Akademik Veri Yönetim Sistemi
EuroDysmorpho 2023, Lisbon, Portekiz, 13 - 16 Eylül 2023, ss.1
Kaufman
oculocerebrofacial syndrome (KOS) (OMIM #244450) is an extremely rare autosomal
recessive disorder caused by biallelic loss-of-function variants in UBE3B.
UBE3B gene encodes an E3 ubiquitin-protein ligase that is highly expressed
during development and in various adult tissues. KOS is characterized by moderate to severe intellectual
disability,growth deficiency,microcephaly and a distinctive facial gestalt.
Common craniofacial features include short upslanting palpebral fissures,
blepharophimosis, ear anomalies, hearing loss and laryngomalacia. Feeding difficulties,low
cholesterol,axial hypotonia,neurological,cardiac and renal anomalies were also
reported.
A
40-day-old female patient was referred to our clinic with dysmorphism.
Polyhydramnios and single umbilical artery were observed on prenatal follow-ups,
and amniocentesis was performed. Conventional cytogenetic studies demonstrated
a normal karyotype and microarray analysis revealed no genomic imbalances. She
was born after a full-term pregnancy by caesarean section. At birth, she
was hospitalized in the neonatal intensive care unit for 10 days due to
meconium aspiration. At initial
admission, her weight was 2,920 gr (-2,6 SD),length was 47cm (-3 SD),occipitofrontal
circumference was 34 cm (-3,2 SD). On examination prominent forehead, bilateral
epicanthus,flat and wide nasal root,thick alae nasi,wide columella,anteverted
nostrils, smooth philtrum,retrognathia,low-set ears,bilateral single transverse
palmar crease and overlapping toes were observed. Midgut malrotation was
suspected on esophagogastroduodenoscopy. On initial echocardiography, multiple cardiac
masses were observed. Brain MRI showed no significant abnormalities. The family
stated a distant consanguinity of unknown degree. Their 9-year-old son had a
history of neuromotor developmental delay,autism,cryptorchidism and similar
dysmorphic features. Laryngomalacia and hypocholesterolemia were observed in
both patients.
We
performed single gene sequencing (Illumina MiSeq/Nextera XT) for UBE3B
and found heterozygous c.142C>T (p.Arg48Ter) and c.1261C>T (p.Gln421Ter)
mutations (NM_183415.3). Sanger sequencing was performed in order to validate
the variants and analyze the segregation. The parents were found to be heterozygous
carriers and probands brother was heterozygous for both mutations.
Although
Blepharophimosis-Intellectual Disability syndromes represent a clinically and
genetically heterogeneous group of disorders, distinct morphological findings
in specific disorders such as KOS, allow us to opt for targeted diagnostic
testing. Intrafamilial clinical variability has
been observed between affected sibs in the literature as well as our patients. Our
report expands the phenotypic and mutational spectrum associated with this rare
disorder.