segmentation of the vertebrae, minor developmental abnormalities of the distal limbs (e.g., clinodactyly, brachydactyly of the fifth fingers, and preaxial polydactyly), ocular colobomas, renal malformations, and congenital heart defects. Other findings included seizures, feeding difficulties, and recurrent respiratory infections. Characteristic facial findings included thin upper lip, long philtrum, flaring of eyebrows, and narrow almond-shaped palpebral fissures. Low et al. (2017) noted striking phenotypic variability among the patients, making the phenotype difficult to recognize.

Santos-Simarro et al. (2017) reported 3 patients with Verheij syndrome with heterozygous mutations in PUF60. The patients had intellectual disability, growth restriction, microcephaly, a consistent facial phenotype, and other malformations, including cardiac defects in 2 patients, eye colobomas in 2 patients, and talipes, white matter abnormalities on brain imaging, and unilateral hypoplasia of the depressor anguli oris muscle, each in 1 patient.

Graziano et al. (2017) reported a 4-year-old boy with features of Verheij syndrome and a heterozygous mutation in PUF60. The child had a developmental eye defect, characterized by bilateral iris, optic nerve, and chorioretinal coloboma associated with a fibrous stalk of vasculature (persistent fetal vasculature syndrome) from the optic nerve head. Inferior lens subluxation and mild microphthalmia were also present. Based on this patient and their review of previously reported patients, Graziano et al. (2017) suggested that ocular developmental defects, especially coloboma, are frequent in patients with a mutation in the PUF60 gene.

Cytogenetics

Verheij et al. (2009) reported 2 unrelated Dutch children with multiple similar congenital anomalies associated with de novo heterozygous deletions of chromosome 8q24. Cytogenetic and FISH analysis showed deletions of 15.1 Mb and 23.5 Mb. The deletion in the second patient included both the TRPS1 (604386) and EXT1 (608177) genes, consistent with a diagnosis of Langer-Giedion syndrome. The commonly deleted region shared by the patients was 8.35 Mb and included the KCNQ3 gene (602232).

Dauber et al. (2013) identified 5 unrelated patients with 5 different heterozygous de novo interstitial deletions of chromosome 8q24.3. The deletions ranged from 78 kb to 1 Mb, and none of the breakpoints were the same. The minimal common deletion encompassed 3 genes: SCRIB, NRBP2 (615563), and PUF60. Morpholino knockout of these genes in zebrafish suggested that haploinsufficiency for SCRIB and PUF60 was responsible for the phenotype, whereas loss of NRBP2 was considered unlikely to contribute to the clinical features. Dauber et al. (2013) found that morpholino-mediated knockdown of either Puf60 or Scrib in zebrafish recapitulated some of the human phenotypes. Knockdown of either gene caused short stature, microcephaly, and reduced jaw size. Knockdown of Scrib alone resulted in coloboma and renal abnormalities, whereas knockdown of Puf60 alone resulted in cardiac structural defects. Knockdown of both genes exacerbated the short stature phenotype. Dauber et al. (2013) concluded that haploinsufficiency of both genes drives the majority of the syndromic phenotypes found in patients with the copy number variation. The authors noted that the zebrafish approach is limited to the assessment of anatomic phenotypes, and that contributions to cognitive and behavioral defects is not possible.

Molecular Genetics

By exome sequencing in a 21-year-old woman with features of Verheij syndrome (VRJS; 615583), Dauber et al. (2013) identified a heterozygous de novo missense mutation in the PUF60 gene (H169Y; 604819.0001).

By whole-exome sequencing (WES) in 5 patients with features of VRJS, El Chehadeh et al. (2017) identified heterozygous de novo mutations in the PUF60 gene (see 604819.0002-604819.0006), including splice site, frameshift, nonsense, and missense variants.

Low et al. (2017) identified 12 patients with VRJS who had de novo heterozygous mutations in PUF60. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, included 4 frameshift mutations resulting in premature stop codons, 3 missense mutations that clustered within the RNA recognition motif, and 5 essential splice site mutations. Analysis of cDNA from a fibroblast cell line from one of the patients with a splice site mutation confirmed aberrant splicing.

Using next-generation sequencing of a custom panel of genes involved in intellectual disability, autism spectrum disorders, and other disorders, Santos-Simarro et al. (2017) identified 3 patients with VRJS who had de novo heterozygous mutations in PUF60 (see, e.g., E18K, 604819.0007). All of the mutations were confirmed by Sanger sequencing.

In a 4-year-old boy with VRJS, Graziano et al. (2017) identified de novo heterozygosity for the same E18K mutation in the PUF60 gene that had been identified by Santos-Simarro et al. (2017). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or in an in-house database of approximately 700 WES sequencing tested persons, mainly of Italian origin.