Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients

Abstract

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.

Blepharophimosis‐ptosis‐intellectual disability syndrome: A report of nine Egyptian patients with further expansion of phenotypic and mutational spectrum

“…In the current study, all our patients were found to harbor homozygous variants in the UBE3B gene. Five different variants were iden- the UBE3B gene were associated with a severe phenotype (Basel-Vanagaite et al, 2012, 2014Flex et al, 2013;Galarreta et al, 2019;Kariminejad et al, 2017;Pedurupillay et al, 2015;Yilmaz et al, 2018). This is in accordance with the phenotypic severity observed in our patients.…”

“…The most characteristic facial dysmorphic features of BPID were striking in the present patients including blepharophimosis, ptosis, sparse arched laterally broad eyebrows, epicanthic folds, sparse hair, long face, frontal bossing, short broad nose, and ear abnormalities. Further, hypotonia and microcephaly were recorded in most of them as previously reported(Basel- Vanagaite et al, 2012;Galarreta et al, 2019;Yilmaz et al, 2018). The constellation of facial dysmorphic features become more pronounced with age specifically the eyebrows, upslanting of palpebral fissures, and face elongates, which were also identified in our older patients (Patients 3, 4, and 9)(Galarreta et al, 2019).Long slender phalanges have been reported and were present in all studied patients (Basel-Vanagaite et al, 2014).…”

“…had hypertrophic cardiomyopathy and one of them had additional subvalvular aortic obstruction that was reported once by Yilmaz et al (2018). Further molecular studies may be needed to rule the possibility of additional etiology of cardiomyopathy in these two sibs, as homozygosity in more than one gene are not uncommon in offspring of consanguineous parents.…”

“…It is characterized by intrauterine and postnatal growth retardation, blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, sparse and laterally broad eyebrows, microcornea, pale optic discs, flat philtrum, preauricular skin tags, high arched palate, micrognathia in addition to microcephaly and intellectual disability (Kaufman, Rimoin, Prensky, & Sly, 1971). Additional features including feeding difficulties, low cholesterol and mildly elevated TSH levels, cardiac and renal anomalies, axial hypotonia, and abnormal neurologic findings were also reported (Basel-Vanagaite et al, 2012;Dentici et al, 2011;Galarreta, Wigby, & Jones, 2019;Yilmaz et al, 2018).…”

HECT E3 ubiquitin ligases – emerging insights into their biological roles and disease relevance

“…In addition, HECTD2 polymorphisms have been shown to be associated with an increased risk of prion infections, including Creutzfeldt-Jakob disease and kuru (Lloyd et al, 2009). Moreover, mutations in UBE3B gene have been correlated with the development of Kaufman oculocerebrofacial syndrome (KOS), a rare autosomal recessive neurodevelopmental disorder (Flex et al, 2013;Pedurupillay et al, 2015;Yilmaz et al, 2018).…”