Disease characteristics. Peters plus syndrome is characterized by anterior chamber eye anomalies, disproportionate short stature, variable developmental delay/intellectual disability, characteristic facial features, and cleft lip/palate. The most common anterior chamber defect is Peters' anomaly, consisting of a central corneal opacification, thinning of the posterior cornea, and iridocorneal adhesions; it ranges from mild to severe. Cataracts and glaucoma are common. Growth deficiency with rhizomelic limb shortening is invariably present. Developmental delay is observed in about 80% of children; although some adults have normal cognitive function, intellectual disability can range from mild to severe. Cleft lip is present in 45% and cleft palate in 33%.
Diagnosis/testing. Diagnosis is based on clinical findings and molecular genetic testing of B3GALTL, the only gene known to be associated with Peters plus syndrome. Most affected individuals tested to date are homozygous for a hot spot splice mutation in intron 8 (c.660+1G>A).
Management. Treatment of manifestations: consideration of corneal transplantation (penetrating keratoplasty) for severe bilateral corneal opacification prior to age three to six months to prevent amblyopia; consideration of simple separation of iridocorneal adhesions in mild cases; management of amblyopia by a pediatric ophthalmologist; surgical/medical intervention for glaucoma as needed; developmental/educational interventions as needed. Surveillance: assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia; regular developmental assessments. Agents/circumstances to avoid: agents that increase risk of glaucoma (e.g., corticosteroids).
Genetic counseling. Peters plus syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and thus carry one mutant allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. There is an increased chance for miscarriages and second- and third-trimester fetal loss of homozygously affected fetuses. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.
Formal 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
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. B3GALTL is the only gene known to be associated with 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 coding sequence of B3GALTL.
When testing identifies an affected individual as an apparent homozygote, the result should be confirmed by testing the parents. This excludes the possibility of a deleted allele. If both parents are not confirmed as heterozygous carriers, the affected individual should be tested by deletion/duplication analysis.
Deletion/duplication analysis can detect large deletions, such as those described in two brothers with Peters plus syndrome [Lesnik Oberstein et al 2006].
Table 1 summarizes molecular genetic testing for this disorder.
Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
---|---|---|---|
Sequence analysis | Sequence variants in B3GALTL | 27% (9/26) 2 | Clinical |
100% (20/20) 3 | |||
Deletion/duplication analysis | Partial- and whole-gene deletions 4 | 2/20 5 |
2. As identified by the Laboratory of Diagnostic Genome Analysis, Leiden, The Netherlands. Note: This is a clinically heterogeneous group.
3. As identified by Lesnik Oberstein et al [2006]. This cohort is clinically well described.
4. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array CGH (see ) may be used.
5. 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].
Confirmation of 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 for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
No other phenotypes are known to be associated with mutations in B3GALTL.
Peters 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.
A severe prenatal presentation of apparent Peters plus syndrome involving chylothorax, hydrops fetalis, and glomerulocystic kidneys has been observed in an individual who did not have a mutation in B3GALTL [Aubertin et al, submitted].
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; Aubertin et al, submitted].
No genotype-phenotype correlation has yet been demonstrated.
Alternate terms for Peters plus syndrome have included Krause-Kivlin syndrome and Krause-van Schooneveld-Kivlin syndrome.
Krause et al [1969] first described a single individual with the association of Peters' anomaly, disproportionate short stature, and mental retardation.
van Schooneveld et al [1984] reported 11 individuals with these features and first proposed the term "Peters'-plus syndrome."
Kivlin et al [1986] described two additional patients, referencing Krause's initial patient.
For some time, the Krause-Kivlin syndrome and Peters plus syndrome were thought to be separate entities, despite the observation by several authors of striking similarities among the persons reported [Frydman et al 1991, de Almeida et al 1991]. Following the extensive review of the literature and proposal of Thompson et al [1993] that these conditions represent the same disorder, the convention has been to use the term Peters plus syndrome.
Alternate spellings of Peters plus syndrome include: Peters'-plus syndrome, Peters'-plus syndrome, Peters' plus syndrome.
The prevalence of Peters plus syndrome is unknown. Fewer than 70 affected individuals have been reported in the literature; they come from varied ethnicities.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Isolated 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:
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)
To 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
Eye. 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.
The following are appropriate:
Assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia
Regular developmental assessments
Agents that increase risk of glaucoma (e.g., corticosteroids) are to be avoided.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search 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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Peters plus syndrome is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and thus carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. There is an increased chance for miscarriages and second- and third-trimester fetal loss of homozygously affected fetuses.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with Peters plus syndrome are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at risk family members is available on a clinical basis once the mutations have been identified in the family.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
B3GALTL | 13q12.3 | Beta-1,3-glucosyltransferase |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
Gene Symbol | Locus Specific | Entrez Gene |
---|---|---|
B3GALTL | B3GALTL | 145173 (MIM No. 610308) |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Homozygosity for loss-of-function mutations in the B3GALTL gene is associated with Peters plus syndrome.
Normal allelic variants. The β1,3-galactosyltransferase-like gene (B3GALTL) 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 [unpublished data]
A deletion of one of the alleles, with a mutation on the trans allele [Lesnik Oberstein et al 2006]
DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences 1 |
---|---|---|
c.347+5G>A | — | NM_194318.3NP_919299.3 |
c.660+1G>A | — | |
c.1098T>A | p.Tyr366X |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Reference sequence (www.ncbi.nlm.nih.gov/Genbank/index.html)
Normal gene product. The B3GALTL gene encodes for 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 aβ1,3 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, and are likely to eliminate B3GALTL activity. One individual was compound heterozygous for a large deletion and the splice mutation of exon 8 [Lesnik Oberstein et al 2006].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
American Cleft Palate-Craniofacial Association
Cleft Palate Foundation
1504 East Franklin Street Suite 102
Chapel Hill NC 27514-2820
Phone: 800-242-5338; 919-933-9044
Fax: 919-933-9604
Email: info@cleftline.org
www.cleftline.org
Foundation Fighting Blindness
11435 Cronhill Drive
Owings Mill MD 21117-2220
Phone: 888-394-3937 (toll-free); 800-683-5555 (toll-free TDD); 410-568-0150 (local)
Email: info@blindness.org
www.blindness.org
Human Growth Foundation
997 Glen Cove Avenue Suite 5
Glen Head NY 11545
Phone: 800-451-6434
Fax: 516-671-4055
Email: hgf1@hgfound.org
www.hgfound.org
The MAGIC Foundation
6645 West North Avenue
Oak Park IL 60302
Phone: 800-362-4423; 708-383-0808
Fax: 708-383-0899
Email: info@magicfoundation.org
www.magicfoundation.org
National Eye Institute
Low Vision
Wide Smiles
PO Box 5153
Stockton CA 95205-0153
Phone: 209-942-2812
Fax: 209-464-1497
Email: josmiles@yahoo.com
www.widesmiles.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
19 March 2009 (cd) Revision: deletion/duplication analysis available clinically
8 October 2007 (me) Review posted to live Web site
24 July 2007 (ga) Original submission