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Kaufman Oculocerebrofacial Syndrome

Synonym: Blepharophimosis-Ptosis-Intellectual Disability (BPID) Syndrome

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: .

Estimated reading time: 13 minutes

Summary

Clinical characteristics.

Kaufman oculocerebrofacial syndrome (KOS) is characterized by severe intellectual disability and distinctive craniofacial features. Most affected children have prenatal-onset microcephaly, failure to thrive, hypotonia, and short stature. Eye abnormalities are common and can include structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia), refractive errors (myopia ± astigmatism, hyperopia), strabismus, and entropion. Less common findings can include: unilateral or bilateral conductive hearing loss or mixed conductive-sensorineural hearing loss of variable severity; congenital heart defects; breathing problems; feeding difficulties; urogenital abnormalities; and/or skeletal abnormalities.

Diagnosis/testing.

The diagnosis of KOS is established in a proband with developmental delay/intellectual disability and biallelic UBE3B pathogenic variants.

Management.

Treatment of manifestations: Educational intervention and speech therapy beginning in infancy; early intervention as needed for feeding problems; routine management of ophthalmologic findings, hearing loss, congenital heart defects, urogenital abnormalities, and skeletal abnormalities.

Surveillance: At least annual assessment of growth, developmental progress, vision, and hearing and examination for evidence of contractures and/or scoliosis.

Genetic counseling.

KOS is inherited in an autosomal recessive manner. 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. Once the UBE3B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.

Diagnosis

No formal diagnostic criteria have been published for Kaufman oculocerebrofacial syndrome (KOS).

Suggestive Findings

Kaufman oculocerebrofacial syndrome (KOS) should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical findings

  • Severe intellectual disability
  • A typical and recognizable pattern of craniofacial features* (see Figure 1):
    • Eyebrows: highly arched, laterally broad with flaring (medial or lateral)
    • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures
    • Ears: often apparently low-set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags
    • Narrow nasal bridge, wide nasal base, anteverted nares
    • Flat zygomata
    • Long, flat philtrum
    • Narrow mouth, thin vermilion of the upper lip with absent cupid's bow
    • Micrognathia
Figure 1. . Facial dysmorphism associated with KOS caused by biallelic UBE3B pathogenic variants.

Figure 1.

Facial dysmorphism associated with KOS caused by biallelic UBE3B pathogenic variants. See text for a detailed description of dysmorphic features. Affected individuals pictured are individuals 1, 2, 3, 4, and 6 in Basel-Vanagaite et al [2014]. Photographs (more...)

*With age, the face becomes more elongated, the zygomata become flatter and the palpebral fissures more upslanted, and the alae nasi thicken [Basel-Vanagaite et al 2014]. Micrognathia also becomes less prominent with age. See Figure 1.

Note: In rare instances individuals with no or only mild characteristic facial features have biallelic UBE3B pathogenic variants [Basel-Vanagaite et al 2014].

Supportive laboratory findings. Low serum concentration of cholesterol (performed as part of routine laboratory testing) in some individuals

Establishing the Diagnosis

The diagnosis of Kaufman oculocerebrofacial syndrome is established in a proband with developmental delay/intellectual disability and biallelic UBE3B pathogenic variants.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of UBE3B is performed first. Although gene-targeted deletion/duplication analysis could be considered if only one pathogenic variant is found, to date no UBE3B deletion has been reported in individuals with a firm clinical diagnosis of KOS, unexplained KOS, or KOS-like syndrome [G Borck, personal observation].
  • A multigene panel that includes UBE3B and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes UBE3B) fails to confirm a diagnosis in an individual with features of KOS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Kaufman Oculocerebrofacial Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
UBE3BSequence analysis 311/11 4
Gene-targeted deletion/duplication analysis 5Unknown
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Pedurupillay et al [2015] and references therein

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

Kaufman oculocerebrofacial syndrome (KOS) was described in 1971 as a distinct clinical entity characterized by severe developmental delay combined with a distinct pattern of ocular and other craniofacial abnormalities [Kaufman et al 1971]. This report was followed by more reports of individuals with the combination of clinical features compatible with KOS [Jurenka & Evans1979, Garcia-Cruz et al 1988, Figuera et al 1993, Briscioli et al 1995].

Subsequently, biallelic pathogenic variants in UBE3B have been described in individuals with KOS [Basel-Vanagaite et al 2012, Flex et al 2013, Basel-Vanagaite et al 2014, Pedurupillay et al 2015].

Some individuals clinically diagnosed with Toriello-Carey syndrome (OMIM 217980) [Toriello et al 2003] and an individual with a syndrome described by Buntinx & Majewski [1990] have later been found to have biallelic UBE3B pathogenic variants [Basel-Vanagaite et al 2014].

As of September 2016, 14 individuals (from 11 families) with KOS and biallelic UBE3B pathogenic variants have been reported; it is anticipated that as more individuals with a molecularly confirmed diagnosis are identified more details about this rare disorder will emerge.

Neurologic abnormalities/cognitive development

  • Most affected children have prenatal microcephaly or a small occipitofrontal head circumference (OFC) at birth (<10th centile) which persists postnatally [Basel-Vanagaite et al 2014]. Microcephaly is often moderate with OFC -2 to -3 SD; it is not currently known to worsen with age. The OFC of the oldest individual with biallelic UBE3B pathogenic variants was at the 75th centile at age 33 years; his father also had a large OFC. Note, however, that only a small number of affected persons have been reported thus far.
  • Hypotonia and delayed motor milestones are universal findings.
  • The onset of independent ambulation varies; in most it is achieved by age four to five years. Gait is frequently described as unsteady.
  • Intellectual disability is severe to profound in the individuals reported to date; rare affected individuals develop limited speech.
  • Seizures are observed occasionally, usually fever related.
  • Structural central nervous system abnormalities include absent or hypoplastic corpus callosum; Chiari 1 malformation has been reported in one individual.

Growth

  • Most affected children have failure to thrive and short stature [Basel-Vanagaite et al 2014].
  • Stature is usually below the 10th centile or -2 to -3 SD; however, the number of reported individuals is small.

Ectodermal abnormalities

  • Sparse scalp hair, thin skin, dry skin, and hyperkeratosis are noted in some infants. The appearance of the scalp hair improves with age.
  • Small teeth and nail dysplasia have also been described [Basel-Vanagaite et al 2014].

Ocular abnormalities (not universally present) can include:

  • Structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia);
  • Refractive errors (myopia with or without astigmatism, hyperopia);
  • Abnormal alignment of the eyes (strabismus);
  • Entropion (inward turning of the lower eyelid).

Hearing loss

  • Hearing impairment, if present, includes unilateral or bilateral conductive hearing loss or mixed conductive-sensorineural hearing loss of variable severity.
  • Two affected individuals had cholesteatoma [Basel-Vanagaite et al 2014].

Congenital heart malformations, observed in some, include:

  • Pulmonary artery stenosis and septal hypertrophy;
  • Atrial septal defect;
  • Ventricular septal defect;
  • Aortic coarctation.

Respiratory tract abnormalities

  • Breathing problems include tracheomalacia, subglottic stenosis, laryngomalacia, and obstructive sleep apnea.
  • Tracheostomy is needed in some instances.

Gastrointestinal tract abnormalities

  • Feeding difficulties are manifest as failure to thrive, poor suck, and gastroesophageal reflux. Feeding by gastric tube is needed in some individuals.
  • Constipation has been present in several individuals.
  • One individual had intestinal malrotation.

Urogenital abnormalities

  • Genital abnormalities (more frequent in females than males) include hypoplastic labia majora and/or minora or clitoromegaly.
  • Micropenis was described in some males.
  • Renal abnormalities include vesicoureteral reflux up to grade V and duplicated renal pelvis.

Skeletal abnormalities

  • Chest is abnormal in shape (bell-shaped thorax, pectus carinatum).
  • Fingers and toes are long and slender. Other findings include bilateral postaxial polydactyly, fifth finger clinodactyly, hypoplastic distal phalanges, and metatarsus adductus.
  • Congenital hip dysplasia or coxa valga has been observed in several affected individuals.
  • An additional skeletal finding is scoliosis.

Endocrine abnormalities

  • Approximately half of affected individuals have abnormal cholesterol levels including low total cholesterol, low HDL, low LDL levels, or a combination of any of these.
  • Transiently elevated TSH, reduced thyroid gland volume, and low GH and ACTH were observed occasionally.

Pregnancy and birth

  • Congenital structural malformations or polyhydramnios may be detected on prenatal ultrasound examination.
  • Affected infants are usually born at term with borderline low or normal birth weight.

Genotype-Phenotype Correlations

UBE3B pathogenic alleles identified in individuals with typical KOS are missense substitutions in highly conserved amino acid residues of the HECT domain or frameshift and nonsense variants that are predicted to lead to nonsense-mediated mRNA decay and/or protein truncation. These variants presumably completely abolish the E3 ligase enzyme activity [Basel-Vanagaite et al 2012, Basel-Vanagaite et al 2014].

One individual with mild craniofacial dysmorphism but without blepharophimosis was homozygous for two missense variants (both carried by both parents) each affecting a conserved amino acid residue outside the IQ and HECT domains [Basel-Vanagaite et al 2014].

Nomenclature

Prior to the identification of causative biallelic UBE3B pathogenic variants, the following phenotypes (now known to be Kaufman oculocerebrofacial syndrome) were thought to be distinct disorders:

  • Blepharophimosis-ptosis-intellectual disability (BPID) syndrome
  • Phenotype seen in a subset of patients clinically diagnosed with Toriello-Carey syndrome [Toriello et al 2003]
  • Phenotype described by Buntinx & Majewski [1990]

Prevalence

The prevalence of Kaufman oculocerebrofacial syndrome (KOS) is unknown.

As of September 2016, 14 individuals (from 11 families) with KOS and biallelic UBE3B pathogenic variants have been reported from different geographic/ethnic origins. While it may be underdiagnosed, KOS is estimated to be very rare.

It is not currently known whether the disease is more prevalent in certain regions (e.g., due to a founder variant).

Differential Diagnosis

Kaufman oculocerebrofacial syndrome (KOS) has a relatively uniform, clinically recognizable phenotype mainly due to the characteristic dysmorphic features combined with severe intellectual disability [Basel-Vanagaite et al 2014]. Because of the co-occurrence of blepharophimosis and intellectual disability, the differential diagnosis mainly includes – besides small chromosomal deletions or duplications identified by chromosomal microarray analysis – other Mendelian blepharophimosis-intellectual disability syndromes; see Table 2.

Table 2.

Disorders to Consider in the Differential Diagnosis of Kaufman Oculocerebrofacial Syndrome (KOS)

DisorderGeneMOIClinical Features
Overlapping w/KOSDistinguishing from KOS
Chromosome 3pter-p25 deletion syndrome (OMIM 613792)ADID; blepharophimosis; growth retardation; postaxial polydactylyTrigonocephaly
Ohdo syndrome (OMIM 249620)See footnote 1ID; blepharophimosis; congenital heart disease; ptosis; hypoplastic teethAbnormal nasal shape not a characteristic feature; normal growth; no limb defects
Say-Barber-Biesecker variant of Ohdo syndrome (also known as Say-Barber-Biesecker/Young-Simpson syndrome)KAT6BADHeart defects; hearing loss; optic atrophy; cleft palate; dental anomalies incl small & pointed teethDistinctive facial features 2; joint limitations; hypothyroidism. Individuals w/this syndrome & the allelic disorder genitopatellar syndrome (OMIM 606170) have patellar hypoplasia.
Maat-Kievit-Brunner syndrome or X-linked Ohdo syndrome (OMIM 300895)MED12XLID; constipation; hypotoniaDistinctive facial features 3
Blepharophimosis w/facial & genital anomalies & intellectual disability, Verloes type (OMIM 604314)See footnote 4Severe microcephaly; cleft palateHypsarrhythmia; adducted thumbs; abnormal genitalia
Smith-Lemli-Opitz syndromeDHCR7ARGrowth retardation; microcephaly; moderate-to-severe ID; cleft palate; cardiac defectsCharacteristic facial features 5; underdeveloped external genitalia in males; 2-3 syndactyly of the toes

AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

The molecular cause of this syndrome is unknown; cryptic chromosomal rearrangement has not been excluded in the original family described by Ohdo.

2.

Bulbous nasal tip, dysplastic ears, mask-like facial appearance, retrognathia

3.

Triangular and coarse facies with thick alae nasi

4.

The genetic basis of this presumably autosomal recessive syndrome is unknown.

5.

Epicanthal folds, ptosis, short nose with anteverted nares

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Kaufman oculocerebrofacial syndrome (KOS), the following evaluations are recommended:

  • Developmental assessment
  • Growth assessment, including assessment of feeding and nutrition
  • Ophthalmologic evaluation for microcornea, cataract, ptosis, coloboma
  • Hearing evaluation for sensorineural or mixed sensorineural/conductive hearing impairment
  • Echocardiogram for congenital heart defects
  • Evaluation for laryngomalacia if respiratory issues are present
  • Evaluation for the presence of gastrointestinal reflux, bowel malrotation if indicated
  • Evaluation of males for cryptorchidism
  • Renal ultrasound examination for structural renal abnormalities and vesicoureteral reflux
  • Hip ultrasound examination to evaluate for femoral head dislocation
  • Evaluation of thyroid function; other hormone levels if clinically indicated
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following treatment recommendations are appropriate:

  • Developmental. Educational intervention and speech therapy beginning in infancy
  • Failure to thrive. Intervention for feeding problems as needed in infancy and childhood
  • Eyes. Cataract and ptosis surgery if indicated
  • Hearing loss. Hearing aids or cochlear implant if needed
  • Cardiac Function assessment and treatment if needed
  • Genital anomalies. Orchidopexy in males with undescended testes
  • Renal anomalies. Treatment of vesicoureteral reflux if indicated
  • Skeletal. Referral to an orthopedist if joint dislocations or scoliosis is present, early referral to physical therapy
  • Endocrine. Thyroid hormone replacement as needed
  • Other facial. Cleft palate repair if present

Surveillance

The following should be assessed at least annually:

  • Growth
  • Developmental progress
  • Vision, hearing
  • Contractures and/or scoliosis

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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.

Genetic Counseling

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. —ED.

Mode of Inheritance

Kaufman oculocerebrofacial syndrome (KOS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one UBE3B pathogenic variant). (De novo UBE3B pathogenic variants, although possible, have not been reported to date.)
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with KOS are not known to reproduce.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a UBE3B pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the UBE3B pathogenic variants in the family.

Related Genetic Counseling Issues

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 carriers or are at risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the UBE3B pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased and preimplantation genetic diagnosis risk for KOS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • VOR: Speaking out for people with intellectual and developmental disabilities
    836 South Arlington Heights Road, #351
    Elk Grove Village IL 60007
    Phone: 877-399-4867
    Fax: 847-253-0675
    Email: info@vor.net

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Kaufman Oculocerebrofacial Syndrome: Genes and Databases

GeneChromosome LocusProteinClinVar
UBE3B12q24.11Ubiquitin-protein ligase E3BUBE3B

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Kaufman Oculocerebrofacial Syndrome (View All in OMIM)

244450KAUFMAN OCULOCEREBROFACIAL SYNDROME; KOS
608047UBIQUITIN-PROTEIN LIGASE E3B; UBE3B

Molecular Genetic Pathogenesis

The primary protein sequence and domain architecture of UBE3B predict an E3 ligase function. The C elegans ortholog of UBE3B is indeed involved in protein degradation by the ubiquitin proteasome system under oxidative stress conditions. It is therefore likely that human UBE3B also functions as an ubiquitin ligase in vivo [Basel-Vanagaite et al 2012]. However, specific ubiquitination targets of UBE3B have not been identified [Gong et al 2003].

In mice, predominant expression of Ube3b has been observed prenatally in the developing central nervous system including the ventricular zone of the cerebral cortex and the hippocampal anlage. Postnatally, prominent Ube3b expression is observed in the cerebral cortex, the cerebellum, and the hippocampus [Basel-Vanagaite et al 2012]. Ube3b-/- mice have severely reduced body weight, small body size, smaller brain, reduced grip strength, lower low-density lipoprotein (LDL) levels, mild hearing impairment, and corneal abnormalities [Basel-Vanagaite et al 2012].

Gene structure. UBE3B has five transcript variants:

For a detailed summary of gene and protein information, see Table A, Gene.

Normal gene product. UBE3B encodes the protein ubiquitin-protein ligase E3B, containing an N-terminal IQ domain and a C-terminal HECT domain. The HECT domain in the C-terminus of the longer isoform of this protein is the likely catalytic site of ubiquitin transfer and forms a complex with E2 conjugating enzyme. Shorter isoforms of this protein lack the C-terminal HECT domain and, if produced, are unlikely to interact with E2 enzymes.

Abnormal gene product. Most UBE3B pathogenic variants in individuals with KOS affect the HECT domain or are expected to result in nonsense-mediated mRNA decay and/or protein truncation, leading to a loss of function [Basel-Vanagaite et al 2012, Flex et al 2013, Basel-Vanagaite et al 2014, Pedurupillay et al 2015].

References

Literature Cited

  • Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miró X, White JK, Désir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmüller J, Nürnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nürnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet. 2012;91:998–1010. [PMC free article: PMC3516591] [PubMed: 23200864]
  • Basel-Vanagaite L, Yilmaz R, Tang S, Reuter MS, Rahner N, Grange DK, Mortenson M, Koty P, Feenstra H, Farwell Gonzalez KD, Sticht H, Boddaert N, Désir J, Anyane-Yeboa K, Zweier C, Reis A, Kubisch C, Jewett T, Zeng W, Borck G. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations. Hum Genet. 2014;133:939–49. [PubMed: 24615390]
  • Briscioli V, Manoukian S, Selicorni A, Livini E, Lalatta F. Kaufman oculocerebrofacial syndrome in a girl of 15 years. Am J Med Genet. 1995;58:21–3. [PubMed: 7573151]
  • Buntinx I, Majewski F. Blepharophimosis, iris coloboma, microgenia, hearing loss, postaxial polydactyly, aplasia of corpus callosum, hydroureter, and developmental delay. Am J Med Genet. 1990;36:273–4. [PubMed: 1694631]
  • Chahrour MH, Yu TW, Lim ET, Ataman B, Coulter ME, Hill RS, Stevens CR, Schubert CR., ARRA Autism Sequencing Collaboration. Greenberg ME, Gabriel SB, Walsh CA. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet. 2012;8:e1002635. [PMC free article: PMC3325173] [PubMed: 22511880]
  • Figuera LE, García-Cruz D, Ramírez-Dueñas ML, Rivera-Robles V, Cantù JM. Kaufman oculocerebrofacial syndrome: report of two new cases and further delineation. Clin Genet. 1993;44:98–101. [PubMed: 8275567]
  • Flex E, Ciolfi A, Caputo V, Fodale V, Leoni C, Melis D, Bedeschi MF, Mazzanti L, Pizzuti A, Tartaglia M, Zampino G. Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome. J Med Genet. 2013;50:493–9. [PMC free article: PMC3717725] [PubMed: 23687348]
  • Garcia-Cruz D, Arreola R, Sanchez-Corona J, Garcia-Cruz O, Renteria R, Villar V, Gonzalez ME, Vargas-Moyeda E, Cantu JM. Kaufman oculocerebrofacial syndrome: a corroborative report. Dysmorph Clin Genet. 1988;1:152–4.
  • Gong TW, Huang L, Warner SJ, Lomax MI. Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing. Genomics. 2003;82:143–52. [PubMed: 12837265]
  • Jurenka SB, Evans J. Kaufman oculocerebrofacial syndrome: case report. Am J Med Genet. 1979;3:15–9. [PubMed: 112864]
  • Kaufman RL, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Artic Ser. 1971;7:135–8. [PubMed: 5006210]
  • Pedurupillay CR, Barøy T, Holmgren A, Blomhoff A, Vigeland MD, Sheng Y, Frengen E, Strømme P, Misceo D. Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B. Am J Med Genet A. 2015;167A:657–63. [PubMed: 25691420]
  • Toriello HV, Carey JC, Addor MC, Allen W, Burke L, Chun N, Dobyns W, Elias E, Gallagher R, Hordijk R, Hoyme G, Irons M, Jewett T, LeMerrer M, Lubinsky M, Martin R, McDonald-McGinn D, Neumann L, Newman W, Pauli R, Seaver L, Tsai A, Wargowsky D, Williams M, Zackai E. Toriello-Carey syndrome: delineation and review. Am J Med Genet A. 2003;123A:84–90. [PubMed: 14556252]

Chapter Notes

Revision History

  • 20 October 2016 (bp) Review posted live
  • 25 January 2016 (lbv) Original submission
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