Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.

Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.

[A man with a tumour of the lower eyelid]. / Een man met een zwelling van het onderooglid.

A 41-year-old patient presented with a tumour arising from the palpebral conjunctiva of the right lower eyelid. Diagnostic excision of the tumour occurred under local anaesthetics. Pathological examination showed a pyogenic granuloma, without malignant cells.

Split rib cranioplasty for aplasia cutis congenita and traumatic skull defects: more than 30 years of follow-up.

Aplasia cutis is a rare skin defect usually presenting over the vertex of the skull. An underlying bone defect is found in approximately 20% of patients. Most skull defects close spontaneously. However, when there are no signs of ossification, closure is mandatory. We present our experience in three patients. Our first patient had an aplasia cutis with a skull defect. The split rib graft procedure was used without complications, and a good cosmetic and functional result was achieved. The second patient was operated on for cerebral bleeding after an arteriovenous aneurysm, and a bony defect could not be closed after that procedure. At a later stage, the defect was filled with split rib grafts, and sufficient protection was achieved and documented after more than 30 years. The third patient was born with an aplasia cutis congenita with a skull defect. The bony defect was filled with split rib grafts without complications at an age of 5 years. Follow-up shows a functional result with a firm skull. Patients with aplasia cutis may have skull defects that will not close by themselves. We present three patients with a bony defect who were reconstructed with split rib grafts. After a long period of follow-up, there remains good cosmetic and functional results. Defects of the skull in children can be reconstructed with split rib grafts that will accommodate the growing skeleton and give good protection of the brain from an early age on.