Clinical characteristics.

Kaufman oculocerebrofacial syndrome (KOS) is characterized by developmental delay, severe intellectual disability, and distinctive craniofacial features. Most affected children have prenatal-onset microcephaly, hypotonia, and growth deficiency. Feeding issues, ocular abnormalities, hearing impairment, and respiratory tract abnormalities are common. Ocular abnormalities can include structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia), refractive errors (myopia ± astigmatism, hyperopia), strabismus, and entropion. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Breathing problems can lead to prolonged hospitalization after birth in more than half of individuals. Less common findings include ectodermal abnormalities, cardiac manifestations, urogenital abnormalities, seizures, and 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; standard treatment with anti-seizure medication in those with seizures; early intervention as needed for feeding problems and respiratory problems; routine management of ophthalmologic issues, hearing impairment, congenital heart defects, urogenital abnormalities, and skeletal abnormalities.

Surveillance: At least annual assessment of developmental progress, growth, vision, and hearing. Assess for seizures and respiratory issues at each visit. At least annual examination for contractures and scoliosis.

Genetic counseling.

KOS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UBE3B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the UBE3B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

KOS should be suspected in individuals with the following clinical and supportive laboratory findings.

Clinical findings

• Microcephaly
• Developmental delay and severe intellectual disability
• Growth deficiency (poor weight gain and/or short stature)
• Ocular anomalies (microcornea, microphthalmia, coloboma, optic nerve hypoplasia, refractive errors, strabismus, entropion)
• 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
  *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: Rarely, individuals with biallelic UBE3B pathogenic variants do not have (or have only mild) characteristic facial features [Basel-Vanagaite et al 2014].

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...)

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

Establishing the Diagnosis

The diagnosis of KOS is established in a proband with developmental delay / intellectual disability and biallelic pathogenic (or likely pathogenic) variants in UBE3B identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic UBE3B variants of uncertain significance (or identification of one known UBE3B pathogenic variant and one UBE3B variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with microcephaly, poor growth, and/or developmental delay are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Kaufman oculocerebrofacial syndrome (KOS) is characterized by prenatal-onset microcephaly, growth deficiency, developmental delay, severe intellectual disability, and distinct facial features. To date, 36 individuals have been identified with biallelic pathogenic variants in UBE3B [Basel-Vanagaite et al 2012, Flex et al 2013, Basel-Vanagaite et al 2014, Pedurupillay et al 2015, Kariminejad et al 2017, Yilmaz et al 2018, Galarreta et al 2019, Zaki et al 2020, Ürel-Demir et al 2021]. Six additional individuals with characteristic clinical features that did not have molecular confirmation have been described [Kaufman et al 1971, Jurenka & Evans 1979, Figuera et al 1993]. The following description of the phenotypic features associated with this condition is based on these reports.

Neurologic abnormalities/cognitive development

• Postnatal microcephaly is frequently present and more than 60% of affected children have prenatal microcephaly or a small occipitofrontal circumference (OFC) at birth (<10^th centile), which in most individuals persists postnatally [Basel-Vanagaite et al 2014, Galarreta et al 2019]. 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 75^th centile at age 33 years; his father also had a large OFC.
• 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 reported in approximately 20% of individuals and are usually fever related.
• Abnormal brain MRI was reported in 19/26 individuals. Anomalies included corpus callosum hypoplasia or agenesis (13 individuals), dilated ventricles (3 individuals), Chiari 1 malformation (2), small pituitary (2), ectopic pituitary gland and hypoplastic vermis (1) [Galarreta et al 2019].
• Significant behavior problems do not appear to be prominent; six individuals were described as having a cheerful disposition [Galarreta et al 2019]. Autistic features were described in 4/9 individuals [Zaki et al 2020].

Growth

• Growth deficiency is common during infancy and most affected children have poor weight gain and short stature [Basel-Vanagaite et al 2014]. Growth may improve with age [Galarreta et al 2019].
• Stature is usually below the 10^th centile or -2 to -3 SD; however, the number of reported individuals is limited.

Gastrointestinal tract abnormalities

• Feeding difficulties are a main complication and manifest as poor weight gain, generalized hypotonia, poor suck, poor swallowing, small oral cavity, palate defects, gastroesophageal reflux, and poor dietary intake. Feeding by nasogastric tube or gastrostomy is needed in some individuals.
• Constipation has been reported in several individuals.
• Three individuals had intestinal malrotation.

Distinct facial features. 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.)

• 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
• Prominent cheeks

Ocular abnormalities can include:

• Structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia, spherophakia);
• Refractive errors (myopia with or without astigmatism, hyperopia);
• Abnormal alignment of the eyes (strabismus);
• Entropion (inward turning of the lower eyelid);
• Epibulbar dermoid in one individual [Ürel-Demir et al 2021].

Hearing impairment

• Hearing impairment is common. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity.
• Ear anomalies include stenotic auditory canals, dysplastic ears, and cupped ears; ear tags are present in about 30%-40% of individuals.
• Two affected individuals had cholesteatoma [Basel-Vanagaite et al 2014].

Respiratory tract abnormalities

• Breathing problems are quite common leading to a complicated course with prolonged hospitalization after birth in more than half of individuals. Breathing problems include a spectrum of abnormalities including laryngomalacia, micrognathia, stridor or noisy breathing at the mild end to subglottic stenosis, tracheomalacia, and tracheostomy with or without mechanical ventilation at the severe end.
• A severe respiratory course was described in at least seven individuals including mechanical ventilation (in 2 individuals), tracheostomy placements (in 4 individuals), laryngeal reconstruction (in 3), and mandibular advancement (in 3) [Basel-Vanagaite et al 2012, Basel-Vanagaite et al 2014, Yilmaz et al 2018, Galarreta et al 2019, Ürel-Demir et al 2021].
• Obstructive sleep apnea is noted in some individuals.

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 or hypoplasia have also been described [Basel-Vanagaite et al 2014, Ürel-Demir et al 2021].

Cardiac manifestations include:

• Pulmonary artery stenosis;
• Atrial septal defect;
• Ventricular septal defect;
• Aortic coarctation, supravalvular or subvalvular aortic stenosis;
• Dysplastic mitral valve;
• Hypertrophic cardiomyopathy (may be obstructive, may involve the left ventricle or the septum only).

Urogenital abnormalities

• Genital abnormalities are more frequent in females than males and include hypoplastic labia majora and/or minora or clitoromegaly.
• Micropenis was described in some males.
• Renal abnormalities are not common and include vesicoureteral reflux (grade V reflux has been reported) and duplicated renal pelvis. Small kidneys with borderline function were reported in one individual.

Skeletal abnormalities

• Chest is abnormal in shape (bell-shaped thorax, pectus carinatum).
• Fingers and toes are long and slender, and fingers may be tapering. Other findings include bilateral postaxial polydactyly, fifth finger clinodactyly, and metatarsus adductus. Absent or hypoplastic distal phalanges of the fingers are probably rare but a valuable diagnostic clue.
• Congenital hip dysplasia or coxa valga has been observed in several affected individuals.
• Clubfoot was described in nine individuals [Yilmaz et al 2018, Zaki et al 2020, Ürel-Demir et al 2021]. Hand contractures and specifically camptodactyly were described in some.
• Scoliosis has also been described.

Endocrine abnormalities. Transiently elevated TSH, reduced thyroid gland volume, and low GH and ACTH were observed occasionally.

Other

• Cleft palate, reported in nine individuals. Small oral cavity, high arched palate, and bifid uvula have also been described.
• Brachycephaly
• Torticollis of a muscular origin in some individuals

Pregnancy and birth

• Congenital structural malformations or polyhydramnios may be detected on prenatal ultrasound examination.
• Intrauterine growth restriction is not a major feature, and most affected pregnancies have an uncomplicated course. However, about 40% of individuals have been small for gestational age [Galarreta et al 2019].
• Affected infants are usually born at term with borderline low or normal birth weight.
• Abnormal fetal lie has been described, probably reflecting hypotonia.

Genotype-Phenotype Correlations

It is not possible to draw conclusions regarding genotype-phenotype correlations until more individuals are reported.

Nomenclature

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

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

Prevalence

The prevalence of KOS is unknown. To date, 36 individuals (from 25 families) with KOS and biallelic UBE3B pathogenic variants have been reported. There are six additional individuals reported with a similar phenotype in whom there is no molecular confirmation. While it may be underdiagnosed, KOS is estimated to be very rare.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with KOS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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 EU Clinical Trials Register 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.

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 presumed to be heterozygous for a UBE3B pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a UBE3B pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a UBE3B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Some intrafamilial clinical variability has been observed between affected sibs; reported phenotypic differences involved seizures, respiratory issues, the severity and extent of hearing impairment, and congenital malformations [Galarreta at al 2019, Ürel-Demir et al 2021].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, 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 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 and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

UBE3B encodes the protein ubiquitin-protein ligase E3B, a mitochondrion-associated protein, 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.

UBE3B is highly expressed in the central nervous system, digestive tract, and respiratory system as well as in multiple cell lineages of skin and other soft tissues. In the brain UBE3B associates with postsynaptic density fractions and regulates dendritic branching in a cell-autonomous manner [Ambrozkiewicz et al 2020].

UBE3B pathogenic variants identified in individuals with 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 suppress all E3 ligase enzyme activity [Basel-Vanagaite et al 2012, Basel-Vanagaite et al 2014, Ambrozkiewicz et al 2020].

Mechanism of disease causation. Loss of function

UBE3B-specific laboratory technical considerations. UBE3B has five transcript variants: two encode longer transcripts (NM_130466.3, NM_183415.2), which comprise 28 exons and encode an 1,068 amino acid protein isoform (~123 kd); three encode shorter transcript variants (NM_001270449.1, NM_001270451.1, NM_001270450.1), which comprise nine exons and are predicted to encode a 244-amino acid protein.

Acknowledgments

We would like to thank Dr Guntram Borck, who unfortunately passed away on 12-7-2021, for his valuable contribution in writing the first version of this GeneReview. His passion, support, and constructive recommendations will always be remembered and much appreciated.

Author History

Lina Basel-Salmon, MD, PhD (2016-present)
Dana Brabbing-Goldstein, MD (2022-present)
Guntram Borck, MD, PhD; University of Ulm (2016-2022)

Revision History

• 28 July 2022 (sw) Comprehensive update posted live
• 20 October 2016 (bp) Review posted live
• 25 January 2016 (lbv) Original submission

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