DiagnosisClinical DiagnosisFormal diagnostic criteria for Peters plus syndrome have not been proposed. A clinical diagnosis of Peters plus syndrome is based on the presence of the following: Anterior chamber anomalies of the eye Disproportionate short stature Characteristic facial features Cleft lip/palate Variable psychomotor delay Molecular Genetic TestingGene. B3GALTL is the only gene in which mutations are known to cause Peters plus syndrome. Clinical testing Sequence analysis. Most affected individuals tested to date are homozygous for a hot spot splice mutation in intron 8 (c.660+1G>A) [Lesnik Oberstein et al 2006].
Sequence analysis should begin with a screen for the common c.660+1G>A mutation, followed by analysis of the remainder of the B3GALTL coding sequence. Deletion/duplication analysis can detect large deletions, such as those described in two brothers with Peters plus syndrome [Lesnik Oberstein et al 2006]. The proximal breakpoint of their deletion is located between exon 7 and 8 of B3GALTL; the distal breakpoint is between exon 13 and 14 of BRCA2. A second deletion including B3GALTL was reported by Haldeman-Englert et al [2009]. Table 1. Summary of Molecular Genetic Testing Used in Peters Plus SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityB3GALTLSequence analysis Sequence variants 2 27% (9/26) 3 Clinical100% (20/20) 4 Deletion/duplication analysis5Partial- and whole-gene deletions 2/20 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. As identified by the Laboratory of Diagnostic Genome Analysis, Leiden, The Netherlands. Note: This is a clinically heterogeneous group.4. As identified by Lesnik Oberstein et al [2006]. This cohort is clinically well described.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.6. Lesnik Oberstein et al [2006] described two brothers with a ~1.5-Mb interstitial deletion on their maternal allele, including B3GALTL. The paternal allele harbored a pathogenic point mutation.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.When a mutation is found in homozygous form, the parents should be tested in order to exclude the presence of a deleted allele, as a large deletion has been described in two brothers with Peters plus syndrome [Lesnik Oberstein et al 2006].Testing StrategyTo confirm/establish the diagnosis in a proband requires identification of two disease-causing alleles by molecular genetic testing. Sequence analysis should be performed first. If both disease-causing mutations are not identified, deletion/duplication analysis is an appropriate second step.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in B3GALTL.}

Natural HistoryPeters plus syndrome is characterized by anterior chamber eye anomalies, disproportionate short stature, variable developmental delay/intellectual disability, characteristic facial features, and cleft lip/palate. Unless otherwise stated, the following description of clinical findings is based on the reports of Maillette de Buy Wenniger-Prick & Hennekam [2002] and Lesnik Oberstein et al [2006].Eyes. The most common anterior chamber defect is Peters' anomaly, which consists of a central corneal opacification, thinning of the posterior cornea, and iridocorneal adhesions. Peters' anomaly may be classified as type I, a mild form, or type II, a more severe form associated with lens abnormalities including cataracts, congenital glaucoma, and a poorer visual prognosis [Yang et al 2004, Zaidman et al 2007]. The eye involvement is usually bilateral. Cataracts and glaucoma can also develop later in life. Other, often unspecified anterior chamber defects have been reported, such as mild mesenchymal dysgenesis [Hennekam et al 1993]. Less expressed symptoms have included iris coloboma. Variation in ocular symptoms may be extensive within a single family. Minor anterior chamber anomalies may not be associated with visual impairment.Growth. Growth deficiency with rhizomelic limb shortening is invariably present, Growth restriction begins prenatally, but birth length is not always below the third percentile. Growth hormone deficiency with good responses to growth hormone replacement therapy has been reported in some children [Maillette de Buy Wenniger-Prick & Hennekam 2002, Lee & Lee 2004]. Adult height range is 128-151 cm in females and 141-155 cm in males.Development. Developmental delay is observed in 78%-83% of children. While some adults appear to have normal cognitive function, intellectual disability in adults can range from mild to severe. Several affected individuals have been diagnosed with classic autism. A behavioral phenotype has not been well delineated thus far.Facial features. Typical facial features include a prominent forehead, narrow palpebral fissures, a long philtrum, and a cupid's bow-shaped upper lip. The facial phenotype does not appear to evolve significantly over time. Cleft lip is present in 45% of cases and cleft palate in 33%. Ear anomalies, including preauricular pits, are seen in more than one-third of affected individuals. A broad neck occurs in approximately 75% of individuals. Associated findings Congenital heart defects (≤33% of individuals), including atrial septal defect, ventricular septal defect, subvalvular aortic stenosis, pulmonary stenosis, and bicuspid pulmonary valve Genitourinary anomalies (10%-19%) including hydronephrosis, renal and ureteral duplication, renal hypoplasia with oligomeganephroma, multicystic dysplastic kidney [Boog et al 2005], and glomerulocystic kidneys Structural brain malformations including: Agenesis of the corpus callosum Hydrocephalus [Krause et al 1969, Frydman et al 1991] Cerebellar hypoplasia with microcephaly in two children suspected of having Peters plus syndrome. One also had hypoplasia of the corpus callosum.Congenital hypothyroidism, reported in two children with features suggestive of Peters plus syndrome and subsequently described in another affected individual [Kosaki et al 2006] Conductive hearing loss, variably present in association with cleft palate but not otherwise a major feature Prenatal complications. The clinical spectrum appears to include nonviable conceptuses. Several authors have observed an increased rate of miscarriage and stillbirth among mothers of affected children [van Schooneveld et al 1984, Hennekam et al 1993, Thompson et al 1993]. Published prenatal data suggest that 37% of couples with a child with Peters plus syndrome have recurrent (≥2) miscarriages and/or stillbirths. Polyhydramnios occurred in 18.6% of pregnancies of affected children. Mortality. Death in early infancy from cardiac failure or undetermined causes has been reported [de Almeida et al 1991, Frydman et al 1991, Lacombe et al 1994].

Differential DiagnosisIsolated Peters' anomaly can be inherited in an autosomal dominant or autosomal recessive manner or can occur in simplex cases (i.e., a single occurrence in a family) in which the mode of inheritance is unknown. It has been reported in association with mutations in the following genes: PAX6, CYP1B1, PITX2 (RIEG1), PITX3, FOXE3, and FOXC1.The differential diagnosis of Peters plus syndrome includes other conditions with short stature and limb shortening, including the following:Cornelia de Lange syndrome Smith-Lemli-Opitz syndrome Robinow syndrome Fetal alcohol syndrome (FAS). FAS can also be associated with similar facial features and anterior chamber eye anomalies, including Peters' anomaly. Other syndromes involving anterior eye chamber anomalies include (but are not limited to) the following:Rieger syndrome SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, teething delay) Walker-Warburg syndrome (see Congenital Muscular Dystrophy Overview) 6p25 microdeletion syndrome [Maclean et al 2005] Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Peters plus syndrome, the following evaluations are recommended:Complete ophthalmologic assessment, including ocular ultrasonography for characterization of the eye anomaly and an assessment for associated ocular defects (indicated if not already done as part of the diagnostic work-up) Growth hormone stimulation testing to address the possibility of a treatable cause of growth delay For neonates or infants, referral to an infant development program for appropriate developmental assessment Echocardiography for congenital heart malformations Abdominal ultrasound examination for renal anomalies Cranial imaging with head ultrasound examination or CT scan/MRI for hydrocephalus and/or structural brain abnormalities Thyroid function testing in all infants who have not undergone newborn screening for congenital hypothyroidism Hearing assessment in a child with cleft palate or speech delay Treatment of ManifestationsEye. Preservation of vision in the affected eye(s) often requires surgery. Consideration of corneal transplantation (penetrating keratoplasty) for severe bilateral corneal opacification is suggested prior to age three to six months to prevent amblyopia, whereas simple separation of iridocorneal adhesions may suffice in mild cases [Traboulsi 2006]. A retrospective review of long-term outcome following penetrating keratoplasty prior to age 18 months in type I Peters' anomaly revealed a visual acuity of 20/400 or better in two thirds of treated persons, and no individuals with phthisis bulbi or visual acuity reduced to light perception only [Zaidman et al 2007]. Management of amblyopia by a pediatric ophthalmologist is recommended for optimal visual outcome.Congenital glaucoma in association with Peters' anomaly is more difficult to treat than primary infantile glaucoma. Surgery and medical management result in adequate intraocular pressure in only 32%, and associated ophthalmologic issues such as amblyopia or postoperative complications contribute to poor visual results in long-term outcome studies [Yang et al 2004]. Development. Children diagnosed as neonates or infants should be referred to an infant development program for appropriate developmental interventions. Other. Additional management is symptomatic and expectant. SurveillanceThe following are appropriate:Assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia Regular developmental assessments Agents/Circumstances to AvoidAgents that increase risk of glaucoma (e.g., corticosteroids) are to be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Peters Plus Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDB3GALTL13q12​.3Beta-1,3-glucosyltransferaseBeta 1,3-GALactosylTransferase-Like (B3GALTL) @ LOVDB3GALTLData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Peters Plus Syndrome (View All in OMIM) View in own window 261540PETERS-PLUS SYNDROME 610308UDP-GAL:BETA-GlcNAc BETA-1,3-GALACTOSYLTRANSFERASE-LIKE; B3GALTLMolecular Genetic PathogenesisHomozygosity for loss-of-function mutations in B3GALTL is associated with Peters plus syndrome.Normal allelic variants. B3GALTL, the β1,3-galactosyltransferase-like gene, contains 15 exons and covers 132 kb. It is expressed in a broad range of human tissues, with tissue-specific regulation. Two transcripts of 4.2 kb and 3.4 kb are produced [Heinonen et al 2003]. Pathologic allelic variants. The mutations reported to date are described below and in Table 2 (see also B3GALTL Database): c.660+1G>A point mutation located in the donor splice site of exon 8, present in one or two copies in all 20 individuals reported by Lesnik Oberstein et al [2006] c.347+5G>A mutation located in intron 5, which changes a highly conserved nucleotide leading to altered splicing p.Tyr366X, a truncating mutation in homozygous form in exon 13 [Aliferis et al 2010].A deletion of one of the alleles, with a mutation on the trans allele [Lesnik Oberstein et al 2006]Table 2. Selected B3GALTL Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences c.347+5G>A—NM_194318​.3
NP_919299​.3c.660+1G>A—c.1098T>Ap.Tyr366XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. B3GALTL encodes B3GALTL, a 498-amino acid-containing transmembrane protein. It has a short N-terminal tail, a transmembrane region, a "stem" region, and a C-terminal catalytic domain. B3GALTL functions as a glycosyltransferase in a specific O-glycosylation step. It contributes to the elongation of O-fucosylglycan, specifically on TSR (thrombospondin type repeat) domains; i.e., it adds a glucose in a β1,3 linkage to a fucose in TSR [Kozma et al 2006, Sato et al 2006]. The human genome encodes approximately 100 TSR-containing proteins that perform a variety of important biologic functions, including regulation of the coagulation system and cell and axon guidance. Abnormal gene product. All affected individuals reported by Lesnik Oberstein et al [2006] had mutations predicted to result in a truncated protein lacking the catalytic domain, likely eliminating B3GALTL activity. One individual was compound heterozygous for a large deletion and the splice mutation of exon 8 [Lesnik Oberstein et al 2006].