Kaufman Oculocerebrofacial Syndrome

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 a pregnancy at increased risk, and preimplantation genetic testing are possible.

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. 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.

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 (<10^th 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 75^th 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 10^th 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).

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 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.