Peters-Plus Syndrome

A number sign (#) is used with this entry because of evidence that the Peters-plus syndrome (PTRPLS) is caused by homozygous or compound heterozygous mutation in the beta-1,3-galactosyltransferase-like gene (B3GALTL; 610308) on chromosome 13q12.

Description

Patients with Peters-plus syndrome exhibit ocular features, systemic malformations, and variable degrees of developmental delay. Ocular abnormalities involve the anterior chamber, and in most patients consist of Peters anomaly, which is characterized by corneal clouding and iridolenticulocorneal adhesions. Growth retardation, short stature, and brachydactyly appear to be present in all patients, and developmental delay is frequent, whereas external ear anomalies, cleft lip and/or palate, and cardiac and genitourinary malformations are less common (Dassie-Ajdid et al., 2009).

Clinical Features

According to van Schooneveld et al. (1984), Peters (1906) described 3 brothers with the disorder that bears his name (Peters anomaly; see ASGD5, 604229). The features of Peters anomaly, a major error in the embryonic development of the eye, are corneal clouding and variable iridolenticulocorneal adhesions. Van Schooneveld et al. (1984) described 11 cases of what they referred to as Peters-plus syndrome. The series included unlike sex twins, both affected, and affected sisters. The parents were consanguineous in 1 case. All the patients had Peters anomaly, were short of stature, and showed brachymorphism and abnormal ears. Several of them had cleft lip and palate. The brachymorphism was most evident in the hands. In most cases the fifth finger was short and showed clinodactyly. Severe mental retardation was present in some.

Kivlin et al. (1986) suggested that Peters anomaly, since it occurs with many syndromes both genetic and nongenetic, is a morphologic entity but not a specific causal entity. Kivlin et al. (1986) reported association of Peters anomaly and short-limb dwarfism in a brother and sister. Both had thin upper lip, hypoplastic columella, and round face. Apparently balanced reciprocal translocation, 46,XY,t(2q-;15q+)(q21;q26.1), in the brother only, was thought to be coincidental.

Thompson and Winter (1988) described a 14-month-old male with extensive congenital bilateral corneal opacification, short stature, and short limbs. They pointed out a striking resemblance of the facies to that in other patients with Peters anomaly and short limbs (Krause et al., 1969; Saal et al., 1988); specifically, the face was round and the lips thin with hypoplastic columella, smooth philtrum, and mild micrognathia. The appearance of the mouth and upper lip was particularly distinctive.

Saal et al. (1988) described an autosomal recessive syndrome resembling Robinow syndrome (180700). Two sisters had short stature, mesomelic brachymelia, macrocephaly, and hypoplastic genitalia. Setting that disorder apart from Robinow syndrome were anterior chamber cleavage anomalies (resembling Peters anomaly or Rieger anomaly) seen in both girls and hydrocephalus seen in the younger sister. One of the sisters also had cleft lip and palate. De Almeida et al. (1991) reported the cases of a brother and sister with similar features and consanguineous parents. They thought that the disorder in these sibs was the same as that described by van Schooneveld et al. (1984) as the Peters-plus syndrome. The first-born child in the family reported by de Almeida et al. (1991), who died soon after birth, had clefts.

Frydman et al. (1991) found this syndrome in 2 cousins and an unrelated patient, all offspring of consanguineous parents. Communicating hydrocephalus (or brain atrophy) and polyhydramnios were found in 2 patients, potentially allowing prenatal diagnosis in secondary familial cases. Ishikiriyama et al. (1992) reported a Japanese case. Bilateral corneal opacities were noted at birth. Adhesion of the iris to the cornea, glaucoma, and corneolenticular approximation, all features of Peters anomaly, were found. Physical examination at 9 months showed also depressed nasal bridge, anteverted nostrils, short columella nasi, thin vermilion border of the upper lip, micrognathia, short limbs, tapering brachydactyly, and clinodactyly of the 5th fingers. Development was delayed. Cranial CT scan showed dilatation of the subarachnoid spaces as well as evidence of cerebral atrophy.

In a review of Peters-plus syndrome, Maillette de Buy Wenniger-Prick and Hennekam (2002) stated that more than 50 cases were known, including their own unpublished cases. Inheritance was clearly autosomal recessive. Most cases have prenatal growth retardation and, postnatally, are disproportionately short. Mental delay was present in 83%. Cupid bow shape of the upper lip with a thin vermilion border is a feature; cleft lip, sometimes accompanied by cleft palate, was found in 45%.

Mapping

The finding of causative mutations in the B3GALTL gene (610308) maps this disorder to chromosome 13q12.3 (Lesnik Oberstein et al., 2006).

Molecular Genetics

To detect potential rearrangements affecting the Peters-plus syndrome locus, Lesnik Oberstein et al. (2006) performed genomewide 1-Mb resolution array-based comparative genomic hybridization on genomic DNA of 2 brothers and 4 isolated patients who all carried the clinical diagnosis of Peters-plus syndrome. In both brothers, 2 adjacent BAC clones were present in single copy, representing an interstitial deletion of approximately 1.5 Mb on chromosome 13q12.3-q13.1. The deletion was found in both brothers and their mother and spanned 5 genes and 13 exons of the BRCA2 (600185) gene. The brothers' family history was positive for breast cancer in at least 2 diseased female relatives, in whom Lesnik Oberstein et al. (2006) established the presence of the deletion by interphase FISH on tumor material. Thus this deletion constituted a novel large BRCA2 rearrangement associated with familial breast cancer. Another gene in the deleted region, LGR8 (606655), was previously associated with cryptorchidism (219050), which was present in both brothers. Lesnik Oberstein et al. (2006) analyzed the B3GALTL gene (610308), which was also located in the deleted region, and identified a splice site mutation (660+1G-A; 610308.0001) on the paternal allele of the 2 brothers. Targeted sequencing analysis in an additional 18 Peters-plus patients from 15 families revealed homozygosity for the 660+1G-A mutation in 16 patients; in the remaining 2 patients (Dutch sibs), the mutation was found in compound heterozygosity with another splice site mutation (610308.0002). Fourteen patients were Dutch whites, and the other patients were Turkish, British, Arab, or Indian. The finding appeared to place Peters-plus syndrome as one of a group of congenital malformations caused by glycosylation defects.

B3GALTL is a beta-1,3-glucosyltransferase involved in the synthesis of the unusual O-linked disaccharide glucosyl-beta-1,3-fucose-O- found on the thrombospondin (see THBS1; 188060) type-1 repeats (TSRs) of many biologically important proteins. Using an immunopurification-mass spectroscopy method, Hess et al. (2008) found that Peters-plus syndrome patients carrying the 660+1G-A mutation in B3GALTL showed only the fucosyl-O- modification in all 4 O-fucosylation sites of the reporter protein properdin (PFC; 300383). In contrast, properdin from heterozygous relatives and a healthy volunteer showed the glucosyl-beta-1,3-fucose-O- modification. Hess et al. (2008) concluded that Peters-plus syndrome is a congenital disorder of glycosylation involving defective O-glycosylation of TSRs.

Reis et al. (2008) examined B3GALTL exons and flanking introns in 4 patients with typical Peters-plus syndrome (anterior chamber anomalies, characteristic facial features, short stature, and brachydactyly) and 4 patients with only some characteristic features of the syndrome. They identified mutations in the B3GALTL gene in all 4 patients with typical Peters-plus syndrome but in none of the 4 patients with some phenotypic overlap. The previously identified 660+1G-A mutation was identified in homozygous state in 2 of the 4 patients and in compound heterozygous state with novel mutations (459+1G-A, 610308.0003 or 230insT, 610308.0004) in the other 2.

In 2 patients with Peters-plus syndrome, Dassie-Ajdid et al. (2009) identified homozygosity for the 459+1G-A mutation in one and compound heterozygosity for the recurrent 660+1G-A mutation and a missense mutation (610308.0005) in the other. Analysis in 2 additional patients who had Peters anomaly and psychomotor delay but who did not meet other Peters-plus syndrome criteria did not reveal any mutations.