Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails

Abstract

Background Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes which were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Methods Clinical investigations coupled with, karyotype analysis, array-CGH, exome and Sanger sequencing were performed to characterize the condition in this child. Results Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay, allowed us to make a diagnosis of KOS. Conclusion Our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

“…The most common findings were hypoplastic or absent nails. Short fingers and nails in an individual with intellectual disability should therefore increase the index of suspicion of IGDs in addition to Coffin‐Siris syndrome (MIM: PS135900), DOORS syndrome (MIM: 220500), Zimmermann‐Laband syndrome (MIM: PS135500), and Kaufman oculocerebrofacial syndrome (MIM: 244450) …”

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

“…Single gene disorders were identified in 14 individuals from nine families. Autosomal recessive mutations were identified in NSUN2 , LIG4 , BRCA1, UBE3B, RNU4ATAC, and PCNT1 (Dieks, Baumer, Wilichowski, Rauch, & Sigler, ; Kariminejad et al, ; Krøigård et al, ; Martinez et al, ; Sawyer et al, ; Table ). Autosomal dominant de novo mutations were reported in ACTB and STAT3 (Beitzke et al, ; Johnston et al, ; Table ).…”

“…These included two sets of concordant monozygous twins (Möhrenschlager, Beham, Abeck, & Ring, ; Urquhart et al, ); one pair with a 19q13 microdeletion. There were three siblings with homozygous NSUN2 mutations (Martinez et al, ), two siblings with biallelic LIG4 mutations (Gruhn et al, ), a sibling pair with biallelic mutations in RNU4ATAC (Krøigård et al, ) and a sibling pair with UBE3B mutations (Kariminejad et al, ). There was also a set of brothers where DS was considered, but subsequently thought unlikely based on detailed clinical assessment (Lemire, Stoeber, Anselmo, & Lowry, ), and an Italian sibling pair was concordant for many features of DS, but was considered to have a blepharophimosis‐intellectual disability syndrome after an extensive work‐up (Dentici et al, ).…”

“…Interestingly, patients with the Kaufman oculocerebrofacial syndrome (associated with blepharophimosis, ptosis, and short stature) as well as short stature, microcephaly and sparse hair (reviewed in Basel‐Vanagaite et al ()) also frequently have low cholesterol, suggesting that there may be a relationship between this gene and a minority of individuals with a DS clinical phenotype. It is therefore not surprising, that recently a set of siblings (Kariminejad et al, ) was reported who were provisionally considered to have DS but were found to have a homozygous mutation in UBE3B , in this family total cholesterol on the surviving affected sibling was normal though high‐density lipoprotein levels were low.…”

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

“…Kaufman oculocerebrofacial syndrome (KOS), a rare autosomal recessive type of the BMRS, was first described in 1971, but it was not until 2012 that its genetic cause was discovered via the identification of biallelic mutations in the ubiquitin ligase E3B encoding gene UBE3B (Basel‐Vanagaite et al, ; Flex et al, ; Kaufman et al, ) With only 15 published patients with biallelic UBE3B mutations reported so far, knowledge on the phenotypic and molecular characteristics of KOS is still expanding. (Basel‐Vanagaite et al, , ; Flex et al, ; Kariminejad et al, ; Pedurupillay et al, ) Apart from the original four patients of Kaufman, five patients with the clinical diagnosis of KOS have been reported between 1971 and 2013 (Briscioli, Manoukian, Selicorni, Livini, & Lalatta, ; Figuera, Garcia‐Cruz, Ramirez‐Duenas, Rivera‐Robles, & Cantu, ; Jurenka & Evans, ; Murano, ). The patient of Briscioli et al () had no blepharophimosis and was later subject of UBE3B sequencing by Flex et al () but no disease‐causing mutation was identified.…”